Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][CH3:14])[C@H:10]([C:15]#[N:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[OH:19]>C(Cl)(Cl)Cl.CC(O)=O.O=[Pt]=O>[C:11]([OH:13])(=[O:19])[CH3:12].[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][CH3:14])[C@H:10]([CH2:15][NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCO
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C#N
Agent: O=[Pt]=O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN
Reaction time: 16 h

Procedure:
80.3 A suspension of (3S,4S)-3-cyano-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg) in 15 ml of EtOH, 0.3 ml of chloroform, 0.38 ml of AcOH and 8 mg of PtO2 was hydrogenated at 22° C. and atmospheric pressure for 16 h. The suspension was filtered and the filtrate evaporated to give 188 mg of (3R,4S)-3-aminomethyl-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester acetate. Colorless semisolid. MS 231.3 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:19].Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])[C:24]([Cl:38])=[CH:23][N:22]=1.Cl.O1CCOCC1.C(=O)(O)[O-].[Na+]>COCCO>[Cl:38][C:24]1[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])=[N:26][C:21]([NH:19][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:22][CH:23]=1
Reactant: COCCNC1CCc2ccc(N)c(OC)c2CC1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: COCCO
Product: COCCNC1CCc2ccc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)c(OC)c2CC1
Temperature: 130 °C
Yield: 14.7 %

Procedure:
1-Methoxy-N*7*-(2-methoxy-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine 200 mg, 0.8 mmol) and (1S,2S,3R,4R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (224 mg, 0.750 mmol) were dissolved in 5 ml 2-methoxyethanol in a reaction tube. 4N HCl in dioxane (0.4 ml, 1.6 mmol) was charged and the reaction heated to 130° C. The reaction was followed by HPLC. Upon completion, the reaction was poured into saturated sodium bicarbonate (50 ml) and extracted with methylene chloride (4×25 ml portions). The combined organic was dried over magnesium sulfate, filtered and evaporated. Purification was carried via preparative HPLC and the desired fractions neutralized and extracted to yield (1S,2S,3R,4R)-3-{5-Chloro-2-[1-methoxy-7-(2-methoxy-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (58.19 mg, 27% yield) as the beige foam free base. Purification separated the compound into its corresponding enantiomers. 1H-NMR (CDCl3) δ 8.17 (d, J=8.3 Hz, 1H), 7.88 (s, 1H), 7.39 (s, 1H), 6.94 (m, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.37 (m, 1H), 6.31 (m, 1H), 5.61 (br s, 1H), 5.36 (br s, 1H), 4.37 (m, 1H), 3.72 (s, 3H), 3.51 (m, 2H), 3.26 (s, 3H), 3.23 (m, 1H), 3.06 (s, 1H), 2.94 (s, 1H), 2.85-2.70 (m, 6H), 2.49 (d, J=8.4 Hz, 2H), 2.24 (d, J=8.9 Hz, 1H), 2.09 (m, 2H), 1.63 (m, 2H), 1.26 (m, 4H). LC/MS (ESI+)=527 (M+H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C@@H:8]([CH:15]([CH3:17])[CH3:16])[C:9]([N:11]1[CH2:14][CH2:13][CH2:12]1)=O.[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[N:11]1([CH2:9][C@@H:8]([NH2:7])[CH:15]([CH3:17])[CH3:16])[CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)[C@H](N)C(=O)N1CCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@H](N)CN1CCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a 1M solution of LAH in THF (19.2 mL, 19.2 mmol) was (S)-2-amino-1-(azetidin-1-yl)-3-methylbutan-1-one (Compound T) (2 g, 12.8 mmol) in THF (12.8 mL) added (over approximately 30 min) at 0° C. under a nitrogen atmosphere. The resultant mixture was stirred at rt for 1 h and heated at 60° C. for 6 h. The reaction was cooled to 0° C. Water (0.73 mL) was slowly added, followed by 15% aq. NaOH (0.73 mL) and additional water (2.2 mL). The reaction mixture was warmed to rt and stirred for 1 h. Celite and Na2SO4 were added. The mixture was filtered and the filtrate concentrated under reduced pressure to give the title compound (1.14 g, 63%). 1H NMR (400 MHz, CDCl3) δ 3.29-3.04, 2.51-2.39, 2.37-2.21, 2.14-1.96, 1.60-1.47, 1.34, 0.94-0.76. Total no of protons: 18.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH:14]([C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][CH:22]=[C:23]2[CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:28]=2[O:37][CH3:38])=[CH:18][CH:17]=1)=[O:15]>CN(C)C=O>[C:14]([C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][CH:22]=[C:23]2[CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:28]=2[O:37][CH3:38])=[CH:18][CH:17]=1)([OH:3])=[O:15]
Reactant: COC(=O)c1ccc(Cc2cccc3ccc(C=O)cc23)c(OC)c1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cc2cccc3ccc(C(=O)O)cc23)c(OC)c1
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of Jones reagent (1.53 ml) [prepared from 26.72 g chromium trioxide in 23 ml concentrated sulfuric acid, diluted with water to 100 ml] was added to a solution of methyl 4-(7-formylnaphth-1-yl-methyl)-3-methoxybenzoate (409 mg) in dimethylformamide (12 ml, distilled over CaH2). The mixture was stirred for 1 h and was partitioned between methylene chloride and 1N HCl. The organic layer was washed (1N HCl (twice), brine), dried (MgSO4) and evaporated. The residue was triturated with ether, ground to a powder and vacuum dried at 120° C. for 12 h to afford methyl 4-(7-carboxynaphth-1-ylmethyl)-3-methoxybenzoate (347 mg, 81%) as a pale yellow solid; mp 229.0°-230° C.; MS(CI), m/e=351(M+H).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:12]=[CH:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][N:14]=2)[CH:9]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.O>ClCCl>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH:11]=[CH:12][C:8]([C:6]([OH:7])=[O:5])=[CH:9]2)=[N:14][CH:15]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1ccc(-n2ccc(C(=O)OC(C)(C)C)c2)nc1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1ccc(-n2ccc(C(=O)O)c2)nc1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
To a solution of 1-(5-acetylpyridin-2-yl)pyrrole-3-carboxylic acid tert-butyl ester (380 mg) in dichloromethane (5 ml) were added trifluoroacetic acid (3 ml) and water (0.3 ml), and stirred at room temperature. After completion of the reaction, the solvent was evaporated in vacuo, to the residue was added water, 1 N aqueous solution of sodium hydroxide was added thereto under ice-cooling to adjust the mixture to pH 10, diethyl ether was added thereto, and the aqueous layer was separated. To the aqueous layer was added concentrated hydrochloric acid under ice-cooling, the precipitated solid was collected by filtration, and dried at 60° C. under air blow to give the titled compound (300 mg) as a white solid. MS (ESI) m/z: 231
Reaction SMILES: Cl([O-])=O.[Na+].S(=O)(=O)(O)N.[CH3:10][C@@:11]([OH:18])([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:12]=[O:13].[OH2:19]>O1CCCC1.O.C(Cl)Cl.CSC>[CH3:10][C@@:11]([OH:18])([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]([OH:19])=[O:13]
Reactant: O
Reactant: CC(C)(C)[C@@](C)(O)C=O
Agent: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)[C@@](C)(O)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium chlorite (1.81 g, 20 mmol) and sulfamic acid (1.94 g, 20 mmol) were added in succession to a stirred solution of (R)-2,3,3-trimethyl-2-hydroxybutanal (2.0 g, 15.4 mmol) in 30 ml of tetrahydrofuran-water (1:1) at 0° C. The mixture was allowed to warm to room temperature, stirred for 30 minutes, diluted with methylene chloride and about 1 ml of methyl sulfide was added followed by a small quantity of water. The organic layer was separated, the aqueous layer was extracted with methylene chloride, and the combined organic layer was dried (magnesium sulfate) and concentrated to afford a yellow gummy solid. Recrystallization from hexanes afford 1.45 g of (R) -2,3,3-trimethyl-2-hydroxybutanoic acid as a pale solid.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([NH:11][CH:12]1[C:34](=[O:35])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:16]([CH3:20])([CH3:19])[S:17](=[O:18])[C@H:13]12)(=[O:10])[CH3:9].[Cl:36]N1C(=O)CCC1=O>O>[CH3:19][C:16](=[CH2:20])[CH:15]([N:14]1[C:34](=[O:35])[CH:12]([NH:11][C:8](=[O:10])[CH3:9])[CH:13]1[S:17]([Cl:36])=[O:18])[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22]
Reactant: CC(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(C)(C)S(=O)[C@H]12
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(C)=O)C1S(=O)Cl

Procedure:
Toluene (500 ml.) was heated in equipment containing a Dean-Stark water trap to azeotropically remove any moisture which may be present. To the resulting dried toluene was added 1.0 gms. (2.4 mmol.) of p-nitrobenzyl 6-acetamido-2,2-dimethylpenam-3-carboxylate-1-oxide. The resulting mixture was refluxed again using a Dean-Stark water trap to remove any additional amounts of water which may be present. The mixture then was cooled, and 400 mg. (2.9 mmol) of N-chlorosuccinimide were added. The mixture then was refluxed for 1 hour. A sample of the reaction mixture was withdrawn, and the solvent was removed. The product which was obtain was consistent by nmr analysis with the structure of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH:23]C(OC)=O)=[N:19][C:18]=3[C:17]([O:28][CH3:29])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>O1CCOCC1.C(O)CO.[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH2:23])=[N:19][C:18]=3[C:17]([O:28][CH3:29])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)Nc1nc2c(OC)ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: C1COCCO1
Product: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(N)nc12
Temperature: 100 °C
Yield: 89.9 %

Procedure:
0.9 g (0.002 Mol) 4-(4-methoxy-2-methoxycarbonylamino-benzothiazol-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester were dissolved in a mixture of 7 ml dioxane, 14 ml ethylene glycol and 14 ml 2 N NaOH and heated to 100° C. for 15 h. After cooling to room temperature the pH was adjusted to 7 with 1 N HCl. A precipitation formed, which was filtered, washed with water and dried in vacuo to yield 0.65 g (84%) 4-(2-amino-4-methoxy-benzothiazol-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a light yellow solid; F.p.: 191-196° C.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[O:20]=[C:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)[C:3]([OH:21])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCOc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCOc2ccccc2)cc1
Yield: 78.3 %

Procedure:
A mixture of alpha-oxo-4-[[(phenoxy)methyl]oxy]benzeneacetic acid methyl ester (0.43 g) in methanol and 0.5N sodium hydroxide (4 mL) was treated as in Example 19. Extraction provided 0.415 g which solidified and was crystallized from benzene-hexane to give 0.32 g of colorless alpha-oxo-4-[[(phenoxy)methyl]oxy]benzeneacetic acid as an 0.2 molar hydrate, mp 72°-74° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[C:16](Br)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26](C2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[OH:37].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C(OCC)(=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>[CH2:1]([N:8]1[CH:17]=[C:16]([C:26]2[CH:25]=[CH:24][C:23]([OH:37])=[C:22]([O:21][CH3:20])[CH:27]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: O=c1c2ccccc2c(Br)cn1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(-c2cn(Cc3ccccc3)c(=O)c3ccccc23)ccc1O
Temperature: 90 °C
Reaction time: 16 h
Yield: 44.5 %

Procedure:
A mixture of 2-benzyl-4-bromoisoquinolin-1(2H)-one (0.50 g, 1.59 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenol (0.477 g, 1.90 mmol) and Na2CO3 (0.843 g, 7.95 mmol) in toluene (30 mL), ethanol (30 mL) and water (5 mL) was degassed under nitrogen. Pd(PPh3)4 (0.183 g, 0.157 mmol) was added and the reaction was stirred at 90° C. for 16 h under nitrogen. After that time, the mixture was cooled to rt and diluted with ethyl acetate (250 mL). The organic phase was separated, washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 70:30 hexanes/ethyl acetate) to give 2-benzyl-4-(4-hydroxy-3-methoxyphenyl) isoquinolin-1(2H)-one (0.253 g, 45%) as a white solid: mp 165-167° C.; 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=8.2 Hz, 1H), 7.58-7.65 (m, 1H), 7.50-7.57 (m, 2H), 7.28-7.40 (m, 5H), 7.05 (s, 1H), 6.99 (d, J=8.6 Hz, 1H), 6.84-6.89 (m, 2H), 5.70 (s, 1H), 5.27 (s, 2H), 3.89 (s, 3H); ESI MS m/z 358 [M+H]+.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([C@@H:19]([NH2:41])[CH:20]([OH:40])[CH:21]([NH:23][S:24]([C:27]1[CH:39]=[CH:38][C:30]2[O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:29]=2[CH:28]=1)(=[O:26])=[O:25])[CH3:22])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:1]([NH:11][C@H:12]([C:17]([C@H:19]([NH2:41])[C:20](=[O:40])[CH:21]([NH:23][S:24]([C:27]1[CH:39]=[CH:38][C:30]2[O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:29]=2[CH:28]=1)(=[O:25])=[O:26])[CH3:22])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)[C@@H](N)C(O)C(C)NS(=O)(=O)c1ccc2oc3ccccc3c2c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)[C@H](N)C(=O)C(C)NS(=O)(=O)c1ccc2oc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
1-(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-(S)-butan-2-ol (240 mg, 0.4 mmol) was dissolved in acetone (2 ml). Jones reagent (0.5 ml, 1.5 M) was added dropwise and the reaction was stirred at RT overnight. The excess Jones reagent was then quenched with isopropanol (1.0 ml), then the reaction was diluted with EtOAc (20 ml) and was extracted with water (2×30 ml) to remove the inorganic salts. The combined organics were dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 2-5% MeOH/methylene chloride) to give the title compound as a white solid (70 mg, 29%). MS(ES) M−H+=578.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C@:8]([C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]1)([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)[OH:9])(=[O:3])[CH3:2]>CC#N.Cl>[Cl:16][C:12]1[CH:11]=[C:10]([C@@:8]([OH:9])([C@@H:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)[CH2:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)NCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CC#N
Product: CC(=O)NCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (R)-tert-butyl 3-((S)-4-acetamido-1-(3-chlorophenyl)-1-hydroxybutyl)-piperidine-1-carboxylate (0.1773 g, 0.4172 mmol) in CH3CN (50 mL) and 2 N aq HCl (45 mL) was vigorously stirred at rt for 24 h. The solvents were removed in vacuo to give the HCl salt of N—((S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butyl)acetamide, which was used in the next step without further purification. LC-MS (3 min) tR=0.91 min, m/z 325, 327 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]=[N:13][CH:14]=[C:15]([N:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)[N:16]=3)[CH:9]=2)[NH:4][N:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]=[N:13][CH:14]=[C:15]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[N:16]=3)[CH:9]=2)[NH:4][N:3]=1
Reactant: Cc1n[nH]c2ccc(-c3nncc(N4CCN(C(=O)OC(C)(C)C)CC4)n3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1n[nH]c2ccc(-c3nncc(N4CCNCC4)n3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To 3-(3-methylindazol-5-yl)-5-(4-Boc-piperazin-1-yl)-[1,2,4]triazine 153 (5.1 mg, 0.013 mmol.) was added a 20% solution of trifluoroacetic acid in DCM. The reaction mixture was stirred at room temperature for 1 hour. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to yield the desired 3-(3-methylindazol-5-yl)-5-(piperazin-1-yl)-[1,2,4]triazine 46 (2.6 mg, 0.0088 mmol.).
Reaction SMILES: N#N.[CH2:3]([O:10][C:11]([C@@:13]1([C:25]([NH2:27])=[O:26])[CH2:17][C@@H:16]([N:18]=[N+:19]=[N-])[CH2:15][N:14]1[C:21]([CH3:24])([CH3:23])[CH3:22])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1>[N:18]#[N:19].[CH2:3]([O:10][C:11]([C@@:13]1([C:25]([NH2:27])=[O:26])[CH2:17][C@@H:16]([NH2:18])[CH2:15][N:14]1[C:21]([CH3:23])([CH3:24])[CH3:22])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)N1C[C@H](N=[N+]=[N-])C[C@]1(C(N)=O)C(=O)OCc1ccccc1
Agent: N#N
Solvent: C1CCOC1
Product: CC(C)(C)N1C[C@H](N)C[C@]1(C(N)=O)C(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 56.1 %

Procedure:
0.345 g of N2 -(benzyloxycarbonyl)-4(R)-azido-N1 -tert.butyl-L-prolinamide was dissolved in 5 ml of dry tetrahydrofuran and the solution was evaporated. The residual gum was dissolved in 10 ml of dry tetrahydrofuran and treated under a nitrogen atmosphere with 0.262 g of triphenylphosphine. The resulting solution was left to stand under a nitrogen atmosphere at room temperature for 18 hours. 0.027 g of water was added and the solution was left to stand at room temperature for 24 hours. The solvent was then removed by evaporation and the residual gum was partitioned between water and diethyl ether. The aqueous phase was back-extracted with diethyl ether. The aqueous phase was then evaporated to give 0.09 g of N2 -(benzyloxycarbonyl)-4(R)-amino-N1 -tert.butyl-L-prolinamide as a gum. After standing overnight at room temperature the diethyl ether extracts were combined and evaporated to give 0.7 g of an oil which was chromatographed on silica gel using 10% methanol in dichloromethane for the elution to give a further 0.16 g of N2 -(benzyloxycarbonyl)-4(R)-amino-N1 -tert.butyl-L-prolinamide as a gum.
Reaction SMILES: [CH2:1]([Si:5]([CH3:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6](O)[CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:2][CH:3]=[CH2:4].CCN(CC)CC.CS(Cl)(=O)=O.[N-:31]=[N+:32]=[N-:33].[Na+].C([Si](C1SCCCS1)(C1C=CC=CC=1)C1C=CC=CC=1)CC=C.C1([Si](C2C=CC=CC=2)(CCC(=O)NCC2C=CC=CC=2)C(NC(=O)C2C=CC=CC=2)CC(C)C)C=CC=CC=1.[SiH3]O[SiH2]O[SiH3].Cl[SiH2]Cl>C(Cl)Cl.CCCCCC.CCOC(C)=O>[N:31]([CH:6]([Si:5]([CH2:1][CH2:2][CH:3]=[CH2:4])([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])=[N+:32]=[N-:33]
Reactant: C=CCC[Si](C)(c1ccccc1)C(O)CC(C)C
Reactant: [N-]=[N+]=[N-]
Agent: C=CCC[Si](c1ccccc1)(c1ccccc1)C1SCCCS1
Agent: CC(C)CC(NC(=O)c1ccccc1)[Si](CCC(=O)NCc1ccccc1)(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC[Si](C)(c1ccccc1)C(CC(C)C)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 46 (3.4 g, 13 mmol) in CH2Cl2 (150 mL) and Et3N (9 mL, 65 mmol) at 0° C. was added dropwise over 5 min methanesulfonyl chloride (7.4 g, 65 mmol), and the mixture was allowed to warm to rt over 1 h. After stirring overnight under argon, the mixture was cooled to 0° C. and quenched with water (50 mL). The organic layer was isolated and the aqueous layer extracted twice with 50-mL portions of CH2Cl2. The combined organic extracts were concentrated in vacuo at rt. The crude mesylate was dissolved in DMF (150 mL), and to this solution was added sodium azide (4.2 g, 64.8 mmol). After stirring overnight at rt, the mixture was partitioned between water (200 mL) and EtOAc (200 mL). The organic layer was isolated and the aqueous layer extracted twice with 50-mL portions of EtOAc. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated. Flash chromatography over silica gel (1/19 EtOAc:hexane) gave a colorless oil of pure 47 as a mixture of diastereomers (3.11 g, 84%): Rf=0.80 (1/9 EtOAc:hexane); 1H NMR (300 MHz, CDCl3) δ 7.53-7.47 (m, 2H), 7.38-7.32 (m, 3H), 5.91-5.78 (m, 1H), 5.0-4.86 (m, 2H), 3.03 and 2.99 (two triplets due to diastereomers, J=2.7 Hz, 1H), 2.08 (q, J=7.8 Hz, 2H), 1.82-1.70 (m, 1H), 1.58-1.47 (m, 1H), 1.19-1.10 (m, 1H), 1.06-0.94 (m, 2H), 0.89-0.83 (m, 6H), 0.38 and 0.36 (two singlets due to diastereomers, 3H); 13C NMR (75 MHz, CDCl3) δ 140.8, 134.2, 134.1, 129.6, 128.0, 113.3, 50.4, 50.3, 38.6, 38.5, 27.5, 25.8, 23.3, 20.7, 11.4, 11.0, −6.8, −7.3; IR (neat) 3067 (w), 2956 (s), 2914 (m), 2865 (m), 2099 (s), 1640 (m), 1469 (w), 1427 (m), 1259 (s), 1113 (m), 999 (w), 909 (m), 795 (m), 738 (m), 699 (m) cm−1; MS (FAB) m/e (rel. intensity) 288 (MH+, 19), 262 (10), 261 (32), 260 (100), 259 (29), 258 (39), 253 (14), 245 (20), 244 (64), 233 (15), 217 (11), 216 (16), 207 (19), 204 (54); HRMS (FAB) calcd for C16H26N3Si: 288.1896, found: 288.1895.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5]([NH:7][C:8]1[O:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=1)=[O:6].[C:19]1([C:25]2[N:29]=[C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:19]1([C:25]2[N:29]=[C:28]([N:30]3[CH2:35][CH2:34][N:33]([C:5]([NH:7][C:8]4[O:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=4)=[O:6])[CH2:32][CH2:31]3)[S:27][N:26]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: COC(=O)c1ccc(NC(=O)OCC(Cl)(Cl)Cl)o1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)o1
Yield: 21.4 %

Procedure:
A mixed solution of methyl 5-{[(2,2,2-trichloroethoxy)carbonyl]amino}-2-furancarboxylate (321 mg, 1.01 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.177 ml, 1.01 mmol) in dimethyl sulfoxide (3.4 ml) was stirred at 70° C. for 5 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 71.7 mg (17.1%) of the desired product as a solid.