Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([CH2:19][CH2:20]OS(C)(=O)=O)[CH:13]=[CH:12]3)[CH:6]=[N:7][CH:8]=1)#[N:2].[CH3:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:20][CH2:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:5]1[CH:6]=[N:7][CH:8]=[C:3]([CH:4]=1)[C:1]#[N:2])[CH:18]=[CH:17]2
Reactant: C[C@@H]1CCCN1
Reactant: CS(=O)(=O)OCCc1ccc2cc(-c3cncc(C#N)c3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCc1ccc2cc(-c3cncc(C#N)c3)ccc2c1
Yield: 57.4 %

Procedure:
Methanesulfonic acid 2-[6-(5-cyano-pyridin-3-yl)-naphthalen-2-yl]-ethyl ester (Example 81B, 190 mg, 0.54 mmol), (2R)-2-methylpyrrolidine (138 mg, 1.62 mmol, 3.0equiv.), and cesium carbonate (176 mg, 0.54 mmol) in anhydrous acetonitrile (6 mL) were stirred in a sealed tube at 50° C. for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous Na2CO3. The organic layer was washed with brine, then dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (98:2: trace dichloromethane/methanol/N H4OH). Fractions containing product were combined and concentrated under reduced pressure to provide the free base of the title compound as a white solid (105.9 mg, 57% yield). This free base was dissolved in methanol and treated with excess dioxane-HCl. Ether was added to induce crystallization of the dihydrochloride salt of the title compound. 1H NMR (CD3OD, 300 MHz) δ 9.26 (br s, 1H), 8.97 (br s, 1H), 8.68 (s, 1H), 8.29 (s, 1H), 8.05 (s, 1H), 8.02 (s, 1H), 7.90 (br s, 1H), 7.88 (dd, J=2, 9 Hz, 1H), 7.56 (d, J=8 Hz, 1H), 3.84–3.49 (m, 7H), 2.45–2.30 (m, 1H), 2.27–1.99 (m, 2H), 1.84–1.69 (m, 1H), 1.50 (d, J=6 Hz, 3H). MS (DCI-NH3) [M+H]+ at 342.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH3:24])(O)[CH2:9][C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)=[C:4]([CH3:25])[CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH3:24])=[CH:9][C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)=[C:4]([CH3:25])[CH:3]=1
Reactant: Cc1cc(F)ccc1C(O)(Cc1nnnn1C)c1ccc(F)cc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1cc(F)ccc1C(=Cc1nnnn1C)c1ccc(F)cc1C
Yield: 61.3 %

Procedure:
A mixture of 1,1-bis-(4-fluoro-2-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol (0.5 g, 1.5 mmoles) and p-toluenesulfonic acid (0.2 g) was heated at reflux in toluene (30 mL) for 16 hours. The mixture was cooled, diluted with diethyl ether (50 mL) and extracted with saturated sodium bicarbonate solution and water. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was triturated with diethyl ether to give 0.3 g of the title compound; m.p.=120°-125° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[CH:6]=[O:7])([O-:3])=[O:2].[BH4-].[Na+]>CO>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[CH2:6][OH:7])([O-:3])=[O:2]
Reactant: O=Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1CO
Reaction time: 1 h
Yield: 75.7 %

Procedure:
To a suspension of 2,6-dinitrobenzaldehyde (19.6 g, 0.1 mole) in methanol (200 ml), sodium boro-hydride (5.8 g) was added in a small portion at 15°-25° C. The resultant mixture was stirred at room temperature for 1 hour and then concentrated. To the residue, H2O (100 ml) and chloroform (100 ml) were added, followed by stirring for 1 hour. The chloroform layer was separated, washed with H2O, dried over anhydrous MgSO4 and evaporated to afford 15.0 g of 2,6-dinitrobenzyl alcohol as yellow crystals, m.p. 92.5°-93.5° C.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]([NH:16][C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[S:25]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)(=[O:27])=[O:26])=[O:18])[Si](C(C)(C)C)(C)C.C(OCC)C>C(Cl)Cl>[OH:8][NH:16][C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[S:25]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)(=[O:26])=[O:27])=[O:18]
Reactant: CC(C)(C)[Si](C)(C)ONC(=O)C1CCCCN1S(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(NO)C1CCCCN1S(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 67 %

Procedure:
Trifluoroacetic acid (few drops) was added to a solution of N-tert-butyldimethylsiloxy-1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxamide (63 mg, 0.12 mmol), [prepared as described in Step 2 above], in methylene chloride (2 ml) and the reaction mixture was stirred at RT for 45 min. The organics were removed in vacuo and the residue was dissolved in methylene chloride (25 ml) and the washed with sat. sodium bicarbonate, brine, and dried over MgSO4. The solvent was removed in vacuo to give a foam which was redissolved in a minimum amount of methylene chloride. Diethyl ether was added and the resulting white precipitates were filtered to give N-hydroxy-1-[4-(4-chlorophenyl)-piperazine-1-sulfonyl]-piperidine-2-(RS)-carboxamide (67%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([Cl:18])=[N:10][N:9]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([OH:25])[CH2:20]1>CS(C)=O>[Cl:18][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([N:19]2[CH2:24][CH2:23][CH2:22][CH:21]([OH:25])[CH2:20]2)=[N:9][N:10]=1
Reactant: OC1CCCNC1
Reactant: Clc1nnc(Cl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: OC1CCCN(c2nnc(Cl)c3ccccc23)C1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A resealable pressure bottle was charged with potassium carbonate (273 mg, 2.0 mmol), 1,4-dichlorophthalazine (590 mg, 3.0 mmol), piperidin-3-ol (200 mg, 2.0 mmol) and methylsulfinylmethane (10 mL, 0.2M). The vessel was sealed and the mixture stirred at 90° C. for 24 hrs. Next day the reaction was cooled to RT and diluted with 5 ml of DMSO. The solution was purified by Gilson reverse phase liquid chromatography (10% to 90% CH3CN/H2O/0.1% TFA) to afford 1-(4-chlorophthalazin-1-yl)piperidin-3-ol. MS m/z=264 [M+1]+. Calculated for C13H14ClN3O: 263.7.
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:12](OCC)(=O)[CH2:13][CH2:14]C.[O-]CC.[Na+]>O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]([CH2:12][CH2:13][CH3:14])=[O:9])[CH:3]=1
Reactant: CCOC(=O)c1cccnc1
Reactant: CCCC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: CCCC(=O)c1cccnc1
Temperature: 100 °C

Procedure:
A mixture of ethyl nicotinate (15.1 g, 0.1 mole), ethyl butyrate (17.4 g, 0.15 mole) and sodium ethoxide (10.2 g, 0.15 mole) was stirred and heated under nitrogen at 100°C. for five hours. After cooling, the mixture was diluted with water (150 ml), extracted with diethyl ether (50 ml) and the aqueous layer made acidic to pH1 with concentrated hydrochloric acid (50 ml). The aqueous layer was heated at 90°C. for 2 hours, cooled, and made alkaline with solid potassium carbonate and extracted with diethyl ether (3×75 ml). The dried (magnesium sulphate) organic layer was concentrated and distilled to give propyl 3-pyridyl ketone (b.pt. 118-120°C./14 mm Hg).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].O1CCCC1.C([Li])CCC.[O:18]([CH2:25][C:26](OCC)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCCCCC.C(O)(=O)C>[O:27]=[C:26]([CH2:25][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCOC(=O)COc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)COc1ccccc1)OC
Reaction time: 0.33 h

Procedure:
40.1 g. of dimethyl methylphosphonate were dissolved in 200 ml. of anhydrous tetrahydrofuran, to which 154 ml. of a 2N n-butyllithium solution in n-hexane were added dropwise whilst maintaining the temperature from -60° to -70°C. After stirring for 20 minutes, 15 g. of ethyl phenoxyacetate in 80 ml. of tetrahydrofuran were added to the solution. The mixture was stirred at the same temperature for 2 hours and then at room temperature overnight. The reaction mixture was neutralized with acetic acid and concentrated under reduced pressure. The residue was dissolved in a small amount of water and extracted with diethyl ether. The ethereal extracts were washed with an aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by distillation in vacuo to give 18.9 g. of the title compound having the following physical characteristics:
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[C:18]=3[NH2:24])[CH2:13][CH2:12]2)=[O:7])=[CH:4][CH:3]=1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28].C(O)C>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:18]4[NH:24][C:27](=[O:28])[NH:23][C:19]=4[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[O:7])=[CH:25][CH:26]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cccc(N2CCN(CCNC(=O)c3ccc(F)cc3)CC2)c1N
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(NCCN1CCN(c2cccc3[nH]c(=O)[nH]c23)CC1)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
10 Mmol (3.57 g) of 4-fluoro-N-[2-{4-(2,3-diaminophenyl)-1-piperazinyl}ethyl]benzamide were dissolved in 35 ml of tetrahydrofuran (which had been distilled over LiAlH4), and the solution was cooled in an ice-bath to 0° C. under an atmosphere of nitrogen. 21 Mmol (3.4 g) of 1,1'-carbonyldiimidazole in 20 ml of tetrahydrofuran was added in one portion to this solution while vigorously stirring. The temperature raised to 10° C. Thereafter the mixture was stirred for 3 hours at room temperature. The reaction mixture was evaporated to dryness under reduced pressure, the residue was taken up into chloroform, and the solution was washed with water. The organic layer was evaporated to dryness, and the residue was chromatographed over silicagel with a mixture of methylene chloride, methanol and 25% of ammonia (92:7.5:0.5) as the eluent. The so obtained base was cyrstallized from ethanol, and the title compound was obtained having a melting-point of 240°-243.5° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:17][NH:18][S:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:20]>>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:24]3[CH:23]=[C:22]([S:19]([NH:18][CH3:17])(=[O:20])=[O:21])[CH:27]=[CH:26][CH:25]=3)[N:3]=2)[NH:8][CH:9]=1)=[O:16]
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: CNS(=O)(=O)c1cccc(B(O)O)c1
Product: CNS(=O)(=O)c1cccc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)c1

Procedure:
3-[7-(2,2-Dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-N-methyl-benzenesulfonamide was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and 3-methylsulfamoylphenylboronic acid following general procedures as described in these Examples. MP 245-247° C., M+H=373.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[C:10](O)(=[O:13])[CH2:11][OH:12].C(N(CC)CC)C>O1CCCC1>[C:1]([S:4][CH2:5][CH2:6][C:7]([O:9][C:11](=[O:12])[CH2:10][OH:13])=[O:8])(=[O:3])[CH3:2]
Reactant: O=C(O)CO
Reactant: CC(=O)SCCC(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)SCCC(=O)OC(=O)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(Acetylthio)propanoic acid (2.96 g) and 1,1'-carboxyldiimidazole (3.24 g) are dissolved in 20 ml of dry tetrahydrofuran with stirring at room temperature. After twenty minutes, a solution of glycolic acid (1.52 g) and 2.80 ml of triethylamine in 15 ml of dry tetrahydrofuran are added. The reaction mixture is stored overnight at room temperature. The tetrahydrofuran is removed in vacuo, the crude residue taken up into ethyl acetate, washed with 1N hydrochloric acid and three times with water, dried over magnesium sulfate and the O-(3-acetylthiopropanoyl)glycolic acid is concentrated to dryness in vacuo, yield 3.9 g. This is dissolved in ether and dicyclohexylamine is added. The dicyclohexylamine salt precipitates, yield 2.85 g.; m.p. 150-157° . The salt is converted to the free acid by adding to ethyl acetate and adding 10% potassium bisulfate solution, yield 1.5 g.
Reaction SMILES: [O:1]([CH2:8][C@H:9]([NH2:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:15][C@@H:16]1[C@H:20]([O:21]C(=O)C)[C@@H:19]([CH2:25][O:26]C(=O)C)[O:18][C@H:17]1[N:30]1[CH:38]=[N:37][C:36]2[C:31]1=[N:32][C:33]([CH3:40])=[N:34][C:35]=2Cl)(=O)C.C(N(CC)CC)C>O1CCOCC1>[CH3:40][C:33]1[N:34]=[C:35]([NH:11][C@H:9]([CH3:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:36]2[N:37]=[CH:38][N:30]([C:31]=2[N:32]=1)[C@@H:17]1[O:18][C@H:19]([CH2:25][OH:26])[C@@H:20]([OH:21])[C@H:16]1[OH:15]
Reactant: C[C@@H](N)COc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1nc(N[C@H](C)COc2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 50 °C
Yield: 50.5 %

Procedure:
(R)-1-phenoxy-2-propylamine (0.56 g, 3 mmol) was reacted with 9-(2,3,5-tri- O-acetyl-β-D-ribofuranosyl)-6-chloro-2-methyl-9H-Purine (0.43 g, 1 mmol) [prepared from 2-methylinosine (Journal of Organic Chemistry, 1967, 32, 3258-3260) by standard acylation and chlorination steps] in dioxan (20 ml) in the presence of triethylamine (0.41 g, 4 mmol). The reaction mixture was heated at 50° C. for 70 h, and at 90° C. for 3 h. before being filtered and evaporated. The product (after purification by flash chromatography) was debenzoylated with methanolic ammonia to provide the title 2-methyl- N-[(R)-1-phenoxy-2-propyl]adenosine (after column chromatography) as a foam (0.21 g, 50%), 1H NMR (DMSO-d6)δ 1.30 (3H, d, --CH3), 2.43 (3H, s, --CH3), 3.53-3.60 (1H, m, H-5'a), 3.66-3.73 (1H, m, H-5'b), 3.94 (1H, dd, --C--H), 3.99 (1H, q, H-4'), 4.12-4.22 (2H, m, H-3' and --C--H), 4.54 (1H, dd, H-2'), 4.76 (1H, m, --CH3C H--), 5.20, 5.52 (2H, 2d, 2' and 3'-OH), 5.73 (1H, t, 5'-OH), 5.87 (1H, d, H-1'), 6.90-7.31 (5H, t, m, t, Ar--H), 7.74 (1H, br d, N--H), 8.28 (1H, s, H-8).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16]2[C@@H:15]3[CH2:17][C@@H:14]3[CH2:13][C:12]=2[C:11]([C:18](O)=[O:19])=[N:10]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH2:63][C:64]([CH3:68])([CH3:67])[CH2:65][OH:66]>CN(C=O)C.O>[OH:66][CH2:65][C:64]([NH:63][C:18]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:17][C@H:15]3[C:16]=2[N:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:10]=1)=[O:19])([CH3:68])[CH3:67]
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO)NC(=O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
To a stirred solution of Intermediate 1 (see Example 1.1, 2 g, 7.24 mmol), benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 4.52 g, 8.69 mmol) and DIEA (2.52 mL, 14.48 mmol) in DMF (20 mL) was added 2-amino-2-methylpropan-1-ol (0.833 mL, 8.69 mmol). The reaction was stirred at room temperature overnight, then poured into water, and extracted with ethyl acetate. The combined organics were dried and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a white solid (2.08 g). LCMS m/z=348.4 [M+H]+; 1H NMR (400 MHz, CDCl3) ppm 0.48 (td, J=4.7, 3.3 Hz, 1H), 1.16 (td, J=7.8, 4.9 Hz, 1H), 1.371 (s, 3H), 1.376 (s, 3H), 2.08-2.13 (m, 1H), 2.25-2.31 (m, 1H), 2.94 (d, J=16.8 Hz, 1H), 3.04 (dd, J=16.4, 6.2 Hz, 1H), 3.68 (d, J=3.5 Hz, 2H), 4.81-4.84 (m, 1H), 6.88 (bs, 1H), 6.99-7.05 (m, 2H), 7.59-7.65 (m, 1H).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:23])[CH2:6][N:7]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10])[CH3:8].O.Cl>C1COCC1.CO.O>[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:15]=[CH:16][C:11]([C:9]([N:7]([CH2:6][C:5]([OH:23])=[O:4])[CH3:8])=[O:10])=[CH:12][CH:13]=1
Reactant: COC(=O)CN(C)C(=O)c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(CC(=O)O)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
LiOH (293 mg, 6.9 mmol) was added to a stirred solution of [(biphenyl-4-carbonyl)-methyl-amino]-acetic acid methyl ester (330 mg, 1.1 mmol) in THF:MeOH:H2O (2:2:1, 10 mL), and the resulting mixture was stirred at room temperature for 4 hrs. The reaction mixture was concentrated under reduced pressure to get the residue. Cold water was then added and acidified it with 10% aqueous HCl, filtered the solid precipitated to afford 250 mg (79.7% yield) of [(biphenyl-4-carbonyl)-methyl-amino]-acetic acid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1.Cl[CH2:14][CH2:15][N:16]([CH2:24][CH2:25]Cl)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]>CS(C)=O.C1COCC1>[C:19]([O:18][C:17]([N:16]1[CH2:24][CH2:25][C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=2)([C:11]#[N:12])[CH2:14][CH2:15]1)=[O:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CCc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(Cl)c2)CC1
Temperature: 0 °C

Procedure:
A suspension of 15.8 g of sodium hydride of a concentration of 60% in oil in 400 ml of DMSO is admixed dropwise at AT under an inert atmosphere with a solution of 30 g of 3-chlorophenylacetonitrile in 200 ml of THF and then with a solution of 45.5 g of tert-butyl bis(2-chloroethyl)carbamate in 200 ml of DMSO and is heated at 60° C. overnight. The reaction mixture is poured into an ice/water mixture and extracted with ether, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM. This gives 33 g of the expected product.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11]C#N)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:14]([N:16]=[C:17]=[O:18])[CH3:15].[CH2:19]([N:21](CC)CC)C>CN(C)C=O>[CH3:11][C:9]1[CH:8]=[C:7]([C:19]#[N:21])[C:5]2[N:6]=[C:2]([NH:1][C:17]([NH:16][CH2:14][CH3:15])=[O:18])[S:3][C:4]=2[CH:10]=1
Reactant: N#CCc1ccc2nc(N)sc2c1
Reactant: CCN(CC)CC
Reactant: CCN=C=O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2c(C#N)cc(C)cc2s1
Temperature: 80 °C

Procedure:
About 1 g of (2-amino-1,3-benzothiazol-6-yl)methyl cyanide is dissolved in about 10 ml dimethylformamide. About 0.8 ml of ethylisocyanate is added followed by about 1.4 ml triethylamine and the solution is heated to about 80° C. under good agitation. The solution is allowed to stir for about 4–6 hours then cooled to RT. The solvent is removed in vacuo and the solids are washed well with ether. The product is recrystallized from hot EtOAc. 1H NMR 1.09 (t, 3H), 3.1 (m, 2H), 4.1 (s, 2H), 6.72 (m, 1H), 7.32 (m, 1H), 7.61 (d, 1H), 7.85 (s, 1H), 10.7 (s, 1H); LC/MS 2.73 min, 261 (M+1), 259 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([I:21])[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCCCCC.CCOC(C)=O>CCOC(C)=O>[CH2:31]([O:11][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([I:21])[CH:15]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(I)c1)C(=O)O
Reactant: BrCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(I)c1)C(=O)OCc1ccccc1
Temperature: 90 °C

Procedure:
(2S)-2-tert-Butoxycarbonylamino-3-(4-hydroxy-3-iodo-phenyl)-propionic acid (490 mg. 1.2 mmol) of Step A is stirred in EtOAc (3.6 mL) with DIEA (418 μL, 2.4 mmol) at RT under N2. Benzyl bromide (171 μL, 1.44 mmol) is then added and the reaction mixture is then heated to 90° C. overnight. TLC in 3/1 hexane/EtOAc shows complete consumption of starting material (ninhydrin positive) and the appearance of two higher rf spots. The reaction is cooled to RT, diluted with EtOAc and washed with 1N HCl (2×30 mL) and with saturated NaHCO3 (2×30 mL). The organics are dried (MgSO4), filtered and concentrated to provide a mixture of mono- and dibenzylated products. Flash chromatography (3:1 hexane/EtOAc) affords the title compound, (2S)-2-tert-butoxycarbonylamino-3-(4-hydroxy-3-iodo-phenyl)-propionic acid benzyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.C([Li])CCC.[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[O:28])[S:25][CH:26]=1.[CH3:29][Si:30](Cl)([CH3:32])[CH3:31]>C1COCC1.CCCCCC>[O:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:27]([O:28][Si:30]([CH3:32])([CH3:31])[CH3:29])[C:24]2[S:25][CH:26]=[C:22]([Br:21])[CH:23]=2)=[CH:3][CH:4]=1)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: O=Cc1cc(Br)cs1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C(O[Si](C)(C)C)c2cc(Br)cs2)cc1
Temperature: 25 °C

Procedure:
5.9 gms (0.02 mol) of 4-bromo t-butyldimethylsiloxybenzene were dissolved in 42 ml of dry THF. The solution was cooled to -78° C. while under an argon atmosphere and 13.1 ml (0.02 mol) of a 1.6M solution of n-butyl lithium in hexane were added. After stirring for fifteen minutes under argon the solution was combined over a twenty-five-minute period with a solution of 4.0 gms (0.02 mol) of 4-bromo-2-thiophene carboxaldehyde in 50 ml. of THF at -78° C. The resulting solution was stirred for one hour and fifteen minutes at -78° C. 1.95 ml of trimethylsilylchloride (TMSCI) were added and the solution was allowed to warm to room temperature overnight with stirring. An additional 10 ml of TMSCl were added and the solution was stirred for six hours. The reaction was quenched with water; the organic phase was separated from the brine, dried over MgSO4, filtered, concentrated and separated by flash chromatography, utilizing hexane as the eluant. 2.5 gms of a clear colorless liquid were recovered having an NMR spectra of:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.[Br:13][C:14]1[C:15](Cl)=[N:16][CH:17]=[CH:18][CH:19]=1>C1COCC1>[Br:13][C:14]1[C:15]([O:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: Clc1ncccc1Br
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2ncccc2Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
3-bromo-2-(4-methoxybenzyloxy)pyridine was prepared by the procedure described in J. Med. Chem., 2008, 51, 3065. A pressure vessel was charged with anhydrous THF (25 ml) and sodium hydride (1.44 g, 36.18 mmol, 60% dispersion). To this stirred mixture was added portionwise a solution of 4-methoxybenzyl alcohol (5.0 g, 36.18 mmol) in anhydrous THF (15 ml). After addition was complete, the mixture was stirred at room temperature for 30 minutes and a solution of 3-bromo-2-chloropyridine (4.64 g, 24.08 mmol) in anhydrous THF (15 ml) was added. The vessel was sealed and the reaction mixture was heated at 75° C. for 6 hours. Upon cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with water, sat'd NaCl(aq.), dried over MgSO4, filtered, and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 4:1 hexanes: EtOAc) gave the title compound as a clear oil (6.51 g, 92%).