Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:24][CH:16]([C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[Br:34][CH2:35][C:36](Br)=[O:37]>C(Cl)Cl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]2[CH:16]3[CH2:24][C:9]([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:36](=[O:37])[CH2:35][Br:34])[CH2:3][CH2:4]4)([C:10]4[C:15]3=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:22]=2[CH:21]=1
Reactant: O=C(Br)CBr
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CBr)NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a cold (ice bath) stirred solution of racemic 4-amino-1-[2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]-piperidine (4.25 g, 12.54 mmol, described in Example 7b), diisopropyl ethylamine (4.37 mL, 25.08 mmol) in methylene chloride (75 mL) was added bromoacetyl bromide (1.36 mL, 15.68 mmol). After stirring the resulting mixture for 1 h at 0° C., the cooling bath was removed and the reaction was allowed to reach ambient temperature and stirred for an additional 18 h. The reaction mixture was treated with saturated sodium bicarbonate (2×150 mL) and brine (100 mL), dried (sodium sulfate), filtered, and concentrated to give the title compound as a brown foamy glass (5.74 g, quant.)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:24](=[O:25])[C:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[CH:22][NH:21][CH:20]=3)=[O:18])=[C:11]([F:33])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:34][N:35]1[CH:39]=[C:38](B(O)O)[CH:37]=[N:36]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:33][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:38]3[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=3)[CH:7]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH:16][C:17]([C:19]1[C:24](=[O:25])[C:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:22][NH:21][CH:20]=1)=[O:18]
Reactant: Cn1cc(B(O)O)cn1
Reactant: O=C(Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)c4c[nH]cc(-c5ccc(F)cc5)c4=O)cc3F)ccn2)cn1
Temperature: 80 °C
Yield: 82 %

Procedure:
N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (0.100 g, 0.212 mmol), 1-methyl-pyrazole-4-boronic acid (0.055 g, 0.265 mmol) and K2CO3 (0.088 g, 0.636 mmol) were combined in dioxane (2 mL) and H2O (0.500 mL), sparged with argon, treated with Pd(PPh3)4 (0.012 g, 10.60 μmol) and heated at 80° C. for 22 h. Additional 1-methyl-pyrazole-4-boronic acid (0.055 g, 0.265 mmol) was added, the mixture sparged with argon, treated with additional Pd(PPh3)4 (0.012 g, 10.60 μmol) and heated at 100° C. overnight. The mixture was cooled to RT, diluted with EtOAc, filtered through diatomaceous earth and the filtrate washed with brine (2×), dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (90 mg, 82%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 13.48 (s, 1H), 12.72 (s, 1H), 8.63 (s, 1H), 8.57 (dd, J=12.6, 6.9 Hz, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.27 (s, 1H), 8.09 (s, 1H), 7.97 (s, 1H), 7.69 (m, 2H), 7.58 (dd, J=11.1, 7.6 Hz, 1H), 7.26 (m, 3H), 6.74 (d, J=5.6 Hz, 1H), 3.84 (s, 3H); MS (ESI) m/z: 518.2 (M+H+).
Reaction SMILES: [C:1]1([CH3:34])[CH:6]=[CH:5][C:4]([N:7]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3([CH2:29][C:30]([O:32]C)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:17][CH2:16]2)[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:3][CH:2]=1.O.[OH-].[Li+].O1CCOCC1.C(O)(=O)C>O>[C:1]1([CH3:34])[CH:6]=[CH:5][C:4]([N:7]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3([CH2:29][C:30]([OH:32])=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:17][CH2:16]2)[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:3][CH:2]=1
Reactant: COC(=O)CC1(CCN2CCC(N(C(=O)c3ccco3)c3ccc(C)cc3)CC2)CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC(=O)O)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.8 %

Procedure:
To methyl [1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetate (0.5241 g) and lithium hydroxide monohydrate (0.94 g) were added 1,4-dioxane (20 mL) and water (5 mL). The resulting suspension was stirred at room temperature for 3 days. The reaction solution was brought to dryness and the residue was diluted with water. Acetic acid (1.0 mL) was then added to the solution and it was extracted with 25% ethanol/chloroform. The extract was dried over (MgSO4) and the solvent was distilled off under reduced pressure. The resulting residue was purified by chromatography (silica gel, 10% methanol/chloroform) to give the title compound (0.36 g), which was then converted to its hydrochloride by hydrochloric acid to give the title compound as a white solid (0.3805 g).
Reaction SMILES: C[Mg]Br.[CH:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4:21]>CCOCC>[C:13]1([Zr:21][C:13]2[C:14]3[NH:15][C:16]4[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=4)[C:9]=3[CH:10]=[CH:11][CH:12]=2)[C:14]2[NH:15][C:16]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: [Zr+4]
Agent: C[Mg]Br
Agent: [Cl-]
Solvent: CCOCC
Product: c1ccc2c(c1)[nH]c1c([Zr]c3cccc4c3[nH]c3ccccc34)cccc12
Temperature: 25 °C

Procedure:
The procedure of Example 16 of U.S. Pat. No. 5,539,124 is followed to prepare a bis(carbazolyl) zirconium complex. This procedure uses methylmagnesium bromide to deprotonate carbazole, and combines the resulting anion with 0.5 eq. of zirconium tetrachloride in ether at −78° C. After warming to room temperature, the mixture is stripped to remove ether. Toluene is added, and the mixture is filtered to remove insoluble material. The filtrate is then stripped to yield the bis(carbazolyl) complex.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[CH:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:11]([OH:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24](OC(C)=O)=[O:25].CCN(CC)CC>C1COCC1.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:22])[CH:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:11]([O:13][C:24](=[O:25])[CH3:23])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)C(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OC(C)C(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.9 %

Procedure:
To a stirred solution of benzyl-2-(tert-butoxycarbonylamino)-3-hydroxybutanoate (2.8 g, 9.06 mmol) in THF (80 mL) was added Ac2O (1.1 g, 10.87 mmol), Et3N (1.51 mL, 10.87 mmol) and DMAP (280 mg) and stirred at RT for 15 min. The volatiles were removed under reduced pressure. The residue obtained was diluted with EtOAc (150 mL) and washed with cold 0.5N HCl solution (2×20 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 3-acetoxy-2-(tert-butoxycarbonylamino)-butanoate 11 (2.8 g, 88%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])([C:12]#[N:13])[CH2:6][C:7](OCC)=[O:8])[CH3:2].[OH:26]O.[OH-].[Na+]>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:18]([O:17][C:15]([NH:14][C:5]1([C:4]([O:3][CH2:1][CH3:2])=[O:25])[CH2:6][C:7](=[O:8])[NH:13][C:12]1=[O:26])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)CC(C#N)(NC(=O)OCc1ccccc1)C(=O)OCC
Reactant: OO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)OCc2ccccc2)CC(=O)NC1=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
A solution of 2-benzyloxycarbonylamino-2-cyanosuccinic acid diethyl ester (15.4 g) in dichloromethane (50 ml) was cooled to ice-bath temperature, and then 30% hydrogen peroxide (21 ml), tetrabutylammonium hydrogen sulfate (3.0 g) and 20% aqueous sodium hydroxide solution (16.6 ml) were added in turn. The resulting mixture was stirred under ice cooling for 30 minutes and then at 25° C. for 1 hour. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was heated at 80° C. for 1.5 hours to give the title compound (11.5 g, 81.2%), which was recrystallized from ethyl acetate/n-hexane to give the pure product, mp 105°-106° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[C:6]([C:9]1[CH:10]=[C:11](/[CH:14]=[C:15]2\[C:16](=[O:26])[NH:17][C:18]3[C:23]\2=[C:22](I)[C:21]([F:25])=[CH:20][CH:19]=3)[NH:12][CH:13]=1)(=[O:8])[CH3:7]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.CCN(CC)CC>[C:6]([C:9]1[CH:10]=[C:11](/[CH:14]=[C:15]2\[C:16](=[O:26])[NH:17][C:18]3[C:23]\2=[C:22]([C:5]#[C:4][CH2:3][NH:2][CH3:1])[C:21]([F:25])=[CH:20][CH:19]=3)[NH:12][CH:13]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1
Reactant: C#CCNC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNCC#Cc1c(F)ccc2c1/C(=C/c1cc(C(C)=O)c[nH]1)C(=O)N2

Procedure:
Using Method C above, N-methylpropargyl amine (43.6 mg, 0.66 mmol) was coupled with (Z)-3-[(4-acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (100 mg, 0.25 mmol) (Example 90B) using (Ph3P)4Pd (30.1 mg) and Cul (6.0 mg) as catalyst in DMF (6 mL) and Et3N (6 mL) as solvent at 89° C. for 5 h to yield (Z)-3-[(4-Acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-[3-(N-methylamino)-1-propynyl]-2H-indol-2-one. (Yield 10 mg, 12%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].C(N(CC)CC)C.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][S:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:25])=[O:24])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Br)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1ccc(Cl)c(Br)c1)c1ccccc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of 3-bromo-4-chloroaniline (200 mg, 0.969 mmol) in dichloromethane (5 mL) was added triethylamine (0.374 mL, 2.91 mmol). The solution was cooled to 0° C. and benzenesulfonyl chloride (188 mg, 1.066 mmol) was added dropwise. After stirring at room temperature for 12 hours, the mixture was extracted with dichloromethane and the organic layer washed with water and brine (25 mL each). Drying over sodium sulfate, filtration and concentration afforded the title compound. LCMS: 346.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[CH:4]=1.F[C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=2)[CH:4]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1

Procedure:
A mixture of 32.4 g of α,α,α-trifluoro-m-cresol, 27.62 g of p-fluoroacetophenone, 55.2 g of potassium carbonate and 250 ml of N,N-dimethylacetamide is heated under Argon overnight with vigorous stirring at 150°-155° C. After cooling the mixture is added to 500 ml of water and extracted with benzene. The combined extracts are washed with two 100 ml portions of 5% NaOH, 100 ml of H2O, 100 ml of saturated brine, and dried over MgSO4. Evaporation of the solvent at reduced pressure affords a brown liquid which is distilled to give the product as a pale yellow oil (bp 122°-142° C at 0.2 mm).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][CH2:10][CH:11]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([NH:8][CH2:9][CH2:10][CH:11]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NC(CCN)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
Acetic anhydride (0.084 mL, 0.89 mmol) was added dropwise to tert-butyl 3-amino-1-(4-chlorophenyl)propylcarbamate (Intermediate 25) (203 mg, 0.71 mmol) and N,N-diisopropylethylamine (0.248 mL, 1.43 mmol) in DCM (5 mL) at 20° C. The resulting solution was stirred at 20° C. for 16 hours. The reaction mixture was quenched with NaHCO3 (2M) (10 mL) and water (10 mL) and extracted with DCM (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 2.5% MeOH in DCM. Pure fractions were evaporated to dryness to afford tert-butyl 3-acetamido-1-(4-chlorophenyl)propylcarbamate (142 mg, 61.0%) as a white solid. 1H NMR (399.9 MHz, DMSO-d6) δ1.36 (9H, s), 1.67-1.82 (2H, m), 1.79 (3H, s), 2.97 (2H, q), 4.50 (1H, d), 7.32 (2H, d), 7.38 (2H, d), 7.43-7.45 (1H, m), 7.79 (1H, s). m/z (ESI+) (M+H)+=327; HPLC tR=2.03 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]#[N:10])[CH:5]=[CH:4][N:3]=1.Br[CH2:12][CH2:13]Br.CCOCC.[H-].[Na+]>CS(C)=O.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2([C:9]#[N:10])[CH2:13][CH2:12]2)[CH:5]=[CH:4][N:3]=1
Reactant: BrCCBr
Reactant: N#CCc1ccnc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: N#CC1(c2ccnc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (2-bromo-pyridin-4-yl)-acetonitrile (1.20 g, 6.09 mmol) and the 1,2-dibromoethane (0.663 mL, 7.61 mmol) in a mixture of dry Et2O (5 mL) and dry DMSO (1 mL) is added to a suspension of NaH (60% dispersion in mineral oil, 585 mg, 14.6 mmol) in dry DMSO (10 mL) while controlling the resulting exotherm by cooling in a water bath, and the resulting mixture is stirred at room temperature. After 18 hours, water (10 mL) and ethyl acetate (10 mL) are added, phases are separated and the aqueous layer is extracted with ethyl acetate (3×10 mL). The combined organic layers are washed with brine (30 mL) and dried over MgSO4, filtered and concentrated. The residue is purified on SiO2 eluting with a gradient of 0-60% ethyl acetate in heptane to afford 1-(2-bromo-pyridin-4-yl)-cyclopropanecarbonitrile as a solid (ES+ m/z 223.36; 225.39).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:25])[C@@H:6]([CH3:24])[CH2:7][CH:8]([NH2:23])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:12][CH:11]=1)[CH3:3].[O:26]1[C:30](=[O:31])[CH2:29][CH2:28][C:27]1=[O:32].N1C=CC=CC=1.Cl>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:25])[C@H:6]([CH3:24])[CH2:7][C@H:8]([NH:23][C:30](=[O:31])[CH2:29][CH2:28][C:27]([OH:32])=[O:26])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:12][CH:11]=1)[CH3:3]
Reactant: CCOC(=O)[C@@H](C)CC(N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)CCC(=O)O
Reaction time: 2 h
Yield: 21.6 %

Procedure:
To a stirred solution of (S)-4-Amino-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester hydrochloric acid salt (200 mg, 0.52 mmol) and dihydrofuran-2,5-dione (68 mg, 0.68 mmol) in 8 ml CH2Cl2 was added pyridine (0.17 ml, 2.1 mmol) and the solution was stirred for 2 hours. The reaction mixture was acidified to pH=3 with 1M HCl. Solvent was removed under reduced pressure and the residue was purified by preparatory HPLC (DAICEL CHIRALCEL OD-H 21×250 mm column, 18 ml/min, 90% heptane 10% EtOH+0.1% TFA), collected a peak at 3.9 minutes, to give 50 mg (2R,4S)-4-(3-carboxy-propionylamino)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester. MS m/z 446.3 (M+H), 444.3 (M−H). LC/MS (Condition A): 1.52 min. 1H NMR (400 MHz, DMSO-d6): 1.04-1.05 (d, J=7.07 Hz, 3H), 1.09-1.13 (t, J=7.07 Hz, 3H), 1.34-1.42 (m, 1H), 1.72-1.79 (m, 1H), 2.24-2.29 (m, 2H), 2.36-2.40 (m, 21-9, 2.64-2.74 (m, 2H), 3.33 (s, 1H), 3.86-3.93 (m, 1H), 3.95-4.01 (q, J=7.33 Hz, 14.40 Hz, 2H), 7.25-7.27 (m, 2H), 7.39-7.41 (m, 1H), 7.46-7.50 (t, J=7.58 Hz, 1H), 7.61-7.64 (m, 3H), 7.70 (t, J=1.77 Hz, 1H), 7.75-7.77 (d, J=8.59 Hz, 1H), 12.08 (br s, 2H).
Reaction SMILES: [NH:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].C=O.[C:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)(=[O:16])[CH3:15].C=O.N(CC(O)=O)[CH2:28]C(O)=O.Cl>O>[C:3]([CH2:2][N:1]([CH2:28][C:22]1[CH:23]=[C:18]([NH:17][C:14](=[O:16])[CH3:15])[CH:19]=[CH:20][C:21]=1[OH:24])[CH2:6][C:7]([OH:9])=[O:8])([OH:5])=[O:4]
Reactant: O=C(O)CNCC(=O)O
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(O)c(CN(CC(=O)O)CC(=O)O)c1
Temperature: 55 °C

Procedure:
Deionized water (35.3 g), 35-3 g of 98% iminodiacetic acid (0.25 mole), and 29.9 g of 50% aqueous sodium hydroxide solution were weighed into a round-bottom reaction flask equipped with a water-cooled reflux condenser, mechanical stirrer, thermometer with a temperature controller, and an addition funnel. The mix was heated, with stirring, to a temperature of 55° C. Aqueous 37% formaldehyde solution (2 1.5 g) was placed in the addition funnel and added to the reaction flask over a 15 minute period. The reaction mixture was heated at 55° C. for approximately 45 minutes, cooled and transferred to an addition funnel. To a round-bottom flask equipped as above was added 38.7 g (0.25 mole) of 98% 4-acetamido-phenol, 35.3 g of deionized water, and 12.2 g of 50% aqueous sodium hydroxide solution. The mix was heated, with stirring, to a temperature of approximately 65° C., and the formaldehyde-iminodiacetic acid adduct solution added over a 30 minute period. The reaction mixture was heated at 65° C. for an additional twelve hours and cooled. Concentrated hydrochloric acid (55.5 g) was added and the reaction mixture stirred for one hour. The solution was allowed to stand for several weeks and then the crystalline precipitate filtered, washed with deionized water and dried in a vacuum oven at 65° C. for several hours. Approximately 17.4 g. of solids were recovered. The structure was confirmed by proton NMR. (See Table I.)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)=[O:18].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([C:17]([O:16][CH3:15])=[O:18])[CH:24]=2)=[CH:4][N:3]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cccc(-c2cnc(Cl)nc2)c1
Temperature: 110 °C
Reaction time: 10.5 h
Yield: 14.9 %

Procedure:
To a solution of 1.93 g (10.0 mmol) of 2-chloro-5-bromopyrimidine in 30 ml of toluene, 4.12 g (30.0 mmol) of potassium carbonate, 1.89 g (10.5 mmol) of 3-(methoxycarbonyl)phenylboronic acid and 1.0 g (0.87 mmol) of tetrakis(triphenyl phosphine)palladium (0) were added, and the reaction solution was stirred at 110° C. for 10.5 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=95/5-0/100 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 0.37 g of the title compound as a yellow solid (yield: 14%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[I-:11].[K+].CC1C=CC(S(NCl)(=O)=O)=CC=1>C(#N)C.O>[I:11][C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[C:6]([CH:7]=[O:8])[C:5]=1[OH:10]
Reactant: [I-]
Reactant: O=Cc1cc(Br)ccc1O
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=Cc1cc(Br)cc(I)c1O
Temperature: 50 °C
Yield: 79.5 %

Procedure:
To a solution of 5-bromosalicylaldehyde (20.0 g, 0.1 mole) and potassium iodide (17 g , 0.1 mole) in acetonitrile (150 mL) and water (50 mL) in a 500 mL round bottom flask with magnetic stirrer was added chloramine T (23 g, 0.1 mole). The mixture was allowed to react for one hour. The reaction mixture was partitioned between hydrochloric acid (10%, 200 mL) and ethyl acetate. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. To the residue was added hexanes and the reaction mixture heated to 50° C. for 15 minutes. The undissolved material was removed by filtration. The filtrate was concentrated in vacuo to leave canary yellow 3-iodo-5-bromosalicylaldehyde (26 g).
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.C([C:20]([O:22][CH3:23])=[O:21])#N>ClCCl>[CH3:23][O:22][C:20]([C:12]1[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6][N:5]=1)=[O:21]
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Reactant: COC(=O)C#N
Solvent: ClCCl
Product: COC(=O)c1nsc2nc3ccccc3n12
Temperature: 25 °C
Reaction time: 21 h
Yield: 88.9 %

Procedure:
A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-one (4.0 g, 16.2 mmole) and methyl cyanoformate (2.75 g, 32.4 mmole) in 30 mL of dichloromethane was stirred at room temperature for 21 h. The precipitate was filtered and washed with dichloromethane to give 3.36 g (84%) of 3-(methoxycarbonyl)-1,2,4-thiadiazolo [4,5-a]benzimidazole as a colourless solid: mp 208-209° C.; 1H NMR (CDCl3) δ 8.61 (d, 1H), 7.82 (d, 1H), 7.51 (t, 1H), 7.31 (t, 1H), 4.17 (s, 3H) ppm; 13C NMR (CDCl3) δ 164.02, 156.51, 150.67, 140.89, 129.34, 125.93, 122.41, 119.48, 115.41, 54.04 ppm; IR (KBr) ν 1733 cm-1 ; HRMS calcd for C10H7N3O2S 233.0259, found 233.0262. Anal. Calcd. for C10H7N3O2S: C, 51.50; H, 3.02; N, 18.02. Found: C, 51.41; H, 2.89; N, 18.16.