Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:53])[CH2:7][N:8]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[CH2:13][CH2:12][N:11]([CH2:25][CH:26]([NH:37][CH:38](C(OC(C)(C)C)=O)[C:39]([O:41]C(C)(C)C)=[O:40])[CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl.CC[O:57][CH2:58][CH3:59].[O:60]1CCOCC1>>[NH2:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][CH2:27][CH:26]([N:37]([CH2:59][C:58]([OH:57])=[O:60])[CH2:38][C:39]([OH:41])=[O:40])[CH2:25][N:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:53])=[O:5])[CH2:16][CH2:15][N:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][CH2:12]2)=[CH:31][CH:32]=1
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(CCCc2ccc(N)cc2)NC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC1
Reactant: C1COCCO1
Agent: Cl
Product: Nc1ccc(CCCC(CN2CCN(CC(=O)O)CCN(CC(=O)O)CC2)N(CC(=O)O)CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To a flask containing compound 7 (8.5 mg, 0.011 mmol) at 0-5° C. was added dropwise 4M HCl (g) in 1,4-dioxane (3 mL) over 20 min. The resulting mixture was gradually warmed to room temperature and continuously stirred for 18 h. Ether (20 mL) was added to the reaction mixture which was then stirred for 10 min. The resulting mixture was placed in the freezer for 1 h. The resulting precipitate was filtered and washed with ether. The solid product was quickly dissolved in deionized water. The aqueous solution was concentrated in vacuo to provide 8 (7.1 mg, 88%) as an off-white solid. 1H NMR (D2O, 300 MHz) δ 1.50-1.73 (m, 4H), 2.53-2.65 (m, 2H), 3.00-3.35 (m, 10H), 3.49-3.85 (m, 13H), 7.17-7.30 (m, 4H); 13C NMR (D2O, 300 MHz) δ 25.7 (t), 26.6 (t), 33.5 (t), 48.2 (t), 49.6 (t), 50.4 (t), 51.8 (t), 52.5 (t), 53.7 (t), 54.0 (t), 56.0 (t), 60.3 (d), 123.0 (d), 127.5 (s), 130.0 (d), 142.2 (s), 168.0 (s), 170.0 (s), 173.6 (s). HRMS (Positive ion FAB) Calcd for C25H40N5O8: [M+H]+ m/z 538.2877. Found: [M+H]+ m/z 538.2880.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[CH2:12][N:13]([CH3:15])[CH3:14].[CH3:16][I:17]>CCOCC>[I-:17].[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[CH2:12][N+:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC1=C(/C=C/CN(C)C)C(C)(C)CCC1
Reactant: CI
Solvent: CCOCC
Product: CC1=C(/C=C/C[N+](C)(C)C)C(C)(C)CCC1
Product: [I-]
Yield: 68.3 %

Procedure:
A solution of [3-(2,6,6-trimethyl-1-cyclohexenyl)-2(trans)-propenyl]dimethylamine (2.0 g) in dry ether (20 cc) was added to methyliodide (2.0 g), and the reaction mixture was allowed to stand over night. Precipitated crystals were gathered by filtration, and recrystallized from a mixed solvent of ethanol, benzene and ether to give colorless crystals (2.3 g) of [3-(2,6,6-trimethyl-1-cyclohexenyl)-2(trans)-propenyl]trimethylammonium iodide, m.p. 180° C.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[O:2].C([O:8][C:9](=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)C.[H-].[Na+].Cl>C(OCC)C>[CH2:4]([O:3][C:1](=[O:2])[CH:10]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH:9]=[O:8])[CH3:5]
Reactant: CCOC=O
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(C=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
Ethyl formate (7.46 g, 0.101 mol) was added dropwise to a stirred ice-cooled suspension of (4-chlorophenyl)acetic acid ethyl ester (20.0 g, 0.101 mol) and NaH (0.131 mol) in diethyl ether (100 mL). The mixture was then allowed to warm to room temperature overnight. The mixture neutralised (1 M HCl); the organic layer was isolated, dried, and the solvent removed to give 2-(4-chlorophenyl)-3-oxo-propanoic acid ethyl ester as a colourless solid (19.8 g, 87%). 1H NMR (CDCl3): δ 12.14 (d, J=12.8, 1H), 7.31-7.18 (m, 4H), 4.29 (q, J=7.2, 2H), 1.57 (br, 1H), 1.29 (t, J=7.2, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:14]1[S:15][C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]([CH:19]([CH3:21])[CH3:20])[N:18]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][N:11]([C:14]2[S:15][C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]([CH:19]([CH3:20])[CH3:21])[N:18]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1sc(Br)nc1C(C)C
Reactant: CC(C)(C)OC(=O)NC1CNC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2CC(NC(=O)OC(C)(C)C)C2)nc1C(C)C
Yield: 65.8 %

Procedure:
A solution of 3-tert-butoxycarbonylaminoazetidine (136 mg, 0.79 mmol), ethyl 2-bromo-4-isopropyl-1,3-thiazole-5-carboxylate obtained in Example (23b) (200 mg, 0.72 mmol) and diisopropylethylamine (0.25 mL, 1.44 mmol) in DMF (8 mL) was stirred at 90° C. for 11 hours. The reaction solution was diluted with ethyl acetate, and then the mixture was washed with 10% saline and dried over anhydrous magnesium sulfate. Following filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1) to obtain 175 mg of the title compound as a white solid (66%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)=[CH:11][C:9]=2[CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.ClCCl>O1CCCC1>[NH2:1][CH2:4][CH2:5][C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)=[CH:11][C:9]=2[CH:10]=1
Reactant: N#Cc1ccc(-c2ccc3oc(CCN=[N+]=[N-])cc3c2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc3oc(CCN)cc3c2)cc1
Reaction time: 72 h

Procedure:
The product from Example 162A was dissolved in 3 mL of tetrahydrofuran, and treated with triphenylphosphine (262 mg, 1 mmol) was added, along with 0.5 mL water. After 3 days, the reaction was poured into dichloromethane and washed with aqueous ammonia. The organic layer was purified by flash chromatography, eluting with 10-20% methanol/dichloromethane, (0.1% NH3) to give the title compound as a white powder. mp 118-120° C.; MS (DCI) m/z 263.0 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 3.00 (m, 2H), 3.08 (m, 2H), 6.64 (s, 1H), 7.56 (m, 2H), 7.82 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[CH2:19]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=[CH2:12]
Reactant: C=CCCCCCCBr
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: C=CCCCCCCOc1ccc(C(=O)O)cc1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
p-hydroxybenzoic acid (33.2 g), 8-bromo-1-octene (57.3 g), potassium carbonate (41.5 g) and N,N-dimethylacetamide (200 mL) were put into a 500-mL three-neck flask, and stirred at 120° C. for 5 hours. After cooled, the reaction mixture was poured into water (200 mL), extracted with ethyl acetate (500 mL), and washed two times with water (100 mL). This was dried with anhydrous magnesium sulfate and then filtered. The solvent was removed through concentration under reduced pressure, the residue was dissolved in methanol (100 mL), and a methanol solution (20 mL) of potassium hydroxide (16.8 g) was dropwise and gradually added thereto, and heated under reflux for 2 hours. After cooled, the formed crystal was collected through filtration and washed with water. This was dried to give TP-5C (63.3 g, 85%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[C:7]([Br:12])=[C:6]([CH3:13])[C:3]=1[C:4]#[N:5].C(N(C(C)C)CC)(C)C.[CH:23]1([C:26](Cl)=[O:27])CC1>C(OCC)(=O)C>[C:26]([O:10][C:9]1[C:8]([F:11])=[C:7]([Br:12])[C:6]([CH3:13])=[C:3]([C:4]#[N:5])[C:2]=1[NH2:1])(=[O:27])[CH3:23]
Reactant: O=C(Cl)C1CC1
Reactant: Cc1c(Br)c(F)c(O)c(N)c1C#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Oc1c(N)c(C#N)c(C)c(Br)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.3 %

Procedure:
2-Amino-5-bromo-4-fluoro-3-hydroxy-6-methylbenzonitrile (I-75) (7.86 g, 32.08 mmol) and diisopropylethylamine (19.5 ml, 112.2 mmol) were dissolved in ethyl acetate (300 ml), and at 0° C., cyclopropanecarbonyl chloride (4.4 ml, 48.12 mmol) was dropwise added, followed by stirring at room temperature for 16 hours under nitrogen atmosphere. After the reaction, ethyl acetate was added to the reaction liquid, followed by washing with water and saturated brine. The organic layer was concentrated under reduced pressure, the resulting residue was recrystallized with diisopropyl ether/ethyl acetate to obtain the entitled compound (8.96 g, 89%) as a white solid.
Reaction SMILES: [O-][CH2:2]C.[Na+].[NH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:20][CH3:21])=[CH:8][C:7]=1[C:22](=[O:24])[CH3:23].C(OCC)=O.Cl>COCCOC.O>[CH2:13]([O:12][C:10]1[CH:11]=[C:6]2[C:7]([C:22]([OH:24])=[CH:23][CH:2]=[N:5]2)=[CH:8][C:9]=1[O:20][CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC[O-]
Reactant: COc1cc(C(C)=O)c(N)cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CCOC=O
Solvent: COCCOC
Solvent: O
Product: COc1cc2c(O)ccnc2cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
Sodium ethoxide (74.8 g, 1.1 mol) was added to a solution of 1-(2-amino-4-benzyloxy-5-methoxyphenyl)ethanone (29.3 g, 108 mmol) in DME (700 mL) and stirred for 30 min. Ethyl formate (44 mL, 540 mmol) was added and the mixture was stirred overnight (in case of incomplete reaction, additional sodium ethoxide can be added and the reaction monitored by LC/MS). After the reaction was complete, the mixture was diluted with water (40 mL) and acidified to neutral pH with 1M HCl. The solid was filtered, washed with water and dried to afford 7-benzyloxy-6-methoxyquinolin-4-ol (22 g, 72%). 1H NMR (400 MHz, CDCl3): δ 10.7 (br s, 1H), 7.70 (s, 1H), 7.49-7.46 (t, 1H), 7.43-7.41 (br d, 2H), 7.37-7.33 (t, 2H), 7.30-7.28 (d, 1H), 6.84 (s, 1H), 6.21-6.19 (d, 1H), 5.21 (s, 2H), 3.96 (s, 3H). LC/MS (M+H=282).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[C:19]([CH3:21])[C:18]([O:22][C:23](=[O:25])[CH3:24])=[C:17]([CH3:26])[CH:16]=4)[C:4]=2[C:3]=1[CH3:27])[CH:12]=[CH:11][CH:10]=[CH:9]3.[Br:28]Br>C(Cl)Cl>[Br:28][C:7]1[C:5]2[S:6][C:2]([CH3:1])=[C:3]([CH3:27])[C:4]=2[C:14]([C:15]2[CH:16]=[C:17]([CH3:26])[C:18]([O:22][C:23](=[O:25])[CH3:24])=[C:19]([CH3:21])[CH:20]=2)=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[CH:12]2
Reactant: BrBr
Reactant: CC(=O)Oc1c(C)cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc1C
Solvent: ClCCl
Product: CC(=O)Oc1c(C)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C
Yield: 55.3 %

Procedure:
A solution of acetic acid 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenyl ester (10.0 g, 26.7 mmol) and ferric chloride (0.23 g, 1.4 mmol) in anhydrous methylene chloride (231 mL) was placed at −78C under nitrogen. The reaction mixture was protected from light and a solution of bromine (1.5 mL, 29.4 mmol) in anhydrous methylene chloride (38 mL) was added dropwise over a period of 50 min. After 30 min the reaction was quenched with dilute sodium bisulfite, diluted with water, and the resulting mixture was extracted with diethyl ether. The diethyl ether layer was washed twice with water, brine, and then dried (MgSO4). Concentration under reduced pressure and chromatography with petroleum ether:ethyl acetate (97:3, then 95:5) gave the title compound as a white solid (6.7 g, 55%): NMR (DMSO-d6): δ 8.27 (d, 1H), 7.60 (d, 1H), 7.56-7.52 (ddd, 1H), 7.38-7.34 (ddd, 1H), 7.06 (s, 2H), 2.43 (s, 3H), 2.41 (s, 3H), 2.22 (s, 6H), 1.64 (s, 3H); MS(EI): [M+], 1 bromine isotope pattern, 452/454; Anal. Calc. for C24H21BrO2S: C, 63.58, H, 4.67, N, 0.00. Found: C, 63.41, H, 4.45, N, 0.08.
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].[F:32]C1C=C(CCBr)C=CC=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[F:32][C:21]1[CH:20]=[C:19]([CH2:18][CH2:17][N:16]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]([CH3:1])([CH3:6])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Fc1cccc(CCBr)c1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCc2cccc(F)c2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl -ureido]-thiazol-5-ylsulfanyl}-propionic acid using 2-(3-fluorophenyl)ethylbromide and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [Na].[CH3:2][Sn:3](Cl)([CH3:5])[CH3:4].Cl[C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([CH3:15])[CH:9]=1>COC(OC)C.COCOC.C(COC)OC.C(OCC)C>[CH3:14][C:12]1[CH:13]=[C:8]([Sn:3]([CH3:5])([CH3:4])[CH3:2])[CH:9]=[C:10]([CH3:15])[N:11]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Cc1cc(Cl)cc(C)n1
Agent: COC(C)OC
Agent: [Na]
Solvent: CCOCC
Solvent: COCOC
Solvent: COCCOC
Product: Cc1cc([Sn](C)(C)C)cc(C)n1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 65.9 %

Procedure:
A mixture of 2,6-lutidine-N-oxide hydrochloride (48 g) and phosphorus oxychloride (110 ml) is heated 6.5 hours at reflux. After cooling the reaction mixture is carefully poured into crushed ice (1 kg). While the temperature is maintained below 15° C., concentrated ammonium hydroxide is added up to reach pH 8. The product that separates is extracted with ethyl ether (2×500 ml) which is dried and distilled off. The residue is dissolved in ethanol (400 ml) and boiled 3 hours with triethylamine (20 ml). After cooling, the solution is evaporated to dryness, treated with water (200 ml) and extracted with ethyl ether (4×150 ml). The combined extracts are dried and the solvent evaporated. The residue after distillation gives 4-chloro-2,6-dimethylpyridine (25 g), b.p. (15 mm)=67°-69° C. To a mixture of sodium (10 g, 30% dispersion in toluene) in anhydrous dimethyoxyethane (40 ml) cooled in an ice-bath and kept under argon, trimethyltin chloride (12.1 g) in dimethoxymethane (6 ml) is added over a one hour period while keeping the temperature at 0° C. The mixture is stirred 2.5 hours at 0° C.; then 4-chloro-2,6-dimethylpyridine (7 g) in dimethoxyethane is slowly dropped into. Stirring is continued for an additional hour then the reaction mixture is allowed to stand overnight at room temperature. The reaction mixture is diluted with ethyl ether (100 ml) and filtered. The solvent is evaporated, the residue dissolved in ethyl ether (100 ml) and filtered again. After evaporation of the solvent the residue is distilled giving 2,6-dimethyl-4-(trimethyl-stannyl)pyridine (8.8 g), b.p. (15 m)=130°-140° C.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[C:8](=[C:9](I)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].C[C@@H:20]1[C:24]2[NH:25][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:23]=2[C:22](=[O:37])[NH:21]1>>[C:1]([NH:5][C:6]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[C:8](=[C:9]([C:26]3[NH:25][C:24]4[CH2:20][NH:21][C:22](=[O:37])[C:23]=4[CH:27]=3)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Reactant: Cn1c(NC(C)(C)C)nc2c(I)cccc2c1=O
Product: Cn1c(NC(C)(C)C)nc2c(-c3cc4c([nH]3)CNC4=O)cccc2c1=O
Yield: 19 %

Procedure:
This compound (54 mg, 0.15 mmol, 19% yield) as a tan solid was prepared according to the procedures described for Example 287, using 2-(tert-butylamino)-8-iodo-3-methylquinazolin-4(3H)-one (701; 281 mg, 0.79 mmol), and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (706; 477 mg, 1.35 mmol) as the starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.10 (s, 1H), 7.84-7.93 (m, 1H), 7.51 (s, 1H), 7.18 (t, J=7.73 Hz, 1H), 6.80 (d, J=1.56 Hz, 1H), 5.96 (s, 1H), 4.25 (d, J=0.59 Hz, 2H), 3.48 (s, 3H), 1.51 (s, 9H). m/z (ESI, +ve) 325.1 (M+H).
Reaction SMILES: [CH3:1][C@:2]1([NH:19]C(=O)OC(C)(C)C)[CH2:6][CH2:5][C@@H:4]([CH2:7][C:8]2[N:12]=[C:11]([C:13](F)(F)F)[O:10][N:9]=2)[C:3]1([CH3:18])[CH3:17].N1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(C(Cl)=O)CCCCC1.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:13]1([C:11]2[O:10][N:9]=[C:8]([CH2:7][C@@H:4]3[CH2:5][CH2:6][C@:2]([CH3:1])([NH2:19])[C:3]3([CH3:17])[CH3:18])[N:12]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CC[C@@H](Cc2noc(C(F)(F)F)n2)C1(C)C
Agent: Cl
Agent: O=C(Cl)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)[C@H](Cc2noc(C3CCCCC3)n2)CC[C@]1(C)N
Reaction time: 3 h

Procedure:
To a solution of tert-butyl {(1S,3S)-3-[(2Z)-2-amino-2-(hydroxyimino)ethyl]-1,2,2-trimethylcyclopentyl}carbamate (prepared in Step-1 example 56)(0.3 g, 1 mmol) in toluene, pyridine (0.079 g, 1 mmol) and cyclohexanecarbonylchloride was added and stirred for 3 hours. The reaction mixture was refluxed for another 12 h. The reaction mixture diluted with ethyl acetate, washed with 0.1N HCl. Ethyl acetate layer was separated, dried and concentrated, residue purified by silica column chromatography using 20% ethyl acetate in hexane. m/z (M+1)−100: 292.1. The product that obtained was dissolved in ethyl acetate. To this a solution of saturated HCl in ethyl acetate (2 mL) was added and reaction mixture was stirred at room temperature for two hours. The volatiles were removed under reduced pressure and triturated with hexane to afford the desired product. 1H NMR (400 MHz, d6-DMSO) δ ppm: 0.8 (s, 3H), 0.9 (s, 3H), 1.2 (s, 3H), 1.42-1.50 (m, 3H), 1.52-1.72 (m, 2H), 1.89-1.92 (m, 5H), 1.95-1.98 (m, 3H), 2.13-2.15 (m, 1H), 2.51-2.54 (m, 1H), 2.74 (m, 1H), 3.02 (m, 1H), 7.95 (bs, 3H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[N:14]=[C:13]([C:15]4[CH:16]=[CH:17][C:18]([O:23][CH:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[C:19]([CH:22]=4)[CH:20]=[O:21])[O:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[BH4-].[Na+].[NH4+].[Cl-:33]>C(O)C>[ClH:33].[NH:3]1[C:4]2[CH:9]=[CH:8][C:7]([C:10]3[N:14]=[C:13]([C:15]4[CH:16]=[CH:17][C:18]([O:23][CH:24]([CH3:29])[C:25]([F:27])([F:28])[F:26])=[C:19]([CH2:20][OH:21])[CH:22]=4)[O:12][N:11]=3)=[CH:6][C:5]=2[N:1]=[CH:2]1
Reactant: CC(Oc1ccc(-c2nc(-c3ccc4nc[nH]c4c3)no2)cc1C=O)C(F)(F)F
Reactant: [Cl-]
Agent: [BH4-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: CC(Oc1ccc(-c2nc(-c3ccc4[nH]cnc4c3)no2)cc1CO)C(F)(F)F
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-[3-(1H-benzimidazol-6-yl)-1,2,4-oxadiazol-5-yl]-2-(2,2,2-trifluoro-1-methylethoxy)benzaldehyde (80 mg) in ethanol (3 ml) was added NaBH4 (9 mg) at 0° C. After stirring at room temperature for 0.5 hour, a saturated NH4Cl solution (10 ml) was added thereto, followed by extraction with EtOAc (20 ml). The organic layer was washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. To a solution of the residue (78 mg) in dioxane was added a 4M HCl/dioxane solution, followed by concentration. The resulting powder was recrystallized with IPA (10 ml) to obtain [5-[3-(1H-benzimidazol-5-yl)-1,2,4-oxadiazol-5-yl]-2-(2,2,2-trifluoro-1-methylethoxy)phenyl]methanol hydrochloride (70 mg) as white powders.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]([C:21](=[O:22])[CH2:20][Cl:19])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(Nc2c(F)cc(F)c(F)c2F)cc1
Product: Cc1ccc(N(C(=O)CCl)c2c(F)cc(F)c(F)c2F)cc1
Temperature: 90 °C
Reaction time: 1.3 h
Yield: 92.2 %

Procedure:
The mixture of N-(2′,3′,4′6′-tetrafluorophenyl)-4-methylanilin (0.82 g, 3.2 mmol) and chloro acetylchloride (1.6 g) is heated with stirring to 90° C. under nitrogen for 1.3 h. To destroy excess of the acid chloride, 2-propanol and water (2 ml each) is added and stirring is continued over night at room temperature. After adding toluene (20 ml), the mixture is extracted with sodium bicarbonate and the organic phase is dried with magnesium sulfate and evaporated to dryness. The residue is purified by flash chromatography (silica, toulene) to obtain N-(2′,3′,4′,6′-tetrafluorophenyl)-N-chloroacetyl-4-methylaniline (0.98 g, 2.95 mmol) as an oil.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][CH:8]=[C:7]([CH:11]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[C@@H:12]([C:16]3[CH:31]=[CH:30][C:19]([C:20]([NH:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:21])=[CH:18][CH:17]=3)[CH2:13][CH2:14][CH3:15])[C:6]=2[CH:5]=[C:4]([Cl:39])[CH:3]=1.[CH3:40][N:41](C=O)C>[C-]#N.[Zn+2].[C-]#N.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:39][C:4]1[CH:3]=[C:2]([C:40]#[N:41])[C:10]2[S:9][CH:8]=[C:7]([CH:11]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[C@@H:12]([C:16]3[CH:31]=[CH:30][C:19]([C:20]([NH:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:21])=[CH:18][CH:17]=3)[CH2:13][CH2:14][CH3:15])[C:6]=2[CH:5]=1
Reactant: CN(C)C=O
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(Cl)cc1)c1csc2c(Br)cc(Cl)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(Cl)cc1)c1csc2c(C#N)cc(Cl)cc12
Temperature: 80 °C

Procedure:
A degassed mixture of ethyl N-(4-{(1S)-1-[(7-bromo-5-chloro-1-benzothien-3-yl)(4-chlorophenyl)methyl]butyl}benzoyl)-β-alaninate (0.128 g, 0.198 mmol), zinc cyanide (0.046 g, 0.40 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.114 g, 0.099 mmol) in anhydrous DMF (2.9 mL) was heated at 80° C. for 2.5 hours. After cooling to room temperature, the solution was concentrated, then the residue was purified by silica gel chromatography eluting with 35% EtOAc/hexanes. The resulting material was further purified by preparative HPLC (Daicel AD-H chiral column, 2 cm×25 cm, 16% IPA/Heptane, 20 mL/min) to provide the title compound as a white solid. LC1: 4.12 min. (M+H)+ 593.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:15])[O:10][C:11]([NH:13][CH3:14])=[N:12][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:16][NH2:17]>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([NH:12][C:11]([NH:13][CH3:14])=[O:10])[C:8]=1[C:9]([NH:17][CH3:16])=[O:15]
Reactant: CN
Reactant: CNc1nc2cccc(OC)c2c(=O)o1
Solvent: CS(C)=O
Solvent: O
Product: CNC(=O)Nc1cccc(OC)c1C(=O)NC
Yield: 81.2 %

Procedure:
A mixture of 5-Methoxy-2-(methylamino)-4H-3,1-benzoxazin-4-one (1.05 g, 5.09 mmol) and methylamine (2.0 M solution in tetrahydrofuran; 12.7 ml, 25.5 mmol) in dimethylsulfoxide (2 ml) was heated in sealed tube for 15 h. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum to afford 0.980 g (81%) of the title compound.