Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[F:11][C:12]1[CH:13]=[C:14]([NH:18]N)[CH:15]=[CH:16][CH:17]=1>C(O)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]2[C:7]3[CH2:8][NH:3][CH2:4][CH2:5][C:6]=3[NH:18][C:14]=2[CH:13]=1
Reactant: NNc1cccc(F)c1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Fc1ccc2c3c([nH]c2c1)CCNC3
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
4-Piperidone hydrochloride monohydrate (4.55 g) and 3-fluorophenylhydrazine hydrochloride (4.85 g) were added to ethanol (80 ml) and the mixture was heated under reflux for one hour. Hydrogen chloride gas was bubbled into the mixture and refluxing was recommenced for another 1.5 hours. The solution was cooled to 0° C., the hydrochloride was filtered off, washed with ethanol, dissolved in boiling water, decolourised with activated charcoal and filtered. 2M Sodium hydroxide solution was added to the warm solution until it was neutral when tested with pH paper. The pale cream solid was filtered off, washed with water and dried. Recrystallisation from acetonitrile gave a white solid which was a mixture of 7-fluoro and 9-fluoro-isomers in a ratio of 86:14 respectively (HPLC).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][C@H:18]2[CH2:31]SC2C=CC=CC=2)[C:13]1=[O:39])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.O.[Ni]>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH2:19][C@H:18]2[CH3:31])[C:13]1=[O:39])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CSc2ccccc2)C1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Yield: 53 %

Procedure:
tert-Butyl (1R,3R,4S)-4-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-3-(phenylthiomethyl)cyclohexylcarbamate (150 mg) was dissolved in EtOH (2 mL) prior to the addition of Raney 2800 nickel (100 mg) in water. The reaction was heated at reflux for 12 h. After cooling to rt, the reaction was concentrated. The resulting residue was purified by flash chromatography to afford tert-butyl (1R,3R,4S)-4-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-3-methylcyclohexylcarbamate (64 mg). MS found: (M+H)+=446.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([OH:14])=[O:13])=[CH:6]2.Cl.[CH2:16](O)[CH2:17][CH3:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH2:16][CH2:17][CH3:18])=[O:13])=[CH:6]2
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: CCCO
Agent: Cl
Product: CCCOC(=O)c1cc2cc(OC)ccc2[nH]1
Yield: 88 %

Procedure:
To a suspension of 300 (670 mg, 3.50 mmol) in anhydrous n-PrOH (20 mL) was added HCl (4 N in dioxane, 2.5 mL). The reaction mixture was heated at reflux for 36 h. Upon completion, volatiles were evaporated in vacuo and the resulting oil was purified by chromatography (0% to 20% EtOAc/hexanes) to produce a white powder (721 mg, 88%): mp 104-107° C. TLC Rf 0.51 (20% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3) δ 8.82 (s, 1H), 7.32-7.31 (d, 1H, J=8.94 Hz), 7.15 (m, 1H), 7.08 (d, 1H, J=2.4 Hz), 7.01-6.99 (dd, 1H, J1=8.94 Hz, J2=2.46 Hz), 4.32-4.29 (t, 2H, J=6.72 Hz), 3.85 (s, 3H), 1.84-1.78 (sex, 2H, J=7.38 Hz), 1.05-1.03 (t, 3H, J=7.38 Hz). 13C NMR (150 MHz, CDCl3) δ 162.0, 154.7, 132.1, 127.88, 127.85, 117.0, 112.7, 108.2, 102.5, 66.5, 55.7, 22.2, 10.5. Elemental analysis calculated for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: C, 66.87; H, 6.44; N; 6.00.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH3:35])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])C.[OH-].[Na+]>CO>[CH3:35][C:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:24]=[CH:25][C:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:27][CH:28]=3)[O:20][C:21]=2[CH3:22])=[CH:12][CH:13]=1)([CH3:6])[C:4]([OH:36])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Reaction time: 0.5 h
Yield: 67 %

Procedure:
2-Methyl-2-{4-[2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethoxy]phenoxy}propionic acid ethyl ester (12.0 g, 24.7 mmol) was dissolved in methanol (200 mL) and 2N NaOH (150 mL) was added. The resulting cloudy solution became clear after 30 min and the reaction was stirred vigorously overnight. The solution was concentrated under reduced pressure, diluted with H2O (100 mL) and acidified to pH=1 with 5N HCl. The mixture was extracted with ethyl acetate (2×200 mL), dried (MgSO4), and concentrated under reduced pressure to provide an oil. The oil (8.23 g) was recrystallized from ethyl acetate (24 mL) and hexanes (56 mL) to afford 2-methyl-2-{4-[2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethoxy]phenoxy}propionic acid (7.57 g, 67%) as colorless needles after drying at 50° C. under vacuum for 6 h: Rf=0.14 in 35% ethyl acetate/hexanes; mp 123-124° C.; 1H NMR (400 MHz, CDCl3) δ8.05 (d, J=8.0 Hz, 2H), 7.67 (d, J=8.0 Hz, 2H), 7.66-7.63 (m, 2H), 7.46 (t, J=7.6 Hz, 2H), 7.38 (t, J=7.6 Hz, 1H), 6.91-6.79 (m, 4H), 4.21 (t, J=6.4 Hz, 2H), 3.01 (t, J=6.4 Hz, 2H), 2.40 (s, 3H), 1.53 (s, 6H); MS m/e calculated. for C28H28NO5 (M++1) 458.2, found 458.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=2[NH2:18])=[N:6][CH:7]=1.[Cl:20]N1C(=O)CCC1=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[C:14]([Cl:20])[CH:13]=[C:12]([O:16][CH3:17])[C:11]=2[NH2:18])=[N:6][CH:7]=1
Reactant: COc1cccc(C(=O)Nc2ccc(Cl)cn2)c1N
Reactant: O=C1CCC(=O)N1Cl
Solvent: c1ccccc1
Product: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1N
Temperature: 52.5 °C
Yield: 91.5 %

Procedure:
To N-(5-chloropyridin-2-yl)-2-amino-3-methoxybenzamide (39 g, 140 mmol) in benzene (2 L) was added N-chlorosuccinimide (20 g, 148 mmol) and the reaction heated at 50-55° C. After 24 hours the reaction was cooled to ambient temperature and concentrated of all volatiles in vacuo. The resulting solid was dissolved in ethyl acetate (1 L), washed with water (3×100 mL), dried over sodium sulfate, and concentrated. Recrystallization from benzene afforded 40 g (90% yield) of N-(5-chloropyridin-2-yl)-2-amino-3-methoxy-5-chlorobenzamide as off-white needles; NMR (CDCl3) 8.6 (br, 1), 8.3 (m, 2), 7.7 (dd, 1), 7.1 (d, 1), 6.8 (d, 1), 5.9 (br, 1), 3.9 (s, 3) ppm.
Reaction SMILES: [K+:1].[C:2]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][C:11](=[CH2:15])[C:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.C(OC(C)C)(=O)C.[H][H]>>[K+:1].[C:2]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:10][C@@H:11]([CH3:15])[C:12]([O-:14])=[O:13])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)C
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Temperature: 25 °C

Procedure:
100 mg (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid potassium salt (2-a, R1=Boc, R2=H, R3=CO2K) (prepared according to procedure in Example 42) is added to isopropyl acetate (1 ml). 10% Platinium on carbon (10 mg) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is stirred at ambient temperature and pressure overnight. The mixture is then filtered over Celite and washed with isopropyl acetate (2×1 ml). The mixture is then concentrated in vacuo to give (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid potassium salt (1-a, R1=Boc, R2=H, R3=CO2K) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid potassium salt (1-b, R1=Boc, R2=H, R3=CO2K). Spectroscopic data as in Example 42, Method 1.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:12][N:11]=2)=[CH:6][CH:5]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:37][CH:38]([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH2:41]O>CN(C)C=O.C(OCC)C>[CH3:37][CH:38]([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH2:41][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:14][N:15]=2)=[CH:8][CH:9]=1
Reactant: CCCCC(C)CCCO
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCc1cnc(-c2ccc(OCCCC(C)CCCC)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.38 g of 55% sodium hydride and 10 ml of dimethylformamide were weighed out and a solution of 2 g of 2-(4-hydroxyphenyl)-5-n-decylpyrimidine in 3 ml of dimethylformamide was added dropwise thereto under ice cooling. After the completion of the addition, the resulting mixture was stirred at room temperature for one hour. Then p-toluene-sulfonate of optically active 4-methyloctanol was added dropwise thereto and the resulting mixture was stirred at 90° C. for two hours. After cooling, the reaction mixture was poured into ice/water, extractd with diethyl ether and dried followed by removal of the solvent. The residue was purified on a silica gel column to thereby give 1.5 g of optically active 2-(4-(4-methyloctoxy)phenyl)-5-n-decylpyrimidine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:15]([Cl:16])=[C:14]([Br:17])[C:13]([CH3:18])=[N:12]2)=[C:4]([F:19])[CH:3]=1.C(O)C.Cl>[Fe].O>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:19])=[C:5]([N:11]2[C:15]([Cl:16])=[C:14]([Br:17])[C:13]([CH3:18])=[N:12]2)[CH:6]=1
Reactant: Cc1nn(-c2cc([N+](=O)[O-])c(Cl)cc2F)c(Cl)c1Br
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1nn(-c2cc(N)c(Cl)cc2F)c(Cl)c1Br
Yield: 95.4 %

Procedure:
12.5 g (0.034 mol) of 1-(4-chloro-2-fluoro-5-nitrophenyl)-3-methyl-4-bromo-5-chloropyrazole (reference example 2) were added in the solution of 13.6 g of iron powder, 44 ml of ethanol, 20 ml of water and 0.2 ml of hydrochloric acid at 70° to 75° C., under stirring. After stirred for 2 hours at 75° C., the reaction mixture was filtered and the filtrate added with cold water was extracted with ethyl acetate. The ester layer was washed with water, concentrated and purified on column chromatography to obtain 11.0 g of brown crystal, melting point: 113° to 116° C. in yield of 96%.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:23])=[O:12])[N:3]=1.[C:24]([O-:27])([O-])=[O:25].[K+].[K+]>O1CCOCC1.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>[Cl:23][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([F:22])([F:21])[F:20])[C:13]=1[C:11]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:24](=[O:25])[O:27][CH2:2]3)=[N:3]1)=[O:12]
Reactant: O=C([O-])[O-]
Reactant: O=C(c1c(Cl)cccc1C(F)(F)F)n1nc(Br)c2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1OCc2cc(-c3nn(C(=O)c4c(Cl)cccc4C(F)(F)F)c4ccccc34)ccc21
Temperature: 100 °C

Procedure:
(0.97 g, 2.48 mmol), (3-bromo-1H-indazol-1-yl)(2-chloro-6-(trifluoro methyl)phenyl)methanone (1.0 g, 2.48 mmol), K2CO3 (1.03 g, 7.44 mmol) and Pd(PPh3)4 (0.143 g, 0.12 mmol) were suspended in 1,4-dioxane (15 mL) and H2O (3 mL). The reaction mixture was heated at 100° C. in a microwave reactor for 2 h. The reaction mixture was cooled to rt and diluted with H2O. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (PE:EA=4:1) to afford the title compound as a pale yellow oil. LCMS (ESI) calc'd for C23H13ClF3N2O3 [M+H]+: 457. found: 457.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5][CH:4]=1.[S]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C=C1CCCc2ccc(OC)cc21
Agent: [S]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cccc2ccc(OC)cc12
Temperature: 215 °C
Reaction time: 0.5 h

Procedure:
50 g of ethyl 7-methoxy-l,2,3,4-tetrahydro-1-naphthylideneacetate are mixed with 7.35 g of sulphur, and the mixture is heated at 215° C. for 10 hours. It is cooled, 300 cm3 of ethyl acetate are added, and the mixture is stirred for 30 minutes and filtered. It is then dried.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([OH:13])=O.C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C)C=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([Cl:17])=[O:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1c(C(=O)O)cc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(C(=O)Cl)cc2ccccc21
Reaction time: 18 h

Procedure:
A suspension of 1-methylindole-2-carboxylic acid (0.805 g, 4.6 mmol) in dichloromethane (3 mL) was treated with oxalyl chloride (0.700 g, 5.52 mmol) and one drop of dimethylformamide. The reaction mixture was shaken for 18 h. The solvent was removed under reduced pressure and dried under high vacuum to afford a quantitative amount of 1-methyl-1H-2-indolecarbonyl chloride. The oil was directly used in the following reaction.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[S:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.O>CS(C)=O>[O:18]1[CH2:4][CH:17]1[C:16]1[CH:15]=[CH:14][C:13]([C:9]2[S:8][CH:12]=[CH:11][N:10]=2)=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(-c2nccs2)cc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: c1csc(-c2ccc(C3CO3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a suspension of 0.063 g (1.5 mmol) of sodium hydride in DMSO (10 mL) was added 0.300 g (1.47 mmol) of trimethylsulfonium iodide as a solution in DMSO (5 mL). After stirring at room temperature for 5 min 0.130 g (0.687 mmol) of the above aldehyde was added as a solution in DMSO (5 mL). The mixture was allowed to stir at room temperature for 2 h. The mixture was poured into H2O and washed with EtOAc. The combined organic phase was washed with H2O, dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to provide 0.129 g (92.3%) of 2-(4-oxiranyl-phenyl)-thiazole as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:13]([OH:14])[CH2:12][CH2:11][C@H:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@H:9]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:4][CH:3]=1.[F:25][C:26]([F:47])([F:46])[C:27]1[CH:28]=[C:29]([C@@H:37](OC(=N)C(Cl)(Cl)Cl)[CH3:38])[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1.[H+].[B-](F)(F)(F)F>CCOCC>[F:25][C:26]([F:46])([F:47])[C:27]1[CH:28]=[C:29]([C@H:37]([O:14][C@H:13]2[CH2:12][CH2:11][C@H:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@@H:9]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C@@H:8]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH3:38])[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1
Reactant: C[C@H](OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)[C@H]1[C@H](c2ccc(F)cc2)[C@@H](O)CC[C@@H]1C(=O)OCC
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: CCOC(=O)[C@H]1[C@H](c2ccc(F)cc2)[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC[C@@H]1C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a solution of 9.09 g (26.9 mmol) of the first eluting isomer diethyl (1S,2S,3R,4S)-3-(4-fluorophenyl)-4-hydroxycyclohexane-1,2-dicarboxylate (step D) and 21.5 g (53.5 mmol) of (1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl-2,2,2-trichloroethanimidoate (step E) in 250 mL of cyclohexane/1,2-chloroethane (3/1) under nitrogen atmosphere at −5° C. was added 0.51 mL (3.58 mmol) of 54% HBF4 in ether. The reaction mixture was stirred at −5° C. to at 0° C. for 2 hr then diluted with ether. The mixture was washed with sat. aq. NaHCO3. The organic layer was dried over drying agent, filtered and the solvent evaporated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with EtOAc/hexanes (1/4) to give 9.2 g of the title compound as an oil. 1H-NMR (CDCl3): δ: 7.70 (1H, s), 7.20 (2H, s), 7.00 (2H, m), 6.85 (2H, t, J=8.5 Hz), 4.43 (1 H, q, J=6.0 Hz), 4.20-4.10 (2H, m), 3.80-3.73 (2H, m), 3.36 (1H, m), 2.90-2.76 (2H, m), 2.40 (1H, m), 2.28 (1H, m), 1.63-1.55 (2H, m), 1.33 (3H, d, J=6.0 Hz), 1.25 (3H, t, J=7.2 Hz), 0.82 (3H, t, J=7.2 Hz). Unreacted starting alcohol could be recovered by flushing the column with EtOAc and reused in the above reaction.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1.Br[CH2:36][C:37]([NH2:39])=[O:38].C(OCC)(=O)C>C1CCCCC1>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][N:32]([CH2:36][C:37]([NH2:39])=[O:38])[CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2cc(C4CCNCC4)ccc2OCC3)c(F)c1
Reactant: NC(=O)CBr
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: NC(=O)CN1CCC(c2ccc3c(c2)-c2nn(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1

Procedure:
Following the procedure for 143, 2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was reacted with bromo acetamide. The crude product was subjected flash chromatography (SiO2, gradient 50 to 100% ethyl acetate in cyclohexane). Pure fractions were combined and concentrated in vacuo and the resultant residue dissolved in DCM and treated with 4M HCl in dioxane then diethyl ether. The resultant precipate was collected by filtration to give 178 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.86 (s, 1H); 8.48-8.43 (m, 1H); 8.30 (s, 1H); 8.05 (s, 1H); 7.85 (td, J=8.75, 5.93 Hz, 1H); 7.74-7.63 (m, 2H); 7.41-7.34 (m, 1H); 7.22 (d, J=2.30 Hz, 1H); 7.10 (dd, J=8.45, 2.35 Hz, 1H); 6.97 (d, J=8.39 Hz, 1H); 4.22 (t, J=5.00 Hz, 2H); 3.98 (d, J=4.37 Hz, 2H); 3.60 (t, J=12.26 Hz, 2H); 3.24-3.13 (m, 2H); 3.06 (t, J=4.95 Hz, 2H); 2.69-2.61 (m, 1H); 1.87 (s, 4H). LCMS: RT=7.46 min, M+H+=506
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=O)=[C:20]([O:27][CH3:28])[CH:19]=1>>[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)=[C:20]([O:27][CH3:28])[CH:19]=1
Reactant: COc1cc(F)ccc1C(=O)O
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 49 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (2.00 g, 9.12 mmol) was converted using 4-fluoro-2-methoxy-benzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 1.59 g, 49%) which was obtained as a white solid. MS: m/e=352.3 [M+H]+.
Reaction SMILES: [CH2:1]([NH:7][C@H:8]([C:13]([O:15]C)=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[Li+].[OH-]>CO.O>[CH2:1]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:10])([CH3:11])[CH3:12])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCCN[C@H](C(=O)OC)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCCCCN[C@H](C(=O)O)C(C)(C)C
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A 0.25M solution of methyl N-hex-5-en-1-yl-3-methyl-L-valinate 99 in a mixture of MeOH:water (3:1) was treated with LiOH (3.0 eq.) at RT. The reaction mixture was stirred at 70° C. for 3 h. The organic solvent was removed under reduced pressure and the residue was acidified with aqueous HCl (1N). The water phase was repeatedly extracted with EtOAc, dried (Na2SO4) and concentrated under reduced pressure to afford the crude product, which was used in the following step without further purification. MS (ES+) m/z 214 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:11])[C:6]=1[C:7](OC)=[O:8].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:11])[C:6]=1[CH2:7][OH:8]
Reactant: COC(=O)c1c(Br)cnn1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: Cn1ncc(Br)c1CO
Reaction time: 2 h
Yield: 43.6 %

Procedure:
Methyl 4-bromo-1-methyl-1H-pyrazole-5-carboxylate (2 g, 9.13 mmol) in DCM (40 mL) was cooled to −78° C. Diisobutylaluminum hydride (36.5 mL, 36.5 mmol) in DCM was added, and the reaction mixture was stirred for 2 hours at the same temperature. The reaction mixture was subsequently quenched with aqueous saturated sodium potassium tartrate and was transferred to a reparatory funnel, where it was washed with water and brine, dried over Na2SO4, and concentrated to give the title compound as a white solid (0.76 g, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH:22]=[O:23])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:30][Mg]Cl>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH:22]([OH:23])[CH3:30])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnc(C=O)cn2)cc1Cl
Reactant: C[Mg]Cl
Solvent: CCOCC
Product: CC(O)c1cnc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-formyl-pyrazin-2-yl)-propionamide (prepared as in Example 18, 218 mg, 0.5 mmol) in diethyl ether (15 mL) at 0° C. was slowly treated with 3.0M solution of methylmagnesium chloride in diethyl ether (0.35 mL, 1.05 mmol). After complete addition, the reaction mixture was stirred at 0° C. for 1 h. The reaction was then quenched by the dropwise addition of a 1N aqueous hydrochloric acid solution. The reaction was then diluted with water (25 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (2×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 3/7 to 7/3 ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(1-hydroxy-ethyl)-pyrazin-2-yl]-propionamide (140 mg, 62%) as a white solid: LC-MS m/e 451 (MH+).