Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[NH:10][C:8]=2[N:9]=1.I[CH2:24][CH2:25][CH2:26][CH3:27]>CN(C)C=O>[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=3[Cl:20])[C:11](=[O:22])[N:10]([CH2:24][CH2:25][CH2:26][CH3:27])[C:8]=2[N:9]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(N)nc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
To a suspension of NaH (60% in mineral oil, 34 mg) in 6 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (202 mg, 0.66 mmol). The mixture was heated to 50° C., resulting in a clear solution. 1-Iodobutane (105 μL, 0.92 mmol) was added, and the solution was stirred at 50° C. for 30 minutes, then cooled to room temperature and poured onto 40 mL of ice water. The resulting precipitate was removed by filtration and washed with water. The residue was dried and purified by flash chromatography, eluting with a gradient of 1:1 hexane:ethyl acetate to all ethyl acetate to provide 152 mg (64%) of 2-amino-8-butyl-6-(2,6-dichlorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one; mp 202-205° C.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[S:8][C:7]2[CH:9]=[C:10]3[C:15](=[C:16]([C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=4)[C:6]=2[C:5]=1[CH3:27])[CH:14]=[CH:13][CH:12]=[CH:11]3.S(=O)(O)[O-].[Na+]>ClCCl.[Fe](Cl)(Cl)Cl>[Br:1][C:9]1[C:7]2[S:8][C:4]([CH3:3])=[C:5]([CH3:27])[C:6]=2[C:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=2)=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[CH:14]2
Reactant: CC(=O)Oc1ccc(-c2c3ccccc3cc3sc(C)c(C)c23)cc1
Reactant: BrBr
Agent: Cl[Fe](Cl)Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Oc1ccc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1
Reaction time: 0.17 h
Yield: 90.8 %

Procedure:
A solution of bromine (0.326 mL, 6.15 mmol) in dichloromethane (9 mL) was added dropwise over a 15 minute period to a solution that was stirred in the absence of light of acetic acid 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester (1.87 g, 5.41 mmol) and iron (III) chloride (50 mg, 0.31 mmol) in dichloromethane (47 mL) at −78° C. under a dry nitrogen atmosphere. After 10 minutes, a dilute aqueous sodium bisulfite solution was added and the reaction mixture was partitioned between water and ether. The ether phase was washed with brine and concentrated to provide the title compound as a white solid (2.09 g, 91%): mp: 190-191° C.; NMR (DMSO-d6); 8.20 (d, J=8 Hz, 1H), 7.65 (ddd, J=8, 7, 1, 1H), 7.49 (ddd, J=8, 7, 1 Hz, 1H), 7.43-7.38 (m, 1H), 7.40 (d, J=9 Hz, 2H), 7.30 (d, J=9 Hz, 2H), 2.43 (d, J=1 Hz, 3H), 2.33 (s, 3H), 1.55 (d, J=1 Hz, 3H); MS (EI): 1 bromine isotope pattern 424 (95%, MI), 426 (100%); Anal. Calc. for C22H17BrO2S: C, 62.12, H, 4.03, N, 0.00. Found: C, 62.46, H, 4.05, N, 0.09.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([N+:14]([O-])=O)[CH:8]=2)([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([NH2:14])[CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)c1cc2ccc(N)cc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a solution of 2-tert-butyl-6-nitro-1H-indole (1.3 g, 6.0 mmol) in MeOH (10 mL) was added Raney Ni (0.2 g). The mixture was stirred at room temperature under H2 (1 atm) for 3 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was washed with petroleum ether to give 2-tert-butyl-1H-indol-6-ylamine (B-6) (1.0 g, 89%). 1H NMR (DMSO-d6) δ 10.19 (s, 1H), 6.99 (d, J=8.1 Hz, 1H), 6.46 (s, 1H), 6.25 (dd, J=1.8, 8.1 Hz, 1H), 5.79 (d, J=1.8 Hz, 1H), 4.52 (s, 2H), 1.24 (s, 9H); ESI-MS 189.1 m/z (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[N:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:31]([N:28]1[CH2:27][CH2:26][N:25]([C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:15](=[O:17])[CH2:14][C:11]3[CH:12]=[CH:13][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=4)=[N:9][CH:10]=3)=[N:24][CH:23]=2)[CH2:30][CH2:29]1)(=[O:33])[CH3:32]
Reactant: O=C(O)Cc1ccc(-c2ccnc(F)c2)nc1
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(F)c4)nc3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-(2′-fluoro-2,4′-bipyridin-5-yl)acetic acid 208-3 (42 mg, 0.18 mmol), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 (40 mg, 0.18 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 68 mg, 0.18 mmol) were added DMF (1 mL) and diispropylethyl amine (DIEA, 0.15 mL, 0.9 mmol) and the mixture was stirred at room temperature overnight. The crude product, a clear DMF solution, was subjected directly for reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(2′-fluoro-2,4′-bipyridin-5-yl)acetamide 209 as white solid. MS m/z 435.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 10.65 (s, 1H), 8.69 (d, 1H), 8.36 (d, 1H), 8.15 (d, 1H), 8.05-8.02 (m, 2H), 7.94-7.90 (m, 2H), 7.81 (s, 1H), 7.42 (dd, 1H), 3.83 (s, 2H), 3.57-3.54 (m, 4H), 3.15-3.13 (m, 2H), 3.09-3.06 (m, 2H), 2.03 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([C:7]([OH:9])=[O:8])[O:5][C@@H:4]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:3]1[OH:28].[CH2:29]([O:36][C:37]([NH:39][CH2:40][CH2:41][C:42](O)=[O:43])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:20]([NH:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@@H:4]1[O:5][C@H:6]([C:7]([OH:9])=[O:8])[C@@H:2]([NH:1][C:42](=[O:43])[CH2:41][CH2:40][NH:39][C:37]([O:36][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:38])[C@H:3]1[OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Product: O=C(CCNC(=O)OCc1ccccc1)N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Yield: 100.2 %

Procedure:
1-(6-Benzoylamino-9H-purin-9-yl)-3-(N-benzyloxycarbonyl-β-alanylamino)-1,3-dideoxy-β-D-ribofuranuronic acid (590 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid (384 mg) prepared in Example 1 with N-hydroxysuccinimide ester of N-benzyloxycarbonyl-β-alanine (450 mg) according to a similar manner to that of Example 5, mp. 136°-141° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH:15]([CH3:17])[CH3:16])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([O:28][CH3:29])[CH:22]=1>>[CH:15]([O:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([O:28][CH3:29])[CH:22]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1)([CH3:17])[CH3:16]
Reactant: CC(C)Oc1cccc(-c2ccnc(Cl)n2)c1
Reactant: COc1cc(CCN)ccc1O
Product: COc1cc(CCNc2nccc(-c3cccc(OC(C)C)c3)n2)ccc1O

Procedure:
Intermediate 45 was coupled with 4-(2-Amino-ethyl)-2-methoxy-phenol following procedure F. LC-MS showed the product had the expected M+H+ of 380. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.3 (m, 1H) 7.6 (m, 2H) 7.36 (m, 1H) 6.9 (m, 2H) 6.83 (m, 1H) 6.72 (m, 2H) 5.5 (m, 1H) 4.62 (m, 1H) 3.75 (s, 3H) 3.7 (m, 2H) 2.88 (m, 2H) 1.32 (d, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.CO.[OH-].[K+].[CH2:15](Br)[CH:16]=[CH2:17]>O>[CH2:17]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: O=C(O)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCOc1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
4-(2-Propenyloxy)benzoic acid was synthesized by Apfel's method (Apfel et al, Anal. Chem., 1985, 57, 651-658). A 1 L three-neck round-bottom flask was equipped with a condenser, 150 mL additional funnel, heating bath, and magnetic stirrer. 90 g (0.65 mol) of 4-hydroxybenzoic acid and 400 mL of methanol were added at 25° C. and stirred. After the acid was dissolved, 105 g (1.9 mol) of potassium hydroxide in 125 mL of distilled water was added dropwise. The reaction mixture was heated to reflux, and 90 g (0.74 mol) of allyl bromide was then added over a 2 hour period. The reaction mixture was allowed to reflux for 8 hours. As the reaction proceeded, potassium bromide precipitated. From this mixture, 250 mL of methanol was removed by evaporation. The remainder of the reaction mixture was cooled to 25° C. and then added to 2.5 L of distilled water. Hexane (250 mL) was added to extract organic impurities. After discarding the organic phase, the aqueous phase was heated to 40° C. and neutralized with 300 mL of 20% HCl. The crude product precipitated during the neutralization, was subsequently collected by filtration and purified by recrystallization from ethanol. Yield: 46 g (40.2%), mp 165° C.
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7](I)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>COCCOC.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>[C:22]([O:26][C:27]([N:29]1[CH2:30][CH:31]=[C:32]([C:7]2[N:6]=[C:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=23)[CH2:33][CH2:34]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
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: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2nc(C3CCC3)n3ccnc(N)c23)CC1
Temperature: 100 °C

Procedure:
To a stirred mixture of 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-amine (100.00 mg, 0.318 mmol), potassium carbonate (154.0 mg, 1.11 mmol) in DME (3.0 mL) and H2O (0.70 mL) was added 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (118.1 mg, 0.38 mmol). The solution was bubbled with nitrogen for 5 min. Then Pd(PPh3)4 (18 mg, 0.016 mmol) was added and the resulting mixture was refluxed at 100° C. for 30 min. The solvent was then removed under reduced pressure and the resulting residue was purified by a flash chromatography (2% MeOH in DCM). 1H NMR (400 MHz, MeOD) δ 1.53 (s, 9H), 1.95-2.07 (m, 1H), 2.14-2.28 (m, 1H), 2.44-2.54 (m, 4H), 2.62-2.71 (m, 2H), 3.73 (t, J=5.68 Hz, 2H), 3.87-3.98 (m, 1H), 4.12-421 (m, 2H), 5.94-6.00 (m, 1H), 6.96 (d, J=5.20 Hz, 1H), 7.33 (d, J=5.20 Hz, 1H). MS (ES+): m/z: 369.94, [MH+], HPLC: tR=2.33 min (OpenLynx, polar—5 min).
Reaction SMILES: CC(C)([O-])C.[K+].Br[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[CH3:15][O:16][N:17]([CH3:26])[C:18]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19].C1(C)C=CC=CC=1>CCOCC>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([N:23]2[CH2:24][CH2:25][CH:20]([C:18]([N:17]([O:16][CH3:15])[CH3:26])=[O:19])[CH2:21][CH2:22]2)=[CH:9][CH:10]=1
Reactant: CON(C)C(=O)C1CCNCC1
Reactant: Clc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CON(C)C(=O)C1CCN(c2ccc(Cl)cc2)CC1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 58.3 %

Procedure:
A flask containing 2-(2′-di-tent-butylphosphine)biphenylpalladium(II) acetate (0.927 g, 2.003 mmol) and potassium tert-butoxide (1.798 g, 16.03 mmol) was flushed with nitrogen and then charged with 4-bromochlorobenzene (3.07 g, 16.03 mmol), N-methoxy-N-methylpiperidine-4-carboxamide (2.3 g, 13.35 mmol) and anhydrous toluene (25 mL). The resulting mixture was stirred under nitrogen at 100° C. for 1.5 h. After this time, the reaction mixture was cooled to room temperature, diluted with ether (200 mL), washed with water and brine, dried over MgSO4 and concentrated to yield a residue. The residue was purified by flash chromatography using a 120 g silica gel cartridge and an eluent gradient from 10:1 Hex/EtOAc to 2:1 EtOAc/Hex. The fractions containing the product were pooled and concentrated on a rotary evaporator to the title compound (2.2 g, 7.78 mmol, 58.3% yield) as a yellow-green solid. LC-MS: (Waters Sunfire C18 4.6 mm×50 mm). 283.19, [M+H]; tR=1.79 min; 4 min gradient from 10/90/0.1 MeOH/H2O/TFA to 90/10/0.1 MeOH/H2O/TFA at 4 mL/min flow rate. 1H NMR (400 MHz, CDCl3) δ ppm 7.13-7.21 (2H, m), 6.81-6.87 (2H, m), 3.72 (3H, s), 3.69 (1H, t, J=3.30 Hz), 3.66 (1H, t, J=2.86 Hz), 3.19 (3H, s), 2.70-2.82 (3H, m), 1.82-1.94 (4H, m).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[N:15]1[C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][CH:17]=[N:16]1.[Cl:29][C:30]1[C:49](I)=[CH:48][C:33]([C:34]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][C:44]([F:47])([F:46])[F:45])=[CH:39][CH:38]=2)=[O:35])=[CH:32][N:31]=1>C1(C)C=CC=CC=1.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>[Cl:29][C:30]1[C:49]([C:19]2[N:15]([CH:10]3[CH2:11][CH2:12][CH2:13][CH2:14][O:9]3)[N:16]=[CH:17][CH:18]=2)=[CH:48][C:33]([C:34]([NH:36][C:37]2[CH:38]=[CH:39][C:40]([O:43][C:44]([F:45])([F:46])[F:47])=[CH:41][CH:42]=2)=[O:35])=[CH:32][N:31]=1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
K3PO4 (5.70 g, 26.8 mmol), followed by 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.73 g, 13.42 mmol) and Pd(PPh3)4 (0.517 g, 0.447 mmol) were added to a solution of 6-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 32.2, 4.0 g, 8.95 mmol) in toluene (45 mL) under an argon atmosphere. The RM was stirred at 80° C. for 5 h, filtered through Hyflo®, washed with EtOAc (100 mL) and the solvent was evaporated off under reduced pressure to give a crude product was purified by flash chromatography (Silica gel column, 80 g, n-hexane/EtOAc from 9:1 to 1:1) and triturated under n-hexane, filtered and dried to afford the title compound as a beige solid. HPLC (Condition 7) tR=7.569 min, UPLC-MS (Condition 3) tR=1.19 min, m/z=466.9 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.38-1.67 (m, 3H) 1.81-2.01 (m, 2H) 2.25-2.39 (m, 1H) 3.34-3.46 (m, 1H) 3.74-3.84 (m, 1H) 5.15 (d, J=8.21 Hz, 1H) 6.62 (s, 1H) 7.40 (d, J=8.21 Hz, 2H) 7.69 (s, 1H) 7.88 (d, J=8.99 Hz, 2H) 8.50 (s, 1H) 9.06 (s, 1H) 10.70 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:12]([C@@H:21]([CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:22])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:32](Cl)([C:45]([CH3:48])([CH3:47])[CH3:46])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>N1C=CC=CC=1>[CH2:1]([O:8][C@H:9]([C@@H:12]([C@@H:21]([CH2:23][O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[OH:22])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:10][O:11][Si:32]([C:45]([CH3:48])([CH3:47])[CH3:46])([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC[C@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](OC[C@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 128.8 %

Procedure:
To an ice-cold solution of Compound 4 (200 g, 0.47 mole) in dry pyridine (1 L), under nitrogen, was added tert-butyldiphenylsilyl chloride (130 mL, 0.50 mole, 1.05 eq.) slowly with vigorous stirring. The reaction mixture was allowed to come to room temperature and stirred overnight. The reaction was then quenched with methanol, and solvent was removed under reduced pressure. The residue was taken up in ethyl acetate and washed successively with, water (twice), 10% citric acid solution, sat. sodium bicarbonate solution, and brine. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 5 (400 g) in 98% yield. The material was of sufficient purity to be used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[O:5][CH:6]([CH2:21][CH3:22])[C:7]([NH:9][C:10]([CH3:20])([CH3:19])[C:11]#[C:12][CH2:13][CH2:14][CH2:15][S:16]([CH3:18])=[O:17])=[O:8].ClC1C=CC=C(C(OO)=[O:35])C=1.CCCCCC.C(OCC)(=O)C>ClCCl>[Cl:26][C:24]1[CH:23]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:25]=1)[O:5][CH:6]([CH2:21][CH3:22])[C:7]([NH:9][C:10]([CH3:19])([CH3:20])[C:11]#[C:12][CH2:13][CH2:14][CH2:15][S:16]([CH3:18])(=[O:35])=[O:17])=[O:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCCCS(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCCCS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(3,5-dichlorophenoxy)-N-(6-methyl-1-methylsulphinyl-hept-4-yn-6-yl) butyramide (0.10 g) in dichloromethane (5 ml) at 0° C. was added 3-chloroperbenzoic acid (0.060 g, 70%, stabilised with water). The mixture was stirred for 0.5 hours at 0° C., then for 1 hour at ambient temperature and stored for 18 hours. The solvent was evaporated under reduced pressure and the residue dissolved in diethyl ether, washed with a saturated aqueous solution of sodium hydrogen carbonate (three times) and water (twice), dried over magnesium sulphate and then evaporated under reduced pressure to give a colourless oil. The oil was fractionated by chromatography (silica; hexane/ethyl acetate, 2:1 by volume) to give the required product as a pale yellow oil, 0.040 g, 1H NMR (CDCl3) δ: 0.98-1.02(3H, t); 1.56(3H, s); 1.58(3H, s); 1.92-2.00(4H, m); 2.36-2.40((2H, t); 2.96(3H, s); 3.22-3.26(2H, m); 4.38-4.42(1H, t); 6.26(1H, s); 6.84(2H, s); 7.02(1H, s).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][C@H:4]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.FC(F)(F)C(O)=O.[NH2:26][CH:27]([CH2:37][CH3:38])[C@@H:28]([C:30]1[N:34]=[C:33]([CH2:35][CH3:36])[O:32][N:31]=1)[OH:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:35]([C:33]1[O:32][N:31]=[C:30]([CH:28]([OH:29])[C@@H:27]([NH:26][C:5](=[O:7])[C@@H:4]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[CH2:3][C:2]([CH3:1])([CH3:18])[CH3:17])[CH2:37][CH3:38])[N:34]=1)[CH3:36]
Reactant: CC(C)(C)C[C@H](CC(=O)N1CCOCC1)C(=O)O
Reactant: CCc1nc([C@@H](O)C(N)CC)no1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc(C(O)[C@H](CC)NC(=O)[C@@H](CC(=O)N2CCOCC2)CC(C)(C)C)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
A solution of (R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid (200 mg, 0.778 mmol) in dimethylformamide (10 ml) was treated successively with (S)-2-Amino-1-(5-ethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol; compound with trifluoro-acetic acid (233 mg, 0.779 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (296 mg, 0.779 mmol) and diisopropylethylamine (0.271 ml, 1.559 mmol). Reaction stirred at room temperature overnight. Solvent evaporated under reduced pressure. Residue taken up in ethyl acetate and washed with 1N hydrochloric acid, saturated aqueous bicarbonate solution and water, dried over Na2SO4 and solvent evaporated under reduced pressure to give (R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid {(S)-1-[(5-ethyl-1,2,4-oxadiazol-3-yl)-hydroxy-methyl]-propyl}-amide as a yellow solid (277 mg).
Reaction SMILES: [Br:1][CH2:2][CH2:3][NH2:4].[C:5](Cl)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>ClCCl>[Br:1][CH2:2][CH2:3][NH:4][C:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: BrCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 62.7 %

Procedure:
To a solution of 2-bromoethanamine (5.00 g) and trityl chloride (6.80 g) in dichloromethane (24 mL) was slowly added triethylamine (7.48 mL) under ice-cooling, and the reaction mixture was stirred under ice-cooling for 2 hr. The resulting solid was removed by filtration, the filtrate was poured into water, and the mixture was extracted with dichloromethane. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from dichloromethane/cyclohexane to give the title compound (5.60 g).
Reaction SMILES: [CH:1]1([N:5]2[C:9]3[CH:10]=[CH:11][C:12]([CH2:14]O)=[CH:13][C:8]=3[N:7]([CH3:16])[C:6]2=[O:17])[CH2:4][CH2:3][CH2:2]1.CS([Cl:22])(=O)=O>ClCCl.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>[Cl:22][CH2:14][C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[C:6](=[O:17])[N:7]([CH3:16])[C:8]=2[CH:13]=1
Reactant: Cn1c(=O)n(C2CCC2)c2ccc(CO)cc21
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(=O)n(C2CCC2)c2ccc(CCl)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
1-Cyclobutyl-5-hydroxymethyl-3-methyl-1,3-dihydro-benzoimidazol-2-one (13.79 g, 59.4 mmol) was diluted with dichloromethane (300 mL) and triethylamine (12.4 mL). The reaction was cooled to 0° C. and methanesulfonyl chloride (6.9 mL, 89.1 mmol) was added. The mixture was stirred for 1 hour at 0° C. then was diluted with saturated sodium bicarbonate and extraced into dichloromethane. The organic layer was dried over sodium sulfate and concentrated. The resulting oil was filtered through silica gel using ethyl acetate containing 1% triethylamine as eluent to give 11.92 g of 5-Chloromethyl-1-cyclobutyl-3-methyl-1,3-dihydro-benzoimidazol-2-one.