Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:29])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][C@H:17]([NH:20]C(=O)OC(C)(C)C)[C@H:16]([OH:28])[CH2:15]2)=[N:4][CH:3]=1.[ClH:30]>C(Cl)Cl.O1CCOCC1>[ClH:30].[ClH:30].[NH2:20][C@H:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][N:9]2[C:10]3[C:5](=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:6]=[CH:7][C:8]2=[O:29])[CH2:15][C@H:16]1[OH:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(CCn2c(=O)ccc3ncc(F)cc32)C[C@H]1O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@H]1CCN(CCn2c(=O)ccc3ncc(F)cc32)C[C@H]1O
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl {(3R,4S)-1-[2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl]-3-hydroxy-4-piperidinyl}carbamate (240 mg, 0.5905 mmol) was dissolved in DCM (10 ml) and the solution was treated with 4M hydrogen chloride in 1,4-dioxane (2 mL). Effervescence and formation of a precipitate was observed. After 2 h, the solvents were removed under reduced pressure and the residue was dried under reduced pressure overnight, to give 1-{2-[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one dihydrochloride as an off-white solid (220 mg).
Reaction SMILES: [Na].[C:2]([O:8][CH3:9])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].O[N:11]=[C:12](Cl)[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1>CO>[CH3:6][C:4]1[O:5][N:11]=[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:3]=1[C:2]([O:8][CH3:9])=[O:7]
Reactant: ON=C(Cl)c1ccncc1
Reactant: COC(=O)CC(C)=O
Agent: [Na]
Solvent: CO
Product: COC(=O)c1c(-c2ccncc2)noc1C
Temperature: 0 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
Sodium (0.400 g, 0.0166 mol) was added to anhydrous methanol under nitrogen. After complete dissolution, the reaction vessel was cooled to 0° C. and methyl acetoacetate (1.8 ml, 0.166 mol) added. A solution of N-hydroxy-4-pyridine carboximidoyl chloride (2 g, 0.0128 mol; prepared according to Kocevar, M., Synth. Commun., 1988, 18(12), 1427) was added dropwise over 20 minutes. The reaction was stirred at 25° C. for 16 h, and quenched with acetic acid (1 ml). The methanol was removed in vacuo and the product partitioned between EtOAc and water. The organic layer was collected, dried over MgSO4, and evaporated. The residue was chromatographed on silica eluting with 20% EtOAc/hexane→EtOAc to obtain the title compound as a beige solid (1.2 g). 1H NMR (400 MHz, CDCl3) δ 8.73–8.71 (m, 2H), 7.57–7.56 (m, 2H), 3.80 (s, 3H), 2.77(s, 3H).
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15]CC)=[O:14].[C:18](=O)([O-])[O-].[K+].[K+].CI.O>CC(C)=O>[CH3:18][O:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)c1c(C)nc2cc(C)nn2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(C(=O)O)c(C)nc2cc(C)nn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
The ethyl 7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxylate (235 mg) obtained above was suspended in acetone (5 ml), and potassium carbonate (138 mg) was added thereto and stirred for 30 minutes at room temperature. Methyl iodide (1.0 ml) was added to the mixture which was then refluxed for 2 hours. The reaction mixture was cooled to room temperature, then water was added to the reaction mixture which was extracted with chloroform, and the organic phase was washed with a saturated saline solution and dried over sodium sulfate anhydrous. The resulting product was concentrated under reduced pressure, and the resulting crystals were dissolved in ethanol (5 ml). 5 N Sodium hydroxide solution (1 ml) was added thereto and stirred for 1 hour at 50° C. The reaction mixture was cooled to room temperature, and water was added to the mixture which was then washed with ethyl acetate. 2 N Hydrochloric acid was added to the aqueous phase until it became acidic, and precipitated crystals were collected by filtration and washed with water and n-hexane. The crystals were dried under reduced pressure to give the title compound (162 mg, Y.:73%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4](F)[N:3]=1.[NH2:12][C@@H:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:14][OH:15].C(N(CC)CC)C>CC#N.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:12][C@@H:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:14][OH:15])[C:5]([F:10])=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC(C)(C)[C@H](N)CO
Reactant: N#Cc1cc(F)c(F)nc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[C@@H](CO)Nc1nc(Cl)c(C#N)cc1F
Temperature: 80 °C
Yield: 72.2 %

Procedure:
A mixture of 2-chloro-5,6-difluoropyridine-3-carbonitrile (6.52 g, 34.13 mmol), (2S)-2-amino-3,3-dimethyl-butan-1-ol (4.00 g, 34.13 mmol) and triethylamine (9.51 mL, 68.26 mmol) in CH3CN (50 mL) and THF (50 mL) was heated at 80° C. for 4 hours. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The crude product was purified via silica gel chromatography (0-60% EtOAc/Hexanes gradient) to afford 6.7 g of the desired product as an off white solid: 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J=9.7 Hz, 1H), 5.32 (m, 1H), 4.19-4.08 (m, 1H), 3.95-3.83 (m, 1H), 3.74-3.51 (m, 1H), 0.92 (s, 9H); LC/MS (60-90% ACN/water 5 min with 0.9% FA) m/z 272.02 (M+H), retention time 1.02 minutes.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([O:11][CH2:12][C@@H:13]3[CH2:15][O:14]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[N:26]1[CH2:33][C@H:32]2[NH:34][CH2:35][C@@H:27]1[CH2:28][CH:29]=[CH:30][CH2:31]2.CCN(C(C)C)C(C)C>C(O)C>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([O:11][CH2:12][C@@H:13]([OH:14])[CH2:15][N:34]3[CH2:35][CH:27]4[N:26]([C:17]5[CH:18]=[CH:19][C:20]6[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=6)[CH:16]=5)[CH2:33][CH:32]3[CH2:31][CH:30]=[CH:29][CH2:28]4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: Cn1ccc2c(OC[C@@H]3CO3)cccc21
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc2c(OC[C@@H](O)CN3CC4CC=CCC3CN4c3ccc4ccccc4c3)cccc21
Temperature: 120 °C

Procedure:
(S)-1-Methyl-4-oxiranylmethoxy-1H-indole (50 mg, 0.25 mmol) and Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (50 mg, 0.189 mmol) were placed in a μW tube with ethanol (2 ml), DIPEA (100 μL, 0.576 mmol) and heated to 120° C. for 900 sec. The solvent was evaporated from the reaction mixture and the residue was purified via flash chromatography (gradient 30% to 100% ethyl acetate/heptane) to yield the title compound as a residue.
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=O)[CH2:3][OH:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:39][C:40]([F:70])([F:69])[C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:68])[O:49][CH2:50][C:51]2([C:57](=[O:67])[NH:58][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=3[Cl:66])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)=[CH:43][CH:42]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:70][C:40]([F:39])([F:69])[C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:68])[O:49][CH2:50][C:51]2([C:57](=[O:67])[NH:58][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=3[Cl:66])[CH2:52][CH2:53][N:54]([C:5](=[O:7])[C@@H:2]([NH:1][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][OH:4])[CH2:55][CH2:56]2)=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)OCC1(C(=O)NCc2ccccc2Cl)CCNCC1
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
Product: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)N1CCC(COC(=O)Nc2ccc(C(F)(F)F)cc2)(C(=O)NCc2ccccc2Cl)CC1
Reaction time: 8 h
Yield: 56.6 %

Procedure:
To a solution of Boc-Ser-OH (162 mg, 0.79 mmol, 2 equiv.) in DMF (2 mL) were added HATU (300 mg, 0.79 mmol, 2 equiv.), followed by addition of (4-(2-chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-(trifluoromethyl)phenylcarbamate (200 mg, 0.39 mmol, 1 equiv.) and DIEA (140 μL, 0.79 mmol, 2 equiv.). The reaction mixture was stirred overnight and purified on RP-HPLC using a mixture of acetonitrile and H2O to give (S)-(1-(2-(tert-butoxycarbonyl)amino-3-hydroxypropanoyl)-4-(2-chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-(trifluoromethyl)phenylcarbamate (145 mg, 56%). LRMS (M+H+-Boc) m/z 557.1.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:30])[CH2:6][CH2:7][NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([CH3:25])=[C:12]2[CH2:26][C:27]([NH2:29])=[O:28].O>CO>[NH2:29][C:27](=[O:28])[CH2:26][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([NH:8][CH2:7][CH2:6][C:5]([OH:30])=[O:4])[CH:10]=2)[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]=1[CH3:25]
Reactant: COC(=O)CCNc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(CC(N)=O)c2cc(NCCC(=O)O)ccc2n1Cc1ccccc1
Reaction time: 1 h
Yield: 19.2 %

Procedure:
One mL of 1N NaOH was added to a solution of 110 mg (0.3 mmol) of 3-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]amino]propanoic acid methyl ester (Example 26) in 5 mL of MeOH, stirred 1.0 hour, then 1 mL of 1N NaOH was added and the mixture stirred 0.5 hour. Water was added, then 2 mL of 1N HCl, and the mixture extracted with EtOAc. This was dried (MgSO4) and concentrated at reduced pressure to give 21 mg (20% yield) of 3-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]amino]propanoic acid.
Reaction SMILES: O[C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9](=[O:15])[O:10]C(C)(C)C.[H-].[Na+].[NH4+].[Cl-]>C1COCC1>[O:15]1[C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:8][C:9]1=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1N[C@H]2CCCC[C@H]2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a stirred solution of tert-butyl (1S,2R)-2-hydroxycyclohexylcarbamate (1.15 g, 5.34 mmol) in THF (40 mL) was added NaH (60%, 0.32 g, 8.0 mmol) at 0° C. The reaction mixture was stirred at ambient temperature overnight. Saturated aqueous NH4Cl solution was added to quench the reaction. The mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (EtOAc/hexanes, 2:1) to give (3aS,7aR)-hexahydrobenzo[d]oxazol-2(3H)-one (0.50 g, 66%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=O)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:5][C:4]=1[CH2:21][CH2:22][C:23]([OH:25])=[O:24].Cl.[NH2:27][OH:28].C([O-])(=O)C.[Na+]>C(O)C>[C:23]([CH2:22][CH2:21][C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([O:9][CH3:10])=[C:6]([CH:5]=1)[C:11](=[N:27][OH:28])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)([OH:25])=[O:24]
Reactant: COc1ccc(C(=O)c2cc(CCC(=O)O)c(OC)cc2OC)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(=NO)c2cc(CCC(=O)O)c(OC)cc2OC)cc1

Procedure:
37 g of 3-[2,4-dimethoxy-5-(4-methoxybenzoyl)phenyl]propionic acid, 22.4 g of hydroxylamine hydrochloride and 21 g of sodium acetate (anhydrous) are added to 300 ml of absolute ethanol, and the mixture is refluxed with exclusion of moisture for 24 hours. Insolubles are removed by suction, the filtrate is concentrated, and water is added to the residue. The pH is then adjusted to 2 with 1N hydrochloric acid, and the mixture is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The residue is recrystallized from ethyl acetate/hexane.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]([CH:24]([O:27][CH3:28])[O:25][CH3:26])[CH2:10][CH2:11][CH2:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][CH:14]=2)=[C:4]([NH2:29])[N:3]=1.[OH-].[Na+].Cl>O1CCCC1.O>[NH2:1][C:2]1[N:3]=[C:4]([NH2:29])[C:5]([CH:9]([CH:24]([O:27][CH3:28])[O:25][CH3:26])[CH2:10][CH2:11][CH2:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[C:6]([NH2:8])[N:7]=1
Reactant: CCOC(=O)c1ccc(CCCC(c2c(N)nc(N)nc2N)C(OC)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(OC)C(CCCc1ccc(C(=O)O)cc1)c1c(N)nc(N)nc1N
Temperature: 40 °C
Reaction time: 8 h

Procedure:
The product of Example 13 (403 mg) was suspended in a mixed solution of tetrahydrofuran-water (5:1, 8.0 ml), 1N aqueous solution of sodium hydroxide (2.0 ml) was added thereto and the mixture was stirred at 40° C. overnight. After neutralizing the mixture by adding 1N hydrochloric acid (2.0 ml), solvent was removed by distillation under reduced pressure and the residue was dried to give crude 4-[4-(2,4,6-triaminopyrimidin-5-yl)-5,5-dimethoxypentyl]benzoic acid. The total amount of the crude product and diethyl glutamate hydrochloride (360 mg) were suspended in dimethylformamide (4.0 ml), a solution (4.0 ml) of diethyl phosphorocyanidate (171 mg) in dimethylformamide was added thereto at 0° C. and the mixture was stirred. Subsequently, a solution (4.0 ml) of triethylamine (303 mg) in dimethylformamide was added dropwise thereto at the same temperature and the mixture was stirred at 0° C. for 30 minutes and then at room temperature for 3 hours, followed by removing solvent by distillation under reduced pressure. The resulting residue was purified by flash column chromatography (15 g of silica gel; dichloromethane-methano 30:1→75:1) to give the subject compound (417 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([O:29][CH3:30])=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][N:21]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[CH:22]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][CH2:39][OH:40]>CC(C)=O>[F:1][C:2]1[C:3]([O:29][CH3:30])=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][N:21]([CH:23]5[CH2:24][CH2:25][N:26]([CH2:38][CH2:39][OH:40])[CH2:27][CH2:28]5)[CH:22]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COc1c(F)cc(F)cc1-c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1c(F)cc(F)cc1-c1c[nH]c2ncc(-c3cnn(C4CCN(CCO)CC4)c3)cc12
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a solution of 282 (50 mg, 0.122 mmol) in acetone was added potassium carbonate (25 mg, 0.244 mmol) and 2-bromo ethanol (18.3 mg, 0.146 mmol) and stirred for 12 h at 60° C. The reaction was filtered through celite bed and washed with ethyl acetate. The organic layer was concentrated to get the crude, which was purified by neutral alumina and the compound was eluted at 2% methanol in chloroform as half white coloured solid 2-(4-(4-(3-(3,5-difluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanol 347. 1HNMR (400 MHz, DMSO) δ: 12.04 (s, 1H), 8.54 (d, 1H), 8.31 (s, 1H), 8.18 (d, 1H), 7.93 (s, 1H), 7.81 (d, 1H), 7.22 (m, 2H), 4.39 (m, 1H), 4.10 (m, 1H), 4.00 (m, 1H), 3.60 (s, 3H), 3.50 (m, 2H), 2.96 (d, 2H), 2.42 (m, 2H), 2.13 (m, 2H), 1.99 (m, 3H), 1.16 (t, 1H) and MS ES+454.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][C@H:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:23]([O-:25])=[O:24].Br[C:27]1[S:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C@H:10]2[CH2:11][CH2:12][C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:23]([O-:25])=[O:24])[CH:4]=3)[N:9]2[C:27]2[S:28][C:29]3[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=3[N:31]=2)=[CH:14][C:15]=1[N+:20]([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cc([C@H]2CC[C@H](c3ccc(Cl)c([N+](=O)[O-])c3)N2)ccc1Cl
Reactant: Brc1nc2ccccc2s1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc([C@H]2CC[C@H](c3ccc(Cl)c([N+](=O)[O-])c3)N2c2nc3ccccc3s2)ccc1Cl
Temperature: 100 °C
Yield: 36.5 %

Procedure:
The product from Example 115B (0.335 g, 0.877 mmol), 2-bromobenzo[d]thiazole (0.281 g, 1.32 mmol), tris(dibenzylideneacetone)dipalladium(0) 0.08 g (0.088 mmol), BINAP (0.055 g, 0.088 mmol), and sodium tert-butoxide (0.126 g, 1.32 mmol) were combined in dioxane (8 mL) and nitrogen was bubbled through the solution for 10 minutes. The tube was sealed and heated at 100° C. for 18 hours. The reaction mixture was partitioned between brine and dichloromethane and the organics were concentrated and purified by combi-flash 24 g silica column, eluting with 1:1 hexanes: dichloromethane, followed by 100% dichloromethane to give 0.165 g (37%) of the title compound.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:22]([NH:24][N:25]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:26](=[O:34])[CH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].[ClH:43]>O1CCOCC1.C(OCC)C>[ClH:43].[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:22]([NH:24][N:25]([CH2:35][CH:36]([CH3:37])[CH3:38])[C:26](=[O:34])[CH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CC1CCNCC1)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CC1CCNCC1)[C@H](C/C=C/c1ccccc1)C(=O)NO

Procedure:
A solution of 0.300 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-[2-(4-piperidinyl)acetyl]valerohydrazide in 3 ml of 4M hydrogen chloride in dioxan was stirred for 2.5 hours at room temperature and diluted with diethyl ether. The solid was filtered off, washed with diethyl ether and dried to give 0.256 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-[2-(4-piperidinyl)acetyl]valerohydrazide hydrochloride in the form of an off-white solid.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH:22]([NH:24][OH:25])[CH3:23].C(N(CC)CC)C.Cl>ClCCl>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH:22]([N:24]([OH:25])[C:8]([C:7]1[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=1)=[O:9])[CH3:23]
Reactant: CC(Cc1ccc(Cl)cc1Cl)NO
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Cc1ccc(Cl)cc1Cl)N(O)C(=O)c1cn(C)nc1C(F)F
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (2.10 g; 11.0 mmol) in dichloromethane (5 ml) was added dropwise to a stirred suspension of N-[2-(2,4-dichlorophenyl)-1-methyl-ethyl]-hydroxylamine (2.0 g; 9.10 mmol), prepared as described in example P17, triethylamine (3.10 ml; 22 mmol) in dichloromethane (15 ml) at 0° C. The reaction mixture was stirred over night at ambient temperature. The reaction mixture was poured onto 1M HCl (50 ml), extracted with dichloromethane (3×20 ml) and then dried over Na2SO4. After removal of the solvent the residue (5.08 g) was purified by flash chromatography over silica gel (eluant: c-hexane/ethyl acetate 7:3). 1.51 g (43.8% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [2-(2,4-dichlorophenyl)-1-methyl-ethyl]-hydroxy-amide (compound 1.028) was obtained in form of a white solid (m.p. 162-167° C.).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH:13]([C:15]1[N:20]2[N:21]=[CH:22][N:23]=[C:19]2[N:18]=[CH:17][CH:16]=1)[CH3:14]>COCCOC>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:13]([C:15]2[N:20]3[N:21]=[CH:22][N:23]=[C:19]3[N:18]=[CH:17][CH:16]=2)[CH3:14])=[CH:5][CH:4]=1
Reactant: CC(Br)c1ccnc2ncnn12
Reactant: CSc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CSc1ccc(OC(C)c2ccnc3ncnn23)cc1
Reaction time: 0.5 h

Procedure:
A solution of 4-(methylthio)phenol (2.80 g) in dry 1,2-dimethoxyethane was added slowly to a stirred suspension of sodium hydride (0.87 g) in dry 1,2-dimethoxyethane (50 ml). The mixture was stirred for 30 minutes, then a solution of 7-(1-bromoethyl)-1,2,4-triazolo[1,5-a]pyrimidine (4.54 g, prepared in a similar manner to that described in Example 6 above) in dry 1,2-dimethoxyethane (150 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature. The sodium bromide was removed from the mixture by filtration. The solvent was evaporated from the mixture and the residue was dissolved in dichloromethane and washed with 200 ml of a 5% aqueous solution of sodium hydroxide followed by water. The organic layer was dried over magnesium sulphate. Evaporation of the solvent afforded a crude product which was purified by column chromatography on silica gel using as eluent a mixture of ethyl acetate and petroleum ether (in the ratio 4:6 respectively), followed by recrystallisation from a mixture of ethyl acetate and hexane, to give 7-{1-[4-(methylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]pyrimidine. Yield 3.66 g, (m.p. 84°-86° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[C:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][C:10]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:8])[CH3:2].Cl.[NH2:38]O>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[C:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:11][C:10]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][N:38]=1)=[O:36])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)c1cc(CC(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cc(CC(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Temperature: 25 °C

Procedure:
4-(2,4-Bis-benzyloxy-5-isobutyl-phenyl)-2,4-dioxo-butyric acid ethyl ester (1 eq) was dissolved in ethanol with stirring. Hydroxylamine hydrochloride (1.2 eq) was added and the solution was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, to give a precipitate. This precipitate was obtained by filtration to give 5-(2,4-Bis-benzyloxy-5-isobutyl-phenyl)-isoxazole-3-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:13][CH3:14])[C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].BrC1C=CC([N+]([O-])=O)=C(OC)C=1[F:27]>>[F:27][C:7]1[C:8]([O:13][CH3:14])=[C:9]([N+:10]([O-:12])=[O:11])[CH:2]=[CH:3][C:4]=1[C:5]#[N:6]
Reactant: COc1cc(C#N)cc(F)c1[N+](=O)[O-]
Reactant: COc1c([N+](=O)[O-])ccc(Br)c1F
Product: COc1c([N+](=O)[O-])ccc(C#N)c1F

Procedure:
The title compound was prepared according to the procedure for 3-fluoro-5-methoxy-4-nitrobenzonitrile (Compound 146F) using 1-Bromo-2-fluoro-3-methoxy-4-nitrobenzene (Compound 147G). 1H NMR (CDCl3, 400 MHz): δ=4.15 (d, J=2.27 Hz, 3 H), 7.45 (dd, J=8.59, 5.56 Hz, 1 H), 7.64 (dd, J=8.59, 1.77 Hz, 1 H).