Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1](Cl)([O:8][CH2:9][CH2:10][CH2:11][CH3:12])([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:2].ClCCl.[CH2:17]([OH:21])[CH:18]([CH3:20])[CH3:19]>N1C=CC=CC=1>[P:1]([O:21][CH2:17][CH:18]([CH3:20])[CH3:19])([O:8][CH2:9][CH2:10][CH2:11][CH3:12])([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:2]
Reactant: CCCCOP(=O)(Cl)OCCCC
Reactant: CC(C)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCOP(=O)(OCCCC)OCC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of di-n-butyl chlorophosphate (130.3 g, 0.57 mole) in 600 mL of dichloromethane containing 55.37 g (0.70 mole) of pyridine was cooled to 0° C. Isobutanol (42.25 g, 0.57 mole) was added dropwise over 1 hour. The formation of a white precipitate was immediately observed. The reaction mixture was then stirred for 24 hours at room temperature. The pyridinium hydrochloride was filtered off, and the solution was washed with water (2×250 mL), aqueous 0.5 N HCl (2×250 mL) and water (25×250 mL). The organic phase was dried over anhydrous magnesium sulfate for 12 hours. Filtration of the drying agent, followed by the removal of the solvent using a Roto-vap, yielded di-n-butyl isobutyl phosphate as a clear colorless liquid. Distillation of the crude product (68° C. at 0.02 torr) gave 125 g of 94.8% di-n-butyl isobutyl phosphate (DBIBP).
Reaction SMILES: O1[C:7]2([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=3[O-:14])[CH:2]1[C:3]([CH2:28][F:29])([CH2:26][F:27])[O:4][C:5]1[CH:18]=[CH:17][C:16]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[CH:15][C:6]=12>[C].[Pd].CO>[F:25][C:19]([F:24])([C:16]1[CH:17]=[CH:18][C:5]2[O:4][C:3]([CH2:28][F:29])([CH2:26][F:27])[CH:2]=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=3[O-:14])[C:6]=2[CH:15]=1)[C:20]([F:23])([F:22])[F:21]
Reactant: [O-][n+]1ccccc1C12OC1C(CF)(CF)Oc1ccc(C(F)(F)C(F)(F)F)cc12
Agent: [Pd]
Solvent: CO
Product: [O-][n+]1ccccc1C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc21
Temperature: 25 °C
Yield: 37.4 %

Procedure:
A mixture of 0.50 g of 2-(3,4-epoxy-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-2H-1-benzopyran-4-yl)pyridine N-oxide, 0.10 g of 10% palladium carbon and 15 ml of methanol was stirred at room temperature under hydrogen stream. The reaction mixture was subjected to vacuum filtration to remove the catalyst and the mother liquor was distilled off. The resultant residue was dissolved in 10 ml of dioxane and 0.82 g of soda talc was added thereto. The mixture was refluxed with heating for 1 hour and subjected to vacuum filtration to remove insoluble materials. Water was added to the mother liquor and the mixture was extracted with methylene chloride. The organic layer was washed with water and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 0.18 g of 2-(6-pentafluoroethyl-2,2-bisfluoromethyl-2H-1-benzopyran-4-yl)pyridine N-oxide.
Reaction SMILES: [NH2:1][C@:2]([CH3:9])([CH2:6][C:7]#[CH:8])[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH3:14]O>>[NH2:1][C@:2]([CH3:9])([CH2:6][C:7]#[CH:8])[C:3]([O:5][CH3:14])=[O:4]
Reactant: C#CC[C@@](C)(N)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: C#CC[C@@](C)(N)C(=O)OC
Temperature: 2 °C

Procedure:
(2R)-2-amino-2-methylpent-4-ynoic acid (1.3 kg) was suspended in methanol (6.5 L) and cooled to 2±3° C. The mixture was treated with thionyl chloride (1.48 L) at 2±3° C. over at least 30 mins. The mixture was heated at 40±3° C. for at least 17 hours then sampled for completion of reaction (COR) by 1H NMR. Once complete, the mixture was stripped to low volume (ca. 1 vol) then azeotroped with toluene (ca. 2×2.5 L) and evaporated to dryness to afford crude methyl (2R)-2-amino-2-methylpent-4-ynoate which was then diluted with dioxane (9.1 L). The suspension was treated with aqueous potassium carbonate (2.82 Kg dissolved in 5.46 L of water) at ambient temperature and stirred for at least 30 minutes. Di-tert butyl dicarbonate (BOC2O) (2.43 Kg) was then added and the mixture heated at 40±3° C. with stirring under inert atmosphere for at least 17 hours. The mixture was sampled for completion of reaction (COR) by 1H NMR Once complete the mixture was filtered to remove solids then diluted with ethyl acetate (5 L), stirred and separated. The organic layer was washed with water (5 L) then the organic layer separated and dried over anhydrous sodium sulphate. The solution was then concentrated to a clear oil which crystallized upon standing. The crude product was recrystallised from cyclohexane (2.6 L) and washed with further cyclohexane (2.6 L). The product was dried in vacuo at 35° C. to furnish the title compound (1.5 Kg.). 1H NMR (400 MHz, MeOD-d4) δppm: 1.42 (9H, s), 1.46 (3H, s), 2.32-2.34 (1H, m), 2.65-2.71 (1H, dd), 2.92-2.99 (1H, d), 3.70 (3H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:14])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.CCCCCCC.[CH3:22][N:23](C=O)C>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-]#N.[Zn+2].[C-]#N>[OH:14][C:4]1[CH:3]=[C:2]([C:22]#[N:23])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=1
Reactant: Oc1cc(Br)cc(-c2ccccc2)c1
Reactant: CN(C)C=O
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]
Solvent: CCCCCCC
Product: N#Cc1cc(O)cc(-c2ccccc2)c1
Temperature: 200 °C
Yield: 38 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (116 mg, 0.1 mmol) was added to 5-bromobiphenyl-3-ol (250 mg, 1 mmol) and zinc cyanide (117 mg, 1.0 mmol) dissolved in DMF (5 mL) in a microwave vessel. The reaction vessel was sealed and then heated at 200° C. for 300 seconds. The reaction was quenched with water and the product was extracted into DCM. The solution was filtered and then concentrated in vacuo. The crude material was then purified by chromatography on silica gel. Elution with 10:90 ethyl acetate:heptane afforded 5-hydroxybiphenyl-3-carbonitrile (74 mg, 0.379 mmol, 38%). M.S. (ESI) (m/z): 194 [M−H]−.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([S:10][CH2:11][CH2:12][OH:13])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[C:1]([C:5]1[N:9]=[C:8]([S:10][CH2:11][CH2:12][O:13][C:30](=[O:31])[NH:29][C:26]2[CH:27]=[CH:28][C:23]([C:22]([F:21])([F:33])[F:32])=[CH:24][CH:25]=2)[NH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1n[nH]c(SCCO)n1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1n[nH]c(SCCOC(=O)Nc2ccc(C(F)(F)F)cc2)n1

Procedure:
To 5 g (20 mmole) of 3-t-butyl-5-(2-hydroxyethylthio)-1H-1,2,4-triazole in 50 ml of chloroform was added 0.1 g of triethylamine and 3.8 g (20 mmole) of 4-trifluoromethylphenylisocyanate. After refluxing for three hours, the mixture was concentrated in vacuo and crystallized from ether/hexane to give 3-t-butyl-5-(2-(4-trifluoromethylphenylcarbamoyloxy)-ethylthio)-1H-1,2,4-triazole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([O:25][C:26](=[O:33])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OC)(OC)OC.[BH4-].[Na+]>CO>[CH2:18]([O:25][C:26](=[O:33])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])=[CH:10][CH:11]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Reactant: NCCCCNC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(CNCCCCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 64.3 %

Procedure:
The compound (951.6 mg) obtained in Example 103-3 was dissolved in anhydrous methanol (38 ml) and added with (4-amino-butyl)-carbamic acid benzyl ester (898.0 mg) and trimethyl orthoformate (1.33 ml), followed by stirring at room temperature for 15.5 hours. After that, the solution was cooled with ice and added with sodium borohydride (458.5 mg), followed by stirring at room temperature for 1.5 hours. After the reaction, the solvent was distilled off and the residue was then added with water, followed by extraction with chloroform. The extract was washed with saturated saline solution and dried with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (1.1479 g) as a colorless oily substance.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:8](=[N:15][OH:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28]>>[C:25]([O:16][N:15]=[C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:7]1[CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]([OH:20])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1)(=[O:29])[CH2:26][CH2:27][CH3:28]
Reactant: CC(C)(C)c1cc(C(=NO)c2ccccc2)cc(C(C)(C)C)c1O
Reactant: CCCC(=O)Cl
Product: CCCC(=O)ON=C(c1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
3,5-di-t-butyl-4-hydroxybenzophenone oxime and butyryl chloride were treated in the same way as in Example 3 to give 3,5-di-t-butyl-4-hydroxybenzophenone O-butyryloxime.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]2[CH2:7][O:8][C:9]3[CH:10]=[C:11]([O:15][CH2:16][CH:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH:12]=[CH:13][C:14]=3[C:2]=12.C1C(=O)N([Br:37])C(=O)C1>C(#N)C>[Br:37][C:12]1[C:11]([O:15][CH2:16][C@@H:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:10][C:9]2[O:8][CH2:7][C:3]3[C:2]([C:14]=2[CH:13]=1)=[CH:1][CH:6]=[N:5][CH:4]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)CC(COc1ccc2c(c1)OCc1cnccc1-2)NC(=O)OC(C)(C)C
Solvent: CC#N
Product: CC(C)C[C@@H](COc1cc2c(cc1Br)-c1ccncc1CO2)NC(=O)OC(C)(C)C
Reaction time: 0.03 h
Yield: 38.7 %

Procedure:
A solution of tert-butyl (1-((5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.072 g, 0.181 mmol) in acetonitrile (5 mL) cooled to 0° C. and stirred for 2 min. NBS (0.029 g, 0.163 mmol) was added in single portion and the reaction mixture stirred at 0° C. for 2 h. The solvent was removed under reduced pressure and water 10 mL) was added. The product was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with water (1×20 mL) dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via preparative TLC (40% EtOAc:pet ether) to obtain (S)-tert-butyl 1-(9-bromo-5H-chromeno[3,4-c]pyridin-8-yloxy)-4-methylpentan-2-ylcarbamate (30 mg, 0.063 mmol, 35% yield). 1H NMR (400 MHz, CD3OD) δ 8.48 (d, J=5.4 Hz, 1H), 8.38 (s, 1H), 8.07 (s, 1H), 7.68 (d, J=5.4 Hz, 1H), 6.73 (s, 1H), 5.21 (s, 2H), 4.02-3.98 (m, 3H), 1.92-1.71 (m, 1H), 1.56-1.52 (m, 2H), 0.97 (t, J=6.8 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].C1COCC1.CO>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C#Cc1ccc(NC(=O)OC(C)(C)C)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)CCc1ccc(NC(=O)OC(C)(C)C)cc1
Reaction time: 15.8 h
Yield: 94.2 %

Procedure:
[4-(3,3-Dimethyl-but-1-ynyl)-phenyl]-carbamic acid tert-butyl ester (37b, 2.50 g, 9.15 mmol) was treated with 1:1 THF/MeOH (50 mL) and Pd/C (0.5 g, 10%), shaken for 15.8 hours under an atmosphere of H2 (51.4 psi). More Pd/C (0.5 g, 20%) was added and the reaction was stirred for an additional 1.13 hours, then filtered and concentrated. The crude material was chromatographed on silica gel eluting with 1:9 EtOAc/Hexane to give 2.39 g (94%) of the desired product.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].O[N:21]=[C:22]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][CH:25]=1)[NH2:23]>>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:12][N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][CH:25]=3)[N:21]=2)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: NC(=NO)c1ccc(CO)cc1
Product: COCc1cc(-c2nc(-c3ccc(CO)cc3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was obtained following procedure described for example 54 step 1 but starting from Intermediate 28 (248.00 mg; 0.90 mmol) and Intermediate 74 (150.00 mg; 0.90 mmol). Recrystallization from Et2O/pentane gave the title compound as a white powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.32 (d, J=1.5 Hz, 1H), 8.16 (dd, J=7.9, 1.8 Hz, 1H), 8.10-8.07 (m, 2H), 7.55 (d, J=8.3 Hz, 2H), 7.41 (d, J=7.9 Hz, 1H), 7.36-7.26 (m, 3H), 7.15-7.13 (m, 1H), 5.38 (t, J=5.7 Hz, 1H), 4.61 (d, J=5.7 Hz, 1H), 4.22 (d, J=12.7 Hz, 1H), 4.15 (d, J=12.7 Hz, 1H), 3.25 (s, 3H), 2.03 (s, 3H). LC/MS (Method B): 387.2 (M+H)+. HPLC (Method A) Rt 5.51 min (Purity: 97.0%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C@@H:15]([NH:21][C:22]([C@@H:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:46])[CH2:31][CH2:32][CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[CH2:25]2)=[O:23])[CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.CO>C(OCC)(=O)C.[Pd]>[C:42]([O:41][C:39]([N:36]1[CH2:35][CH2:34][CH:33]([CH2:32][CH2:31][C:30]([N:26]2[CH2:27][CH2:28][CH2:29][C@@H:24]([C:22](=[O:23])[NH:21][C@H:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=3)[CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:25]2)=[O:46])[CH2:38][CH2:37]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cccc(O)c1
Reaction time: 16 h
Yield: 75.8 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-({(1S)-1-[3-(benzyloxy)phenyl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (650 mg, 1.02 mmol) was dissolved in ethyl acetate (45 mL) and methanol (7.4 mL) and palladium on charcoal (65 mg, 10%) was added. The mixture was shaken under a hydrogen atmosphere for 16 hours filtrated through celite which were washed with methanol. The filtrate was concentrated and purified by chromatography on silica gel (methanol in ethyl acetate 0% to 25%) to yield 422 mg of tert-butyl-4-{3-[(3R)-3-{[(1S)-1-(3-hydroxyphenyl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]([F:28])([F:27])[C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[C:15](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:14]2[CH:26]=1.O>CS(C)=O>[F:28][C:10]([F:9])([F:27])[C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]3[CH2:4][CH:20]3[C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:14]2[CH:26]=1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1cccc2nc(C(F)(F)F)cn12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1c1cccc2nc(C(F)(F)F)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
To a suspension of 60% sodium hydride (1.24, 28.5 mmol) in dimethyl sulfoxide (50 mL) was added trimethylsulfoxonium iodide (6.26 g, 28.5 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl (2E)-3-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]acrylate (6.74 g, 23.7 mmol) in dimethyl sulfoxide (100 mL) at 0° C., and the mixture was stirred at room temperature for 4 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=33/67) to give the title compound (3.40 g, yield 48%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([N:14]1[CH2:15][CH2:16][N:11]([C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[F:1])[CH2:12][CH2:13]1)(=[O:26])[CH3:25]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)c(F)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A stirred solution of 1-(2-fluoro-4-nitrophenyl)piperazine (15 g, 66.6 mmol) in DCM (160 ml) was cooled to 0° C. Triethylamine was then added (11.23 ml, 79.92 mmol) followed by dropwise addition of acetyl chloride (5.68 ml, 79.92 mmol). The solution was allowed to warm to ambient temperature and stir for 1.5 hour. The reaction mixture was diluted with DCM, washed with water, sat. sodium hydrogen carbonate and brine. It was dried and the solvent was evaporated to give the title compound as a solid which was dried in vac oven overnight at 50° C. (17.46 g, 98%). NMR (400 MHz) 2.05 (s, 3H), 3.30 (dt, 4H, under H2O signal), 3.61 (m, 4H), 7.18 (t, 1H), 8.02 (d, 1H), 8.02 (dd, 1H); m/z 268.
Reaction SMILES: CCN(CC)CC.[N:8]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[N+:9]=[N-:10].C(Cl)(=O)C(C)(C)C.[CH2:24]([C@H:31]1[CH2:35][O:34][C:33](=[O:36])[NH:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[N:8]([CH2:11][CH2:12][CH2:13][C:14]([N:32]1[C@@H:31]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:35][O:34][C:33]1=[O:36])=[O:16])=[N+:9]=[N-:10]
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: [N-]=[N+]=NCCCC(=O)O
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
NEt3 was added to a stirred mixture of 4-azidobutanoic acid in THF (0.3 M) cooled to −78° C. and stirring was continued at this temperature for 10 min. Pivaloyl chloride (1.3 eq) was added dropwise. The resulting mixture was warmed to 0° C. and stirred for 1 h before re-cooling to −78° C. In a separate flask, (4S)-4-benzyl-1,3-oxazolidin-2-one was dissolved in THF (0.8 M) and cooled to −78° C. before dropwise addition of N-BuLi (1.6M, 1.35 eq.) over 10 min. The mixture was stirred at −78° C. for 1 h and then transferred into the −78° C. solution of mixed anhydride using a syringe. The reaction was stirred at −78° C. for 1 h, then at RT for a further 1 h. The reaction was quenched by addition of sat. aq. NH4Cl before partitioning between H2O and EtOAc. The layers were separated and the aqueous phase re-extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by FC eluting with 10 to 30% EtOAc/PE to give the product as a colourless oil (74%). (ES+) m/z 289 (M+H)+.
Reaction SMILES: [ClH:1].[NH:2]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:23][S:24]C1C=C(C=CC=1)N>CN(C)C=O>[ClH:1].[CH3:23][S:24][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[NH:2][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1
Reactant: CSc1cccc(N)c1
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Agent: Cl
Solvent: CN(C)C=O
Product: CSc1cccc(Nc2cc(C)nc3ccc4nc[nH]c4c23)c1

Procedure:
A mixture of 21.7 g. (0.1 m.) of the compound of Example I, C., 13.9 g. (0.1 m.) of 3-methylmercaptoaniline and 250 ml. of dimethylformamide was refluxed overnight with stirring. It was chilled, filtered, washed with ether and air-dried to give 29 g. m.p. 310°-313°C.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:6][C:5]=1[OH:26].[CH2:28](Br)[CH:29]([CH3:31])[CH3:30]>>[F:27][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:6][C:5]=1[O:26][CH2:28][CH:29]([CH3:31])[CH3:30]
Reactant: Cc1cccnc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Reactant: CC(C)CBr
Product: Cc1cccnc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(OCC(C)C)c2)n1

Procedure:
Using the compound obtained in Example 97 and isobutyl bromide, colorless oily N-[2-(4-difluoromethoxy-3-isobutoxy phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained following the procedure of Example 3.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[S:16](Cl)([CH3:19])(=[O:18])=[O:17]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Dissolved 1-Boc-4-hydroxymethyl-piperidine in anhydrous CH2Cl2 (50 ml) and TEA (4.5 ml) and cooled to 0° C. Mesyl chloride (840 μl) was added and the mixture was stirred for 15 min then at RT for 45 min. The mixture was washed with brine/1N HCl and then brine, dried over Na2SO4, concentrated in vacuo and dried under high vacuum to provide 1-Boc-4-methylsulfonyloxymethyl-piperidine as a yellow orange thick oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[C:9]1[C:10](=[O:26])[N:11]([C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=2[CH3:25])[C:18]([O:20]C)=O)[CH:12]=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]1([NH2:35])[CH2:34][CH2:33]1>O>[CH:32]1([NH:35][C:18](=[O:20])[C:17]2[CH:22]=[CH:23][C:24]([CH3:25])=[C:15]([N:11]3[CH:12]=[CH:13][N:14]=[C:9]([N:8]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:10]3=[O:26])[CH:16]=2)[CH2:34][CH2:33]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(C)c(-n2ccnc(N(CCN(C)C)Cc3ccccc3)c2=O)c1
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(N(CCN(C)C)Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 240 h

Procedure:
A mixture of 3-{3-[benzyl-(2-dimethylamino-ethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-4-methyl-benzoic acid, methyl ester (Example 121a, 50 mg), cyclopropylamine (1 mL) and water (0.5 mL) was stirred at room temperature for 10 days. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound as a solid (10 mg).