Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[C:16]([CH2:19][CH2:20]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:18])=[O:17].[H-].[Na+]>CS(C)=O.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:20][CH2:19][C:16]([OH:18])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=CCC(=O)O)CC1
Temperature: 0 °C
Reaction time: 20 h
Yield: 24.9 %

Procedure:
A mixture of 7.53 g (37.8 mmol) of 1-t-butoxycarbonyl-piperidin-4 one and 14 g (37.8 mmol) of (3-carboxypropyl)triphenyl-phosphonium chloride (from EXAMPLE 98, Step A) were dissolved in 100 mL of 1:1 v/v DMSO/THF. The mixture was cooled to 0° C. and was then added to 2 g (83.2 mmol) of dry 95% sodium hydride powder at 0° C. over a 10 min period. After stirring this mixture at 0 ° C. for 20 h, the reaction was quenched with H2O, treated with sat'd NaCl and extracted 2× with CH2Cl2. The aqueous phase was acidified to pH 1 with 1 N HCl, and extracted 3× with CH2Cl2. The combined organic layers were washed with sat'd NaCl and H2O, dried over Na2SO4, filtered and the filtrate concentrated. The residue was purified by column chomatography on 150 g of silica using a gradient of 25-50% acetone/hexanes (v/v), to give 2.4 g (25%) of the title compound: 1H NMR (500 _MHz) δ 1.47 (s, 9H1.2.21 (d, J=5.5,44H), 3.12 (d, J=7.3,22H), 3.42 (d, J=5.7, 4H), 5.41 (t, J=7.1, 11H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([CH:19]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH3:20])[CH:18]=1)[C:13]([O-:15])=[O:14])(=[O:3])[CH3:2]>C1COCC1.CO.O.[OH-].[Na+]>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([CH:19]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH3:20])[CH:18]=1)[C:13]([OH:15])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCCC1c1cc(C(=O)[O-])cc(C(C)C2CCCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)N1CCCCC1c1cc(C(=O)O)cc(C(C)C2CCCCC2)c1
Reaction time: 3 h

Procedure:
To a solution of 3-(1-acetylpiperidin-2-yl)-5-(1-cyclohexylethyl)benzoate (80 mg, 0.22 mmol) in THF:MeOH:water (1:1:1, 6 mL) was added NaOH (6 N, 10 drops) and the mixture was stirred for 3 h. The volatiles were removed in vacuo and the mixture was acidified with aqueous HCl (6 N) to a pH of about 2. The mixture was extracted with EtOAc (3×10 mL). The combined organics were washed with water (1×10 mL), brine (1×10 mL), dried over sodium sulfate, filtered and concentrated. The title compound was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])[CH:7]=[CH:6][C:5]=1[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:23][C:24]=2[CH3:25])[CH:7]=[CH:6][C:5]=1[CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(OCc2ccccc2OCc2nc(-c3ccccc3)oc2C)cc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCOc1cc(OCc2ccccc2OCc2nc(-c3ccccc3)oc2C)ccc1CCC(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a mixture of ethyl 3-[2-ethoxy-4-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate (0.62 g), tetrahydrofuran (3 mL) and ethanol (3 mL) was added a 1N aqueous sodium hydroxide solution (2.4 mL) and the mixture was stirred at 50° C. for 2 hrs. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.50 g, 85%) of 3-[2-ethoxy-4-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 112-113° C.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][OH:14])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15]Br>C(Cl)Cl.C1COCC1>[Br:15][C:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][NH:9][C:10]=1[CH2:12][CH2:13][OH:14]
Reactant: BrBr
Reactant: OCCc1cc(-c2ccccc2)n[nH]1
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCCc1[nH]nc(-c2ccccc2)c1Br
Reaction time: 2 h
Yield: 93.3 %

Procedure:
2-(3-Phenyl-1H-pyrazol-5-yl)ethanol (664 mg, 3.53 mmol) was dissolved in dry DCM (40 mL) and THF (10 mL). The reaction was cooled in an ice bath and Br2 (363 μL, 7.06 mmol), pre-dissolved in DCM (3 mL), was added slowly dropwise via addition funnel. The reaction was stirred for 2 h in an ice bath, then the reaction was quenched by the addition of Na2SO3 (20 mL of 10% solution; the reaction went from reddish-brown to clear and some bubbling was observed). The reaction was extracted (100 mL each of H2O and DCM). The aqueous layer was extracted again with DCM (100 mL). The combined organic layer was back extracted again with H2O (200 mL). The organic layer was dried and concentrated to yield the title compound (880 mg) as a light yellow solid. LCMS m/z=267.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.78 (t, J=7.14 Hz, 2H), 3.66 (t, J=7.14 Hz, 2H), 7.35-7.42 (m, 1H), 7.43-7.51 (m, 2H), 7.72-7.84 (m, 2H).
Reaction SMILES: C1C=CC=CC=1.[Cl:7][C:8]1[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:9]=1[O:10][CH2:11][C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>C(N(CC)CC)C>[Cl:7][C:8]1[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:9]=1[O:10][CH2:11][C:12]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[O:13]
Reactant: Nc1ccccn1
Reactant: O=C(Cl)COc1cc(Cl)c(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(COc1cc(Cl)c(Cl)cc1Cl)Nc1ccccn1

Procedure:
After filling in a dry 250 ml flask respectively 150 ml of anhydrous benzene and 32.5 g (0.118 mol) of 2,4,5-trichlorophenoxyacetyl chloride synthesized in Example 14, 11 g (0.118 mol) of 2-aminopyridine was added with vigorous stirring, and then 8.1 ml of triethylamine was slowly dropped to be heated and refluxed for 2-3 hours, while the external temperature was maintained at 80°-90° C.
Reaction SMILES: CS(C1C=CC(C2C=CC3[N:15](N=C(N)N=3)C=2)=CC=1)(=O)=O.Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[N:28]1([C:25]2[CH:26]=[CH:27][C:22]([NH2:15])=[CH:23][CH:24]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: Brc1ccc(N2CCOCC2)cc1
Reactant: CS(=O)(=O)c1ccc(-c2ccc3nc(N)nn3c2)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: Nc1ccc(N2CCOCC2)cc1

Procedure:
N-(5-bromo-2-pyridinyl)-N′-carboethoxy-thiourea was prepared from 2-amino-5-bromopyridine (10.0 g, 0.0578 mol) in a manner analogous to Step 2a. The reaction product was isolated as a yellow solid and used without further purification. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 12.14 (br s, 1H), 11.72 (br s, 1H), 8.67-8.55 (m, 1H), 8.53 (d, J=2.4 Hz, 1H), 8.13 (dd, J=9.0, 2.5 Hz, 1H), 4.23 (q, J=7.0 Hz, 2H), 1.26 (t, J=7.0 Hz, 3H). MS=304, 306 (MH)+. 36b) 6-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from N-(5-bromo-2-pyridinyl)-N′-carboethoxy-thiourea in a manner analogous to Step 2b. The reaction product was isolated as a white solid (7.84 g, 63%). MP=187-189° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.92 (d, J=1.9 Hz, 1H), 7.55 (dd, J=9.2, 1.9 Hz, 1H), 7.33 (d, J=9.4 Hz, 1H), 6.13 (br s, 2H). MS=213, 215 (MH)+. 36c) 6-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (200.0 mg, 0.9388 mmol) and (4-methylsulfonylphenyl)boronic acid (210.0 mg, 1.050 mmol) in a manner analogous to Step 2c. The reaction product was isolated as an off-white solid (0.158 g, 58%). MP=301-303° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.08-9.05 (m, 1H), 8.06-7.97 (m, 4H), 7.86 (dd, J=9.2, 1.7 Hz, 1H), 7.48 (d, J=9.1 Hz, 1H), 6.15 (s, 2H), 3.26 (s, 3H). MS=289 (MH)+. 36d) 6-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was prepared from 6-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (50.0 mg, 0.173 mmol) and 4-(4-bromo-phenyl)-morpholine (51.0 mg, 0.211 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (20.0 mg, 0.0366 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.011 g, 14%). MP=>300° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.41 (s, 1H), 9.28 (s, 1H), 8.09 (d, J=7.7 Hz, 2H), 8.03-7.96 (m, 3H), 7.64 (d, J=8.8 Hz, 1H), 7.59 (d, J=7.9 Hz, 2H), 6.93 (d, J=8.0 Hz, 2H), 3.77-3.71 (m, 4H), 3.28 (s, 3H), 3.05-3.00 (m, 4H). MS=450 (MH)+.
Reaction SMILES: [P:1]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH:21]=O)[CH:15]=1)([S:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])([S:3][CH2:4][CH3:5])=[O:2].[CH2:23]([C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[C:29]([NH:31][NH2:32])=[O:30])[CH:24]=[CH2:25]>CO.C(Cl)Cl>[P:1]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH:21]=[N:32][NH:31][C:29](=[O:30])[C:28]2[CH:33]=[CH:34][CH:35]=[C:26]([CH2:23][CH:24]=[CH2:25])[CH:27]=2)[CH:15]=1)([S:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])([S:3][CH2:4][CH3:5])=[O:2]
Reactant: C=CCc1cccc(C(=O)NN)c1
Reactant: CCCCCCSP(=O)(Oc1cccc(CC=O)c1)SCC
Solvent: CO
Solvent: ClCCl
Product: C=CCc1cccc(C(=O)NN=CCc2cccc(OP(=O)(SCC)SCCCCCC)c2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of S-ethyl S-hexyl O-(3-Formylmethylphenyl) dithiophosphate (0.02 mole) in methanol (50 ml) and 3-allylbenzoylhydrazine (0.02 mole) are charged into a glass reaction vessel and the mixture is stirred at room temperature for a period of about 12 hours. After this time the reaction mixture is stripped of methanol under vacuum and the residue is dissolved in methylene chloride (100 ml) and the resulting solution is washed with water (75 ml), with aqueous sodium hydroxide (75 ml; 0.1 N) and again with water (75 ml). The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product S-ethyl S-hexyl O-{3-[2-(3-allylbenzoylhydrazono)ethyl]phenyl} dithiophosphate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[N:4][C:3]=1[OH:9].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Oc1nncc(Cl)c1Cl
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
4,5-Dichloro-3-hydroxypyridazine (3000 g, 18.18 moles), dihydropyran (1943 g, 23.08 mole), p-toluenesulfonic acid monohydrate (283 g, 1.49 moles) and 16 L of tetrahydrofuran were added to a 50 L round bottomed flask equipped with a heating mantle, reflux condenser and a mechanical stirrer. The mixture was stirred at reflux for 29 h. Additional dihydropyran was added at 6 h (1328 g, 15.79 mol) and at 21 h (780 g, 9.25 moles). The reaction mixture was allowed to cool to room temperature overnight. The mixture was concentrated in vacuo to an oily residue. The residue was taken up in 16 L of ethyl acetate and washed with 2N NaOH (2×6 L). The organic solution was dried (MgSO4) and concentrated in vacuo to give 4,5-dichloro-2-(tetrahydro-2H-pyran-2-yl)-3(2H)-pyridazinone which was a black oily solid which was used without further purification in the next step. The product was purified by filtration through silica gel with ethyl acetate followed by evaporation and recrystallization from ethyl acetate/cyclohexane to give a white solid, mp=74°-76° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[C:28]([F:31])([F:30])[F:29]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:9]([C:3]1[C:2]([NH:1][S:24]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([C:28]([F:31])([F:29])[F:30])[CH:20]=2)(=[O:26])=[O:25])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cc(Cl)cnc1C(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
A solution of (3-amino-5-chloro-pyridin-2-yl)-phenyl-methanone (40 mg, 0.17 mmol), 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (72 mg, 0.26 mmol), and DMAP (11 mg, 0.09 mmol) in anhydrous pyridine (0.5 mL) was heated at 60° C. for 4 days. The product was separated by preparative HPLC and pure product fractions were lyophilized to provide pure product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:17]([O-:20])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40]C=2)=O)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:29]=[C:30]([C:36]5([CH:17]=[O:20])[CH:38]=[CH:43][CH:42]=[CH:41][CH2:40]5)[CH:31]=[CH:32][C:33]=4[O:34][CH3:35])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1ccc(C(=O)c2ccccc2)cc1OCCCCl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C2(C=O)C=CC=CC2)cc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazole (2.01 g; 9.13 mmol), K2CO3 (2.0 g), and ]-[3-(3-chloropropoxy)-4-methoxy-phenyl]phenyl-methanone (3.93 g; 11.3 mmol) and acetonitrile (50 ml) was heated at reflux for 4 hours. At the end of the reaction, the solvent was evaporated and the residue was partitioned between water (150 ml) and dichloromethane (400 ml). The dichioromethane solution was washed with water and brine (100 ml), dried over MgSO4, then concentrated to an oil. The purification was done by flash chromatography over a silica gel column (SiO2 40 g; eluted with dichloromethane, 300 ml; 1% methanol in dichloromethane, 850 ml). The material thus obtained as a colorless oil solidified on standing. Recrystallization from ethanol (150 ml) gave 1-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyphenyl]-phenylmethanone as white crystals, 3.07 g (63%), m.p.=140°-141° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH:17]C(=O)OC(C)(C)C)=[N:9]3)=[CH:4][C:3]=1[O:25][CH3:26].C(O)(C(F)(F)F)=O>C(Cl)Cl.O.[OH-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]23[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH2:17])=[N:9]3)=[CH:4][C:3]=1[O:25][CH3:26]
Reactant: COc1cc(C23CCCC2CSC(NC(=O)OC(C)(C)C)=N3)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1cc([C@]23CCCC2CSC(N)=N3)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
To a solution tert-butyl 7a-(4-fluoro-3-methoxyphenyl)-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-ylcarbamate (1.04 g, 2.73 mmol) in CH2Cl2 (20 mL) is added TFA (5 mL) and the reaction is stirred at room temperature for 16 hr. The solvent is removed under reduced pressure to give a residue that is diluted with water and 5N NaOH. The aqueous layer is extracted four times with EtOAc. The organic layer is dried over Na2SO4 and the solvent is removed under reduced pressure. The crude product is purified with a 10 g SCX column using 4:1 CH2Cl2:MeOH and then 2:1 CH2Cl2: 7 N NH3 in MeOH to elute the product and give the title compound (0.756 g, 99%). ES/MS m/e: 281 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)C(C)C)(C)C.[Cl:19][S:20]([C:23]1[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[C:24]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:22])=[O:21].Cl>O1CCCC1>[ClH:19].[N:4]1([CH2:3][CH2:2][NH:1][S:20]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[C:24]=2[C:25]([O:27][CH3:28])=[O:26])(=[O:21])=[O:22])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: NCCN1CCCCC1
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCN1CCCCC1

Procedure:
A solution of 1-(2-aminoethyl)piperidine (0.23 g, 1.79 mmol) and N,N-diisopropylethylamine (0.23 g, 1.79 mmol) in tetrahydrofuran (5 ml) is added over 15 minutes to a stirred solution of methyl 2-chlorosulfonyl-6-nitrobenzoate (0.50 g, 1.79 mmol) in tetrahydrofuran (25 ml) cooled with an ice bath. The product is isolated following the procedure of Example 1 and converted to the hydrochloride salt with anhydrous ethanolic hydrogen chloride.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:26][C:27](Br)=[O:28].[CH3:30][O:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][NH2:35]>>[CH3:24][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][N:9]2[CH2:26][C:27]([NH:35][CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=2[O:31][CH3:30])=[O:28])=[CH:22][CH:23]=1
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(N(C)C)cc1)NCC2
Reactant: O=C(Br)CBr
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNC(=O)CN1CCc2cc(OC)c(OC)cc2C1Cc1ccc(N(C)C)cc1

Procedure:
prepared by reaction of 1-(4-Dimethylamino-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-methoxy-benzylamine
Reaction SMILES: [CH2:1]([O:3][P:4]([NH:23][C@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:25]1=[O:36])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1C(=O)C2=CC=CC=C2C1=O)=[O:5])[CH3:2].O.NN>O1CCOCC1.C1(C)C=CC=CC=1>[NH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][P:4]([NH:23][C@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:25]1=[O:36])([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)CN1CCC[C@H](NP(=O)(CCCCCCN2C(=O)c3ccccc3C2=O)OCC)C1=O
Agent: NN
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)CN1CCC[C@H](NP(=O)(CCCCCCN)OCC)C1=O
Temperature: 25 °C

Procedure:
A solution of (S)-3-[[ethoxy(6-phthalimidohexyl)phosphinyl]amino]-2-oxo-1-piperidineacetic acid, ethyl ester in dioxane is treated with hydrazine hydrate and stirred at room temperature under argon. After the reaction is completed, the mixture is diluted with toluene and the solvents decanted. The residue is triturated with methylene chloride and filtered. The combined filtrate is evaporated to dryness to give (S)-3-[[(6-aminohexyl)ethoxyphosphinyl]amino]-2-oxo-1-piperidineacetic acid, ethyl ester.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:23][CH3:24])[CH:10]([C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]=1)[OH:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:9]([CH2:23][CH3:24])[CH:10]([C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]=1)[OH:11]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(O)c1nc(-c2ccccc2)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](N)C(O)c1nc(-c2ccccc2)no1
Reaction time: 1 h

Procedure:
3-tert-Butoxycarbonylamino-2-hydroxy-pentanoic acid (500 mg, 2.14 mmol) was combined with EDC (600 mg, 3.14 mmol), HOBt (600 mg, 3.92 mmol), and N-hydroxy-benzamidine (292 mg, 2.14 mmol). Dichloromethane (10 mL) was added and then 4-methylmorpholine (1 mL). The reaction mixture was stirred at ambient temperature for 16 h. After dilution with ethyl acetate (200 mL), the solution was washed with water (30 mL), saturated aqueous NaHCO3 solution and brine, dried with MgSO4 and evaporated under vacuum. The crude product was dissolved in pyridine (10 mL) and heated at 80° C. for 15 h. The pyridine was evaporated under vacuum and the residue was purified by flash chromatography on silica gel (eluent:ethyl acetate) to yield 2(S)-tert-butoxycarbonylamino-1-(3-phenyl-[1.2.4]oxadiazol-5-yl)butan-1-ol (290 mg, 0.83 mmol). 2(S)-tert-butoxycarbonylamino-1-(3-phenyl-[1.2.4]oxadiazol-5-yl)butan-1-ol (145 mg, 0.41 mmol) was dissolved in CH2Cl2 (4 mL) and TFA (4 mL) was added. After stirring for 1 h, the reaction mixture was evaporated to dryness to yield 2(S)-amino-1-(3-phenyl-[1.2.4]oxadiazol-5-yl)-butan-1-ol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([C:16]([O:18]CC)=O)[C:11](OCC)=[O:12].C(N(CC)CC)C.[NH2:28][C:29]1[N:33]=[CH:32][NH:31][N:30]=1.[OH-].[Na+]>O>[OH:18][C:16]1[C:10]([C:3]2[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=2[F:9])=[C:11]([OH:12])[N:30]2[N:31]=[CH:32][N:33]=[C:29]2[N:28]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc(F)cc1F
Reactant: Nc1nc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Product: Oc1nc2ncnn2c(O)c1-c1c(F)cc(F)cc1F
Temperature: 180 °C
Reaction time: 6 h

Procedure:
A mixture of 22 mmol of diethyl 2-(2,4,6-trifluorophenyl)malonate, 24 mmol of triethylamine and 22 mmol of 3-amino-1,2,4-triazole was heated with stirring at 180° C. for 6 hours. The reaction mixture was then cooled to 50° C., admixed with a solution of 2.2 g of sodium hydroxide in 25 ml of water and stirred for 30 minutes. The aqueous phase was washed with ether and then acidified with conc. hydrochloric acid. The precipitated colorless solid was filtered off, washed with water and diisopropyl ether and dried. The yield of the title compound was 85% (m.p.: 200-201° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:28])[C@@H:13]([NH:20]C(=O)OC(C)(C)C)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:28])[C@@H:13]([NH2:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC(Oc2ccc(F)c(F)c2)CC1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](C(=O)N1CCC(Oc2ccc(F)c(F)c2)CC1)c1ccccc1

Procedure:
The product from Example 20, step a (0.650 g) was dissolved in dichloromethane (7 ml) and trifluoroacetic acid (2 ml) was added. After 3 hr at room temperature the solution was evaporated and aqueous NaOH (2M) added. The product was extracted with ethyl acetate, the combined organic extracts dried with Na2SO4 and concentrated to give the sub-title product as an oil (0.544 g).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][N:6]1[C:12](=[O:13])[CH:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:10]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:9]=2[CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[CH2:7]1)C.[OH-].[Na+].Cl>O1CCOCC1.O>[Cl:22][C:20]1[CH:19]=[CH:18][C:10]2[CH:11]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:12](=[O:13])[N:6]([CH2:5][C:4]([OH:31])=[O:3])[CH2:7][CH:8]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[C:9]=2[CH:21]=1
Reactant: CCOC(=O)CN1CC(c2ccccc2OC)c2cc(Cl)ccc2C(CC(C)C)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1C1CN(CC(=O)O)C(=O)C(CC(C)C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
85 mg of the compound from Example 23A (0.19 mol) are dissolved in 3.5 ml of dioxane/water (1:1) and mixed with 0.29 ml of 1 N sodium hydroxide solution (0.29 mol). The reaction mixture is stirred at room temperature for 3 h. It is acidified with 5 ml of 1 N hydrochloric acid, and the mixture is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated in a rotary evaporator. 80 mg (100% of theory) of the title compound are obtained.