Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:8]([C:17]([O:19]CC)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].O[Li].O>>[C:1]([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:8]([C:17]([OH:19])=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc(C(C)(C)C)nc1-c1cccnc1
Agent: [Li]O
Solvent: O
Product: CC(C)(C)c1ncc(C(=O)O)c(-c2cccnc2)n1
Yield: 71.3 %

Procedure:
Using a procedure analogous to Example B39, ethyl 2-tert-butyl-4-(pyridin-3-yl)pyrimidine-5-carboxylate (0.17 g, 0.60 mmol) was treated with LiOH.H2O (57 mg, 2.38 mmol) to afford 2-tert-butyl-4-(pyridin-3-yl)pyrimidine-5-carboxylic acid (0.11 g, 72% yield). MS (ESI) m/z: 258.0 (M+H+).
Reaction SMILES: CO[C:3](=[O:23])[C:4]([OH:22])=[CH:5][C:6](=[O:21])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[O:8][CH2:9][CH:10]([CH3:12])[CH3:11].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:32][N:33](C)[C:34](C1CN(C)C(=O)C=1O)=O>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:7]([O:8][CH2:9][CH:10]([CH3:11])[CH3:12])[C:6]([C:5]2[CH2:32][N:33]([CH3:34])[C:3](=[O:23])[C:4]=2[OH:22])=[O:21])=[CH:19][CH:18]=1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)cc1)OCC(C)C
Agent: C=O
Agent: CN
Product: CC(C)CON(Cc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 40 %

Procedure:
3-[(4-Fluorobenzyl)-isobutoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 58-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (40% yield); mp 96–97° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 0.98 (6H, d, J=6.5 Hz, CH3), 1.96 (1H, m CH), 3.12 (3H, s, NCH3), 3.69 (2H, d, J=6.4 Hz, OCH2), 4.1 (2H, s, NCH2), 4.85 (2H, s, NCH2), 7.06 (2H, m, aromatics), 7.33 (2H, m, aromatics), 11.65 (1H, broad s, OH). HRMS (ES+) calculated for C17H22FN2O4, [M+H]+: 337.156361. found: 337.156153.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[CH2:13]([C:17]1[CH:22]=[CH:21][C:20](Cl)=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16]>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].CC1C=CC(C(C2C=CC(C)=CC=2)C(=O)C(C)C)=CC=1.CC(O)(C)C>[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([NH:3][C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=2)=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1ccc(Cl)cc1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: [Pd]
Agent: Cc1ccc(C(C(=O)C(C)C)c2ccc(C)cc2)cc1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: CCCCc1ccc(Nc2ccc(C(=O)O)cc2)cc1
Temperature: 100 °C
Yield: 92.1 %

Procedure:
An oven-dried resealable Schlenk flask was evacuated and backfilled with argon. The flask was charged with Pd2 dba3 (9.2 mg, 0.01 mmol, 2 mol % Pd), Ligand 1 (19 mg, 0.04 mmol, 4 mol %), pulverized KOH (168 mg, 3.0 mmol), and 4-amino-benzoic acid (165 mg, 1.2 mmol). The flask was evacuated and backfilled with argon (3×) and then capped with a rubber septum. To the flask was added t-BuOH (2.0 mL), 4-n-butylchlorobenzene (168 mg, 1.0 mmol) and t-BuOH (0.5 mL). The septum was replaced with a Teflon screwcap, the flask was sealed, and the mixture was heated to 100° C. with stirring until the starting aryl chloride was consumed by GC analysis (3 h). The reaction was cooled to room temperature, diluted with 5% aq. NaOH and extracted with Et2O. The aqueous layer was cooled to 0° C. and acidified with HCl (12.0 M) until pH ˜4. The aqueous layer was extracted with Et2O, dried over anh. MgSO4, filtered, and concentrated under reduced pressure to give crude product (248 mg). The product was purified by re-crystallizing in hot hexanes/chloroform to give faint brown platelets (209 mg, 78%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N+:16]([C:19]1[C:20]([C:24](O)=O)=[N:21][NH:22][CH:23]=1)([O-:18])=[O:17].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CC(O)=O>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]3[NH:14][C:24]([C:20]4[C:19]([N+:16]([O-:18])=[O:17])=[CH:23][NH:22][N:21]=4)=[N:15][C:10]=3[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Reactant: Nc1ccc(CN2CCOCC2)cc1N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4-morpholin-4-ylmethyl-benzene-1,2-diamine (2.30 g, 11.1 mmol), 4-nitro-1H-pyrazole-3-carboxylic acid (1.57 g, 10.0 mmol), EDC (2.13 g, 11.1 mmol) and HOBt (1.50 g, 11.1 mmol) in dry DMF (25 ml) was stirred at ambient temperature for 24 h. The mixture was reduced in vacuo and the crude residue dissolved in AcOH (40 ml) and heated at reflux for 3 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography eluting with 0-20% MeOH in EtOAc to give 5-morpholin-4-ylmethyl-2-(4-nitro-1H-pyrazol-3-yl)1H-benzimidazole as a yellow solid. (1.0 g, 61%). (LC/MS: Rt 1.83, [M+H]+ 329).
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([C:10]1[O:11][C:12]2[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=2[C:14]=1[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)O)[CH3:9].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:15]([C:14]1[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[O:11][C:10]=1[CH2:8][CH3:9])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCc1oc2ccccc2c1C(O)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1oc2ccccc2c1Cc1ccccc1
Yield: 102.8 %

Procedure:
Triethylsilane (18.46 g; 0.159 mol) was added slowly to the solution of (2-ethyl-benzofuran-3-yl)-phenyl-methanol (20 g; 0.079 mol) in methylene chloride (200 mL) while stirring and cooling in ice bath under an atmosphere of nitrogen. Trifluoroacetic acid (40 mL) was then added dropwise. The mixture was then stirred at room temperature for one hour and the solvent was then evaporated. The residue was extracted with ether and the ethereal extracts were combined, washed with sodium bicarbonate solution, water, dried over anhydrous magnesium sulfate and the solvent was evaporated to give the product (19.2 g) as an oil. Mass spectrum (ESI, [M+] m/z 236. 1HNMR (400 MHz, DMSO-d6): δ 1.22 (t, 3H, J=7.47 Hz), 2.91 (q, 2H, J=7.47 Hz), 3.97 (s, 2H), 7.08 (dt, 1H, J=7.25, 1.1 Hz), 7.12-7.2 (m, 2H), 7.24-7.26 (m, 4H). 7.34-7.37 (m, 1H), 7.43-7.46 (m, 1H). Elemental Analysis for C17H16O: Calculated: C, 86.41; H, 6.82. Found: C, 86.16; H, 6.71.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[NH:12][C:13]2[C:18]([C:19]=1[CH2:20][CH3:21])=[CH:17][CH:16]=[CH:15][CH:14]=2)=O.C(OCC)(=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCCC1.CO>[CH2:20]([C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[CH2:9][OH:8])[CH3:21]
Reactant: CCc1c(C(=O)OC)[nH]c2ccccc12
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1c(CO)[nH]c2ccccc12
Temperature: 25 °C
Yield: 73.1 %

Procedure:
To the suspension of lithium aluminum hydride (4.15 g) in tetrahydrofuran (41 ml) at 15°-30° C. under a nitrogen atmosphere was added dropwise over 45 minutes 3-ethyl-2-indolecarboxylic acid methyl ester (22.2 g) in tetrahydrofuran. After the mixture was stirred at room temperature for an hour, ethyl acetate (200 ml) was added dropwise at 20°-30° C., followed by the addition of methanol (10 ml) at the same temperature. The reaction mixture was treated with saturated aqueous potassium sodium tartrate solution (150 ml). Separated organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (10% ethylacetate-n-hexane) to give 3-ethyl-2-hydroxymethylindole (14.0 g) as crystals.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([C:11]1[N:12]=[C:13]([CH3:16])[NH:14][CH:15]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:12]1[C:11]([CH:9]=[O:10])=[CH:15][N:14]=[C:13]1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nc(C=O)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncc(C=O)n1Cc1ccccc1
Temperature: 25 °C

Procedure:
Benzyl bromide (21.4 ml, 0.18 mol) was added carefully to a mixture of 4-formyl-2-methylimidazole (18.1 g, 0.16 mol) and potassium carbonate (45.0 g, 0.33 mol) in DMF (100 ml) at 0° C. and the reaction mixture allowed to warm to ambient temperature. The mixture was then partitioned between EtOAc and saturated aqueous sodium hydrogen carbonate solution, the organic phase separated and dried. The volatiles were removed by evaporation to give the title compound as crude mixture of regioisomers 32.0 g, (99%). M/z: 201.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:14]=[C:13]([C:15](C)(C)[O:16][SiH2]C(C)(C)C)[CH:12]=[C:11]([C:24](C)(C)[O:25][SiH2]C(C)(C)C)[CH:10]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]([CH2:24][OH:25])[CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1
Reactant: COC(=O)CCCC#Cc1cc(C(C)(C)O[SiH2]C(C)(C)C)cc(C(C)(C)O[SiH2]C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCCC#Cc1cc(CO)cc(CO)c1
Reaction time: 1.25 h
Yield: 85.9 %

Procedure:
To a cooled (0° C.) solution of 6-[3,5-Bis-(tert-butyl-dimethyl-silyloxymethyl)-phenyl]-hex-5-ynoic acid methyl ester (140 mg) in anhydrous tetrahydrofurane (0.3 mL) was slightly added a solution of tetrabutylammonium fluoride 1 M in THF (716 μL). After 75 min at rt, ethyl acetate (20 mL) was added and the organic phase was washed three times with water (5 mL) and once with a saturated aqueous solution of sodium chloride (5 mL), dried over sodium sulfate and concentrated in vacuo to a residue. The residue was purified by silica gel chromatography (Merck SuperVarioFlash 15 g column, Si60 15-40 μm), using gradient elution with a mixture of heptane (A)/ethyl acetate (B), (gradient: 50% A: 50% B down to 10% A: 90% B) to give 6-(3,5-Bis-hydroxymethyl-phenyl)-hex-5-ynoic acid methyl ester (64.3 mg) as a pale yellow oil. LC/MS (Method A3): ES: m/z 263 (M+H)+; RT=0.62 min
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[CH:14][C:13]=1[F:25]>C1COCC1>[Cl:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:15]=[CH:14][C:13]=2[F:25])=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C(Nc1c(F)ccc(O)c1Cl)c1cc(-c2cccc(F)c2)ccc1F
Solvent: C1CCOC1
Product: Oc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1Cl
Temperature: 60 °C
Yield: 82.5 %

Procedure:
To a solution of N-(2-chloro-6-fluoro-3-hydroxy-phenyl)-2-fluoro-5-(3-fluorophenyl) benzamide (180 mg, 0.48 mmol, 1.0 eq) in THF (2.5 mL) at 0° C. under N2 was added dropwise a solution of BH3 (1M in THF, 2.86 mL, 2.86 mmol, 6.0 eq). The reaction mixture was heated at 60° C. for 3 h, then cooled and quenched by addition of water. The mixture was extracted with EtOAc and the organic extract was washed with NaHCO3, water and brine, dried (Na2SO4), filtered, evaporated in vacuo and purified by column chromatography (EtOAc:petroleum ether, 1:10, 1.2:10) to give the title compound as an oil (144 mg, 83%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12](O)=[O:13]>O.[Zn]>[Cl:8][C:7]1[C:2]2[NH:1][C:12](=[O:13])[CH2:11][S:9][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CBr
Reactant: Nc1c(S)cccc1Cl
Agent: [Zn]
Solvent: O
Product: O=C1CSc2cccc(Cl)c2N1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
The zinc salt (2.0 g) of 2-amino-3-chlorothiophenol was suspended in water (30 ml), and bromoacetic acid (1.6 g) was added thereto, followed by stirring at 70° C. for 3 hours. The precipitated crystals were filtered, washed with water and dried to obtain 1.8 g of the objective 5-chloro-2,3-dihydro-1,4-benzothiazine-3-one (m.p. 160°-161° C.).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[CH3:22][N:23]1[CH2:28][CH2:27][CH:26]([NH:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH2:25][CH2:24]1.C(O)C.O>Cl.C(OCC)(=O)C>[CH:16]1([N:7]2[CH2:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:39][C:36]4[CH:35]=[CH:34][C:33]([S:30]([NH:29][CH:26]5[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]5)(=[O:32])=[O:31])=[CH:38][CH:37]=4)=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: CN1CCC(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN1CCC(NS(=O)(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(C)(C)C(=O)N4C)cc2)CC1
Yield: 42.2 %

Procedure:
A mixture of 0.0203 g (0.000066 mole) of 2-chloro-9-cyclopentyl-5,7,7-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-38), 0.0207 g (0.000077 mole) of N-(1-methyl-piperidin-4-yl)-4-nitro-benzenesulfonamide, 0.6 mL of ethanol, 2.4 mL of water and 2 drops of hydrochloric acid was heated at reflux for 17 hrs. The mixture was taken up in 50 mL of ethyl acetate and washed successively twice with 7 mL of 1M sodium hydroxide, twice with 7 mL of water and 7 mL of brine. The organic layer was concentrated under reduced pressure and the residue purified by silica gel chromatography, elution with dichloromethane-methanol 95:5-80:20) gave 0.0151 g of 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzenesulfonamide (I-64) as an off-white solid.
Reaction SMILES: C[O:2][C:3](=[O:29])[C@@H:4]([N:15]1[CH2:19][C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])=[CH:17][C:16]1=[O:28])[CH2:5][CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].O1CCCC1.O.[OH-].[Li+]>O>[C:11]([Si:8]([CH3:10])([CH3:9])[O:7][CH2:6][CH2:5][C@H:4]([N:15]1[CH2:19][C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])=[CH:17][C:16]1=[O:28])[C:3]([OH:29])=[O:2])([CH3:13])([CH3:12])[CH3:14]
Reactant: COC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC[C@@H](C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.3 %

Procedure:
A mixture of (S)-4-(t-butyl-dimethyl-silanyloxy)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-butyric acid methyl ester (250 mg, 0.57 mmol) in a 1:1 solution of tetrahydrofuran:water (8 mL) was treated with lithium hydroxide monohydrate (48 mg, 1.14 mmol) and stirred for 1.5 h at 25° C. After such time, the mixture was concentrated in vacuo to remove the tetrahydrofuran and diluted with water (10 mL) and the pH adjusted to pH=5 with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layers were then dried and concentrated in vacuo to afford (S)-4-(t-butyl-dimethyl-silanyloxy)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-butyric acid (195 mg, 81%) as an off-white foam: HR-ES-MS m/z calculated for C20H28NO5ClSi [M+H]+ 426.1498, observed 426.1498.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:10](=[O:12])[N:9]([OH:13])[CH:8]=[N:7][C:6]=2[N:5]([C@@H:14]2[O:20][C@H:19]([CH2:21][OH:22])[C@@H:17]([OH:18])[C@H:15]2[OH:16])[CH:4]=1)#[N:2]>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[C:1]([C:3]1[C:11]2[C:10](=[O:12])[N:9]([OH:13])[CH:8]=[N:7][C:6]=2[N:5]([C@@H:14]2[O:20][C@H:19]([CH2:21][O:22][C:17](=[O:18])[CH3:19])[C@@H:17]([O:18][C:15](=[O:16])[CH3:14])[C@H:15]2[O:16][C:10](=[O:12])[CH3:11])[CH:4]=1)#[N:2]
Reactant: N#Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2ncn(O)c(=O)c12
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C#N)c3c(=O)n(O)cnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 5 h

Procedure:
5-Cyano-3-N-hydroxy-7-(β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidin-4-one was dissolved in a mixture of 50 ml of pyridine and 25 ml of acetic anhydride. The solution was allowed to stand at room temperature for 5 hr and evaporated in vacuo to a thick oil. This residue was triturated with 100 ml of ethanol and the mixture was evaporated in vacuo to a solid foam which was again triturated with 100 ml of ethanol and evaporated in vacuo to dryness. The resulting foam was heated at reflux temperature with 100 ml of methanol for 1 hr. The methanol was removed in vacuo and an additional 100 ml of methanol was added and removed in vacuo to furnish a solid foam which was used without further purification.
Reaction SMILES: [ClH:1].C(OC([NH:9][C@H:10]([C:26]([NH:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33]([F:60])[C:34]=1[CH2:35][CH2:36][C@H:37]1[O:42][CH2:41][C@@H:40]([CH2:43][O:44][C:45](=[O:52])[NH:46][CH2:47][C:48]([F:51])([F:50])[F:49])[N:39](C(OC(C)(C)C)=O)[CH2:38]1)=[O:27])[CH:11]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH:11]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C@@H:10]([C:26]([NH:28][C:29]2[CH:30]=[N:31][CH:32]=[C:33]([F:60])[C:34]=2[CH2:35][CH2:36][C@H:37]2[O:42][CH2:41][C@@H:40]([CH2:43][O:44][C:45](=[O:52])[NH:46][CH2:47][C:48]([F:50])([F:49])[F:51])[NH:39][CH2:38]2)=[O:27])[NH2:9])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)Nc1cncc(F)c1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCC(F)(F)F)CO1)C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](C(=O)Nc1cncc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 4 h

Procedure:
4M HCl (3.54 mL, 14.17 mmol) in dioxane was added to a solution of tert-Butyl (2R,5S)-2-[2-(3-{[N-(tert-butoxycarbonyl)-4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]amino}-5-fluoropyridin-4-yl)ethyl]-5-({[(2,2,2-trifluoroethyl)carbamoyl]oxy}methyl)morpholine-4-carboxylate (1.19 g, 1.42 mmol) in Dioxane (14 mL) at ambient temperature and the reaction stirred for 4 hours. The solvent was removed in vacuo and ether was added to the residue. The title compound was filtered off as a white solid (1.00 g, 1.34 mmol, 94% yield), MS (ESI): m/z=640.40 (MH+); 100% pure by LCMS.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][C:6](=[CH:12][CH:13]=[C:14]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]([O:9][CH2:10][CH3:11])=[S:8].C(N(CC)CC)C.O>O1CCCC1.C1CCCCC1.C(OCC)(=O)C.ClCCl>[C:1]([O:5][C:6](=[CH:12][CH:13]=[C:14]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]([O:9][CH2:10][CH3:11])=[S:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C(=CC=C(O)C(=S)OCC)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C(=CC=C(OC(C)=O)C(=S)OCC)c1ccccc1

Procedure:
Acetyl chloride (1.2 cc) is added at a temperature of approximately 20° C., and in the course of 5 minutes, to a stirred solution, through which a stream of nitrogen is passed, of diethyl 2-hydroxy-5-phenylthio-2,4-hexadienedioate (5 g) and triethylamine (2.4 cc) in tetrahydrofuran (45 cc). Stirring is maintained for 2 hours at the same temperature. The mixture is taken up with water (100 cc) and dichloromethane (100 cc). The organic phase is separated off after settling has taken place, and the aqueous phase is extracted with dichloromethane (2×50 cc). The organic phases are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The oil obtained is dissolved in a mixture (10 cc) of cyclohexane and ethyl acetate (70:30 by volume), and poured onto silica (300 g) contained in a column 4 cm in diameter. Elution is performed with a mixture of cyclohexane and ethyl acetate (70:30 by volume), and the corresponding eluate is concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). Diethyl 2-acetoxy-5-phenylthio-2,4-hexadienedioate (4.5 g) is obtained in the form of an orange-coloured oil [Rf=0.50; thin layer chromatography on silica gel; eluent: cyclohexane/ethyl acetate (70:30 by volume)].
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[C:25]([O:32][CH3:33])[N:24]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][O:22][C:23]1[N:24]=[C:25]([O:32][CH3:33])[C:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@H:11]([N:13]5[CH2:17][CH2:16][CH2:15][C@@H:14]5[CH3:18])[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:27][N:28]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: OB(O)c1cncnc1
Product: COc1ncc(-c2ccc3nc([C@H]4C[C@H](N5CCC[C@@H]5C)C4)sc3c2)c(OC)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 11A for the product of Example 1E and substituting 2,6-dimethoxy-5-pyrimidineboronic acid for pyrimidine-5-boronic acid. 1H NMR (500 MHz, CDCl3) δ ppm 8.32 (s, 1H) 8.02 (d, J=8.54 Hz, 1H) 7.98 (d, J=1.53 Hz, 1H) 7.57 (dd, J=8.39, 1.68 Hz, 1H) 4.06 (s, 3H) 4.05 (s, 3H) 3.83-3.95 (m, 1H) 3.51-3.72 (m, 1H) 3.10-3.29 (m, 1H) 2.68-2.80 (m, 3H) 2.40-2.65 (m, 3H) 1.49-2.13 (m, 4H) 1.10-1.27 (s, 3H). MS: (M+H)+=411.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH:2]=[CH2:3].C([Li])CCC.CCCCCC.[I:33]I>C1COCC1>[CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:10][C:11]([I:33])=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH:2]=[CH2:3]
Reactant: C=CCn1ccnc1-c1sccc1-c1ccc(Cl)cc1Cl
Reactant: II
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCn1ccnc1-c1sc(I)cc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To a solution of 1-allyl-2-[3-(2,4-dichlorophenyl)-2-thienyl]-1H-imidazole (2.50 g, 7.46 mmol) in THF (80.0 mL) cooled to −78° C. was added dropwise 2.50 M of n-butyllithium in hexane (3.28 mL, 8.20 mmol) and the mixture was stirred for 30 min. To the solution was added dropwise a solution of iodine (2.84 g, 11.2 mmol) in THF (10.0 mL) and the resulting solution was stirred for 15 min at −78° C. The reaction mixture was quenched by addition of saturated sodium bisulfite solution (200 mL) and the resulting mixture was warmed to room temperature while stirring for 30 min. The mixture was extracted with EtOAc (3×250 mL) and the combined organic layers were washed with brine (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, elution with 1-6% EtOAc in hexane) to give crude product which was further purified by column chromatography (SiO2, elution with 2% MeOH in DCM) to provide 2.57 g of product (71%). LC/MS (FA), ES+ 462. 1H NMR (400 MHz, d6-DMSO) δ: 7.30 (d, J=2.2 Hz, 1H), 7.09 (s, 1H), 6.97 (dd, J=2.2, 8:2 Hz, 1H), 6.75 (d, J=1.3 Hz, 1H), 6.71 (d, J=8.2 Hz, 1H), 6.60 (d, J=1.3 Hz, 1H), 5.10-5.21 (m, 1H), 4.60-4.65 (m, 1H), 4.35-4.41 (m, 1H), 3.80-3.85 (m, 2H).