Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9](I)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.C1COCC1.C(N(CC)CC)C.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27]>C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: C#C[Si](C)(C)C
Reactant: Ic1ccc(OCC2CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1ccc(OCC2CC2)cc1
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a solution of 1-(cyclopropylmethoxy)-4-iodobenzene (2.49 g, 9.09 mmol) and copper(I) iodide (86.6 mg, 0.455 mmol) in a mixed solvent of THF-triethylamine (8 mL-2 mL) was added bis(triphenylphosphine)palladium(II) chloride (319 mg, 0.455 mmol), and the mixture was deaerated. Trimethylsilylacetylene (1.54 mL, 10.9 mmol) was added dropwise thereto, and the mixture was stirred under a nitrogen atmosphere for 30 min. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solution was purified by basic silica gel column chromatography (ethyl acetate), and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=9:1) to give the title compound (1.52 g, yield 69%) as an oil.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].C([Li])CCC.[C:17]1([CH2:23][C:24](OC)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.CCCCCC.C(O)(=O)C>[O:25]=[C:24]([CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)Cc1ccccc1
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)Cc1ccccc1)OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 29 %

Procedure:
A solution of 6.2 g (50 mmoles) dimethyl methylphosphonate (Aldrich) in 125 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 21 ml of 2.37 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 18 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 7.5 g (50.0 mmole) methyl phenylacetate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 3.5 hours at -78°, the reaction mixture was allowed to warm to ambient temperature, neutralized with 6 ml acetic acid and rotary evaporated (water aspirator) to a white gel. The gelatinous material was taken up in 75 ml water, the aqueous phase extracted with 100 ml portions of chloroform (3x), the combined organic extracts were backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p. 134°-5° (<0.1 mm) to give 3.5 g (29% dimethyl 2-oxo-3-phenylpropylphosphonate (2a).
Reaction SMILES: [ClH:1].FC1C=C2C(=CC=1)NC=C2[C@H:12]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)[C@@H:13]([OH:17])[CH2:14][NH:15][CH3:16].[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)N([C@@H](C1C=CC=CC=1)[C@H](O)COS(C1C=CC(C)=CC=1)(=O)=O)C=[CH:29]2.[CH3:56][NH2:57]>>[ClH:1].[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:57]([C@@H:12]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)[C@H:13]([OH:17])[CH2:14][NH:15][CH3:16])[CH:56]=[CH:29]2
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](c2ccccc2)n2ccc3cc(F)ccc32)cc1
Reactant: CNC[C@H](O)[C@@H](c1cccc(F)c1)c1c[nH]c2ccc(F)cc12
Reactant: CN
Agent: Cl
Product: CNC[C@@H](O)[C@H](c1cccc(F)c1)n1ccc2cc(F)ccc21

Procedure:
In an analogous manner to EXAMPLE 5, (1S,2R)-1-(5-fluoro-1H-indol-3-yl)-1-(3-fluorophenyl)-3-(methylamino)propan-2-ol hydrochloride was prepared from (2S,3S)-toluene-4-sulfonic acid 3-(5-fluoro-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester and methylamine as a light tan solid. MS (ES) m/z 317.2; HRMS: calcd for C18H18F2N2O+H+, 317.14599; found (ESI, [M+H]+), 317.1472.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1.[CH:18]12[CH2:25][CH:22]([CH2:23][CH2:24]1)[C:21](=[O:26])[O:20][C:19]2=O>>[N:17]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[N:9]1[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]2[C:19](=[O:20])[CH:18]3[CH2:25][CH:22]([CH2:23][CH2:24]3)[C:21]2=[O:26])[CH2:11][CH2:10]1
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Reactant: O=C1OC(=O)C2CCC1C2
Product: O=C1C2CCC(C2)C(=O)N1CCCCN1CCN(c2ncccn2)CC1
Yield: 34 %

Procedure:
The title compound was prepared from 1.92 g (8.2 mmol) of 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine and 1.14 g (8.14 mmol) of 3-oxabicyclo[3.2.1]octan-2,4-dione, substantially following the procedure of Example 1. Yield: 1.0 g (34% yield).
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][C:10]2([S:17][C:18]3[CH:23]=[CH:22][C:21]([C:24](=[O:31])[CH2:25][CH2:26][C:27]([O:29]C)=[O:28])=[CH:20][CH:19]=3)[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[OH:16])=[C:6]([CH2:34][CH2:35][CH3:36])[C:5]=1[OH:37])(=[O:3])[CH3:2].[OH-].[Na+]>>[C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][C:10]2([S:17][C:18]3[CH:19]=[CH:20][C:21]([C:24](=[O:31])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:22][CH:23]=3)[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[OH:16])=[C:6]([CH2:34][CH2:35][CH3:36])[C:5]=1[OH:37])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCC2(Sc3ccc(C(=O)CCC(=O)OC)cc3)CCCCC2O)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Product: CCCc1c(OCC2(Sc3ccc(C(=O)CCC(=O)O)cc3)CCCCC2O)ccc(C(C)=O)c1O

Procedure:
The isomer of the title compound of Step A of Example 2 was treated with sodium hydroxide as described in Step E of Example 1 to afford the title compound, m.p. 65°-67° remelts at 125°-127° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH2:16](O)[CH3:17]>C1C=CC=CC=1>[OH:1][C:2]1[C:3]([C:8]([O:10][CH2:16][CH3:17])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)c1ncccc1O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCOC(=O)c1ncccc1O
Yield: 58 %

Procedure:
To a stirred solution of 5.0 g (36 mmol) of 3-hydroxylpicolinic acid in 120 mL ethanol and 40 ml benzene was added 2.0 ml of 98% sulfuric acid. The reaction was refluxed for 40 h. After the solvents were evaporated, the residue was dissolved in 100 ml of water, neutralized with saturated sodium bicarbonate solution and extracted with dichloromethane 3 times. The combined organics were dried over magnesium sulfate, filtered and evaporated in vacuo to afford 3.5 g (58% yield) of the title compound as a brown residue that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])=[C:4]([NH:14][C@H:15]([OH:18])[CH2:16][OH:17])[N:3]=1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].N1C=CN=C1>CN(C=O)C>[Si:19]([O:17][CH2:16][C@H:15]([NH:14][C:4]1[C:5]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])=[C:6]([Cl:8])[N:7]=[C:2]([Cl:1])[N:3]=1)[OH:18])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CN(C)C(=O)c1c(Cl)nc(Cl)nc1N[C@H](O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1c(Cl)nc(Cl)nc1N[C@H](O)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the subtitle product of step iv) (0.50 g) in DMF (10 ml) was added tert-butyldimethylsilyl chloride (0.51 g) at −10° C. in portions. To this mixture was then added imidazole in portions. The mixture was then stirred at 0° C. for 1 h and allowed to come to room temperature and stirred for 16 h. The mixture was quenched with water and extracted with EtOAc (2×250 ml). The combined organics were washed with water (3×20 ml) and brine (3×20 ml), the organic layer dried (MgSO4) and the solid filtered. The filtrate was evaporated to dryness and the residue chromatographed on silica gel eluting with EtOAc/isohexane (1:1) to yield the subtitle compound as an oil. Yield 1.0 g.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15]([CH:16]([CH3:18])[CH3:17])=[C:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:13](=[O:26])[NH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:33]([O:39][C@@H:40]1[C@@H:45]([O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@H:44]([O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:43]([CH2:60][O:61][C:62](=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64])[O:42][C@@H:41]1Br)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35].O>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[C:15]([CH:16]([CH3:18])[CH3:17])=[C:14]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:13]([O:26][C@@H:41]2[O:42][C@H:43]([CH2:60][O:61][C:62](=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64])[C@@H:44]([O:53][C:54](=[O:59])[C:55]([CH3:56])([CH3:57])[CH3:58])[C@H:45]([O:46][C:47](=[O:52])[C:48]([CH3:49])([CH3:50])[CH3:51])[C@H:40]2[O:39][C:33](=[O:38])[C:34]([CH3:37])([CH3:35])[CH3:36])=[N:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: CC(C)c1c(Cc2ccccc2)c(=O)[nH]n1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)c1c(Cc2ccccc2)c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)nn1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 58.8 %

Procedure:
To a solution of 1-benzyloxycarbonyl-4-benzyl-5-isopropyl-1,2-dihydro-3H-pyrazol-3-one (0.16 g) in acetonitrile (5 mL) were added potassium carbonate (0.0757 g) and 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (0.278 g) successively under stirring at room temperature. In addition, the mixture was stirred at 50° C. for 4 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/6) to give 1-benzyloxycarbonyl-4-benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole (0.228 g).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[CH2:13][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br:19]Br>C(Cl)(Cl)Cl>[Br:19][CH:13]1[CH2:12][C:11]2[C:15](=[CH:16][CH:17]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:10]=2)[C:14]1=[O:18]
Reactant: BrBr
Reactant: CCCCCCCCc1ccc2c(c1)CCC2=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCc1ccc2c(c1)CC(Br)C2=O
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
To a solution of 2 (1.094 g, 4.48 mmol) in CHCl3 (10 mL) at 40° C. was added Br2 (0.23 mL, 4.477 mmol) dropwise over 15 minutes. The reaction was left to stir for 30 minutes. The resulting solution was concentrated and purified with silica gel chromatography eluding with hexanes-EtOAc (9:1). The reaction provided 3 (1.212 g, 3.75 mmol, 84%) as an orange liquid.
Reaction SMILES: [CH2:1](OC(OCC)CBr)[CH3:2].Cl.[NH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)[CH:15]=[CH:14][N:13]=1.C([O-])(O)=O.[Na+]>O.O1CCOCC1.CO>[N:11]1[CH:1]=[CH:2][N:13]2[CH:14]=[CH:15][C:16]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:12]=12
Reactant: Nc1cc(-c2ccc(C=O)cc2)ccn1
Reactant: CCOC(CBr)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccc(-c2ccn3ccnc3c2)cc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A mixture of bromoacetaldehyde diethyl acetal (0.49 mL, 23.3 mmol, 2.0 equiv) and concentrated HCl (0.05 mL, 0.4 equiv) in water (10 mL) was stirred at 23° C. for 2 h, then heated at 80° C. for 30 min. The mixture was allowed to cool to 23° C., and 4-(2-aminopyridin-4-yl)benzaldehyde (2-2, 323 mg, 1.63 mmol, 1 equiv) and NaHCO3 (324 mg, 3.91 mmol, 2.40 equiv) were added. The resulting mixture was then heated to 50° C. where MeOH (2 mL) and dioxane (3 mL) were added to increase solubility. The reaction mixture was stirred at 50° C. for 18 h, then concentrated. The residue was partitioned between EtOAc (200 mL) and brine (200 mL). The organic layer was concentrated to provide 4-imidazo[1,2-a]pyridin-7-ylbenzaldehyde (2-3) as a brown solid. LRMS m/z (M+H) Calcd: 223.2, found 223.0.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C[Si]([C:17]#[N:18])(C)C>[I-].[Zn+2].[I-]>[OH:10][CH:9]([C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:12][CH:11]=1)[C:17]#[N:18]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)Cc1ccc(C=O)cc1
Agent: [I-]
Agent: [Zn+2]
Product: CC(C)Cc1ccc(C(O)C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.5 %

Procedure:
Zinc iodide (0.21 g) was added to a mixture of 4-isobutylbenzaldehyde (6.5 g) and trimethylsilylcyanide (5.0 g). The mixture was stirred at room temperature for 30 minutes and partitioned between ethyl acetate and 7% hydrochloric acid. The organic layer was washed with 7% hydrochloric acid and water and dried over magnesium sulfate. The solvent was removed in vacuo to give 2-hydroxy-2-(4-isobutylphenyl)acetonitrile as a yellow oil (8.15 g).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.CCCCCC.[NH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+].[CH2:28]([CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH2:29][CH2:30][CH3:31]>O1CCCC1.O>[CH2:28]([CH:32]1[CH2:37][CH2:36][N:35]([CH2:1][CH2:2][CH2:3][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH2:34][CH2:33]1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCC1CCNCC1
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)CCCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC1CCN(CCCN2CCCc3ccccc32)CC1
Reaction time: 0.5 h
Yield: 35 %

Procedure:
A solution of n-butyllithium in hexane (1.5M, 7.3 mL, 11 mmol) was added drop wise to a solution of 1,2,3,4-tetrahydro-quinoline (1.256 mL, 10 mmol) in tetrahydrofuran (10 mL) at −78° C. under an atmosphere of argon. The reaction mixture was stirred for ½ h then 1-chloro-3-iodropropane (1.0 mL, 9.5 mmol) was added. The reaction mixture was stirred at −78° C. for ½ h then stirred for additional 16 h at room temperature. Tetrahydrofuran was evaporated off and the solid was dissolved in acetonitrile (10 mL). KI (1.83 g, 11 mmol), K2CO3 (2.76 g, 20 mmol) and 4-butylpiperidine (1.66 mL, 10 mmol) were added. The slurry was stirred at 50° C. for 48 h then water (10 mL) was added and the product was extracted with ethyl acetate (2×20 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The product was purified by column chromatography (eluent: ethyl acetate) to give the title compound (1.11 g, 35%) Oxalate-salt was prepared from oxalic acid (1.1 eq.) in acetone HPLC-MS: M+1+=315.1 (MS(%)=95). 1H NMR (400 MHz, CDCl3): δ=0.89 (3H, t), 1.18-1.34 (9H, m), 1.64-1.70 (2H, m), 1.79 (2H, quin.), 1.85-1.98 (4H, m), 2.36 (2H, t), 2.74 (2H, t), 2.92 (2H, broad d), 3.24-3.31 (4H, m), 6.54 (1H, ddd), 6.60 (1H, dd), 6.93 (1H, dd), 7.03 (1H, ddd). 13C NMR (CDCl3): δ 14.3, 22.5, 23.1, 24.2, 28.4, 29.3, 32.7, 36.0, 36.5, 49.6, 49.8, 54.4, 56.7, 110.9, 115.5, 122.5, 127.3, 129.3, 145.6.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH:20]([CH3:22])[CH3:21])C(OC(=O)C)C#N)=O)C1C=CC=CC=1.Cl.C1([O:30]C)C=CC=CC=1.[O:32]1[CH2:37][CH2:36][O:35]CC1>>[NH2:11][C@@H:12]([CH:20]([CH3:22])[CH3:21])[CH:36]([OH:35])[C:37]([OH:32])=[O:30]
Reactant: CC(=O)OC(C#N)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reactant: C1COCCO1
Reactant: COc1ccccc1
Agent: Cl
Product: CC(C)[C@H](N)C(O)C(=O)O
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution containing 3-(S)-[(benzyloxycarbonyl)amino]-2-acetoxy-4-methylpentanenitrile (see example 1 of WO 96/16080) (15.2 g, 50.0 mmol) in 183 mL of dioxane was added 183 mL of concentrated hydrochloric acid and 7.45 mL of anisole. The reaction mixture was heated to reflux overnight. The hydrolysis reaction was allowed to cool to room temperature and then concentrated in vacuo. The resulting aqueous solution was extracted with ether (2×). The aqueous phase was placed on a Dowex 50X8-100 column (H+ form, preeluted with deionized water to pH=7). The column was eluted with 2.0 N ammonium hydroxide and the pure fractions concentrated to afford 5.53 g (75%) of 3-(S)-amino-2-(R,S)-hydroxy-4-methylpentanoic acid as a pale yellow solid. FAB MS [M+H] m/z; Calcd: 148, Found: 148.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH:27]([F:29])[F:28])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[Li+].[OH-].O>C1COCC1.O.CO>[C:30]1([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH:27]([F:28])[F:29])[CH2:24][CH2:25]3)[C:11]([C@H:13]3[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]3)=[O:12])[CH:8]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=1
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(CC(F)F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCCCC3)sc2C(=O)O)C2CCN(CC(F)F)CC2)CC1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 5-cyclohex-1-enyl-3-[[1-(2,2-difluoro-ethyl)-piperidin-4-yl]-(trans-4-methylcyclohexanecarbonyl)amino]-thiophene-2-carboxylic acid methyl ester (40 mg, 0.08 mmol) in THF:H2O:MeOH (3:1:2) (1 mL), was added LiOH in water (1N) (0.16 mL, 0.16 mmol). The reaction mixture was stirred at 70° C. for 5 h. The mixture was concentrated under reduced pressure on a rotary evaporator and the residue was treated with a solution of 0.1 N HCl and extracted in EtOAc. The EtOAc layer was dried over Na2SO4. Filtration and removal of the solvent under reduced pressure on a rotary evaporator followed by HPLC purification afforded 5-cyclohex-1-enyl-3-[[1-(2,2-difluoro-ethyl)-piperidin-4-yl]-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (9.0 mg, 39%) as a foam.
Reaction SMILES: [Cl:1][C:2]1[C:44]([Cl:45])=[CH:43][C:5]2[NH:6][C:7]([O:9][CH:10]([C:19]3([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([C:41]#[N:42])[CH:36]=5)=[CH:31][CH:30]=4)[CH2:24][CH2:23][N:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:21][CH2:20]3)COCC[Si](C)(C)C)=[N:8][C:4]=2[CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:44]([Cl:45])=[CH:43][C:5]2[NH:6][C:7]([O:9][CH2:10][C:19]3([C:29]4[CH:30]=[CH:31][C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([C:41]#[N:42])[CH:36]=5)=[CH:33][CH:34]=4)[CH2:20][CH2:21][N:22]([S:25]([CH3:28])(=[O:26])=[O:27])[CH2:23][CH2:24]3)=[N:8][C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCOCC(Oc1nc2cc(Cl)c(Cl)cc2[nH]1)C1(c2ccc(-c3cccc(C#N)c3)cc2)CCN(S(C)(=O)=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCC(COc2nc3cc(Cl)c(Cl)cc3[nH]2)(c2ccc(-c3cccc(C#N)c3)cc2)CC1
Temperature: 60 °C
Yield: 44.9 %

Procedure:
To a solution of 0.044 g of crude 4′-{4-[5,6-dichloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxymethyl]-1-methanesulfonyl-piperidin-4-yl}-biphenyl-3-carbonitrile from the previous step (˜0.05 mmol) in 2 mL of tetrahydrofuran was added tetrabutylammonium fluoride (1M in THF, 0.1 mL, 0.1 mmol, 2 eq) and the resulting mixture was heated to 60° C. for 18 h. After cooling to room temperature, the reaction mixture was diluted with 10 mL of ethyl acetate and washed with H2O and saturated brine. The organic extracts were combined and dried over Na2SO4, filtered and concentrated by rotary evaporation to give the crude product as a pale foam. Purification by flash silica gel chromatography eluting with a gradient of 20-70% ethyl acetate in hexane gave a pale foam which was re-purified by reverse phase preparative HPLC to yield 0.016 g of the desired product 4′-[4-(5,6-dichloro-1H-benzoimidazol-2-yloxymethyl)-1-methanesulfonyl-piperidin-4-yl]-biphenyl-3-carbonitrile 56 as a white foam. 1H NMR (300 MHz, CDCl3): δ 7.84-7.83 (t, 1H), 7.80-7.77 (dt, 1H), 7.66-7.44 (m, 8H), 4.54 (s, 2H), 3.64-3.40 (d, 2H), 3.02-2.95 (t, 2H), 2.74 (s, 3H), 2.60 (br. s, 1H), 2.47-2.43 (d, 2H), 2.22-2.12 (t, 2H). MS (ESI): Calcd m/z for C27H24Cl2N4O3S.H+=554.1. Found m/z=554.6/556.7 [(M+1)+/(M+3)+].
Reaction SMILES: C(N(CCCC)CCCC)CCC.C(O)=O.I[C:18]1[C:19]([O:32][CH2:33][C:34]([C:36]2[S:40][CH:39]=[C:38]([C:41]([O:43][CH3:44])=[O:42])[CH:37]=2)=[CH2:35])=[CH:20][C:21]2[C:22]([CH3:31])([CH3:30])[CH2:23][CH2:24][C:25]([CH3:29])([CH3:28])[C:26]=2[CH:27]=1>C(#N)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:35][C:34]1([C:36]2[S:40][CH:39]=[C:38]([C:41]([O:43][CH3:44])=[O:42])[CH:37]=2)[CH2:33][O:32][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][C:18]1=2)[C:25]([CH3:29])([CH3:28])[CH2:24][CH2:23][C:22]3([CH3:31])[CH3:30]
Reactant: C=C(COc1cc2c(cc1I)C(C)(C)CCC2(C)C)c1cc(C(=O)OC)cs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O=CO
Solvent: CCCCN(CCCC)CCCC
Solvent: CC#N
Product: COC(=O)c1csc(C2(C)COc3cc4c(cc32)C(C)(C)CCC4(C)C)c1
Temperature: 60 °C

Procedure:
A mixture of tributylamine (3.64 ml, 25.16 mmol), palladium diacetate (74 mg, 0.33 mmol), formic acid (0.28 ml, 7.28 mmol) and methyl 5-[1-(3-iodo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yloxymethyl)-vinyl]-3-thiophenecarboxylate (3.38 g, 6.62 mmol) in acetonitrile (100 ml), was heated at 60° C. for 4 h. The reaction medium was concentrated in a rotary evaporator under vacuum at 40° C., treated with water and extracted with ethyl ether. After decantation, the organic phase was washed twice with water, dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[Br:16]Cl>C(Cl)CCl.CCOCC>[Br:16][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:15])=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: ClBr
Solvent: ClCCCl
Solvent: CCOCC
Product: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of 2,6-di-tert-butylphenol (2.06 g, 10 mmol) in EDC (50 mL) in a 200-mL round bottom flask, was added the stabilized BrCl brominating reagent (12 mL, about 11 mmol) dropwise, with stirring at room temperature. Initially, the orange reddish color of the reagent disappeared quickly. The color from the last 1 mL persisted for several minutes. The reaction mixture was allowed to stand for 30 minutes before being quenched with a few drops of sodium sulfite solution. After phase separation, it was diluted with EDC (50 mL), washed with water (100 mL) and dried (Na2SO4). The organic layer was concentrated under reduced pressure to afford a glue-like material. The material was redissolved in ether (10 mL) and after solvent removal, a crystalline solid 4-bromo-2,6-di-tert-butylphenol product (2.63 g, 92% recovered yield) was obtained in high purity (>98% by GC).