Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:35][CH:36]([C:38]([O:40]CC)=[O:39])[CH3:37])=[CH:15][N:16]3[CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.O.O.[OH-].[Li+]>O1CCCC1>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:35][CH:36]([C:38]([OH:40])=[O:39])[CH3:37])=[CH:15][N:16]3[CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)C(C)Cc1cn(Cc2ccc(C(=O)OC(C)(C)C)cc2OC)c2cc(C(=O)NCC3CCCC3)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)OC(C)(C)C)ccc1Cn1cc(CC(C)C(=O)O)c2ccc(C(=O)NCC3CCCC3)cc21
Reaction time: 6 h
Yield: 95.3 %

Procedure:
A solution of t-butyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-(2-ethoxycarbonylpropyl)indol-1-ylmethyl]-3-methoxybenzoate (0.75 g) in a mixture of tetrahydrofuran (3.5 ml), methanol (3.5 ml), and water (1.3 ml) was treated with lithium hydroxide monohydrate (0.33 g). The mixture was stirred at 30° for 6 hours and then concentrated to remove the organic solvents. The residue was dissolved in water, and the solution was acidified with 10% (v/v) hydrochloric acid. The precipitate which formed was collected by filtration and dried to give t-butyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-(2-carboxypropyl)indol-1-ylmethyl]-3-methoxybenzoate (0.68 g, 95%) as a white powder; mp 195°-197°; partial NMR (80 MHz, CDCl3): 2.55-3.24(m, 3H, CH2CHCH3), 3.38(t, 2H, NHCH2), 3.91(s, 3H, OCH3), 5.24(s, 2H, NCH2), 6.17(br t, 1H, NH), 6.61(d, 1H, Ar), 7.04(s, 1H, H2 -indole), 7.85(br s, 1H, H7 -indole).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][NH:7][CH2:6]1)=[O:4].[CH2:9]([N:11]([CH2:38][CH3:39])[C:12]1[CH:17]=[C:16]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[C:27]([CH3:29])[C:26]([O:30][CH2:31][C@@H:32]4[CH2:34][O:33]4)=[C:25]([CH2:35][CH3:36])[CH:24]=3)[N:19]=2)[CH:15]=[C:14]([CH3:37])[N:13]=1)[CH3:10].C(N(CC)CC)C.CC(=O)OCC>CO>[CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:34][C@H:32]([OH:33])[CH2:31][O:30][C:26]2[C:27]([CH3:29])=[CH:28][C:23]([C:20]3[N:19]=[C:18]([C:16]4[CH:15]=[C:14]([CH3:37])[N:13]=[C:12]([N:11]([CH2:38][CH3:39])[CH2:9][CH3:10])[CH:17]=4)[O:22][N:21]=3)=[CH:24][C:25]=2[CH2:35][CH3:36])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CNC1
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OC[C@@H]1CO1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OC[C@@H](O)CN1CC(C(=O)OC)C1

Procedure:
A solution of azetidine-3-carboxylic acid methyl ester (40 mg, 0.355 mmol) and diethyl-{4-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridin-2-yl}-amine (300 mg, 0.71 mmol, Example 18 step a)) in methanol (5 mL) and triethylamine (0.1 mL) is stirred at 60° C. for 2 days. The mixture is dissolved with EA and washed with sat. aq. NaHCO3-solution. The org. extract is collected and concentrated. The crude product is purified by prep. HPLC to give the title compound (60 mg) as pale yellow oil; LC-MS: tR=0.79 min; [M+1]+=538.04; 1H NMR (CDCl3): δ 1.25 (t, J=6.8 Hz, 6H), 1.32 (t, J=7.5 Hz, 3H), 2.40 (s, 3H), 2.50 (s, 3H), 2.71-2.80 (m, 4H), 3.06 (s br, 1H), 3.35-3.46 (m, 2H), 3.48-3.54 (m, 2H), 3.58-3.72 (m, 6H), 3.75 (s, 3H), 3.81-3.86 (m, 2H), 3.93-4.00 (m, 1H), 7.01 (s, 1H), 7.10 (s, 1H), 7.87 (s, 1H), 7.88 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:27]O)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[CH:15][CH:14]=2)[O:10][N:9]=1)[CH3:2].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:54]1[CH2:57][CH:56]([C:58]([O:60][CH3:61])=[O:59])[CH2:55]1.C(N(CC)C(C)C)(C)C>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:27][N:54]2[CH2:57][CH:56]([C:58]([O:60][CH3:61])=[O:59])[CH2:55]2)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[CH:17][CH:18]=2)[O:10][N:9]=1)[CH3:2]
Reactant: COC(=O)C1CNC1
Reactant: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3cccc(F)c3)cc2)n1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3cccc(F)c3)cc2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using (4-ethyl-5-{5-[4-(3-fluorophenoxy)phenyl]-1,2,4-oxadiazol-3-yl}-2-thienyl)methanol (0.15 g, 0.38 mmol) that was obtained in Example 17 (17b), carbon tetrabromide (0.15 g, 0.45 mmol), triphenylphosphine (0.12 g, 0.45 mmol), methyl 3-azetidinecarboxylate hydrochloride (86 mg, 0.57 mmol), and N,N-diisopropylethylamine (0.19 mL, 1.1 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography using a mixed solvent of ethyl acetate and hexane (5:5) to afford the title compound (0.16 g) in a yield of 85% as a pale yellow oily product.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:6]1[N:7]([CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH2:4][CH3:5].C1(C)C=CC=CC=1>C(O)C>[CH2:3]([C:6]1[N:7]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH2:4][CH3:5]
Reactant: CCCc1nc2cnc3cccnc3c2n1CCCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCc1nc2cnc3cccnc3c2n1CCCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
Aqueous sodium hydroxide (2.4 mL of 6 M) was added to a solution of ethyl 4-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]butanoate (2.37 g, 7.26 mmol) in ethanol (25 mL); the reaction was stirred at ambient temperature for two hours and concentrated under reduced pressure. The residue was dissolved in water (15 mL) and adjusted to pH 4 with the addition of 2 M hydrochloric acid. A precipitate formed, was isolated by filtration, and was mixed with toluene, which was removed under reduced pressure to provide 1.78 g of 4-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]butanoic acid as a tan powder.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[O:11])[CH2:8]2.O[NH:13]S(O)(=O)=O.[OH-].[Na+]>C(O)=O>[CH:3]12[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]([CH2:8]3)[C:2](=[O:11])[NH:13]1)[CH2:4]2
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: O=S(=O)(O)NO
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: O=C1NC2CC3CC(C2)CC1C3
Temperature: 25 °C
Yield: 97.3 %

Procedure:
To a solution of 2-adamantanone (2.00 g) in formic acid (10 ml) was added dropwise a suspension of hydroxyamine-O-sulfonic acid (2.26 g) in formic acid (7 ml) under stirring at ambient temperature. The mixture was heated at reflux temperature for 3.5 hours. The reaction mixture was allowed to cool to room temperature, alkalined with 1N sodium hydroxide aqueous solution and extracted with chloroform twice. The combined extracts were washed with water and dried over sodium sulfate. Removal of the solvent gave 2-azatricyclo[4.3.1.14,8 ]undecan-3-one (2.14 g), which was used in a following reaction step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].Cl.Cl.[CH2:9]([N:16]1[CH2:21][CH2:20]C(NC)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:24]([N:26](CC)[CH2:27]C)C.O>C(Cl)(Cl)Cl>[CH2:9]([N:16]1[CH2:21][CH2:20][CH:1]([N:2]([CH3:6])[C:3]([N:26]([CH3:27])[CH3:24])=[O:4])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCN(CC)CC
Reactant: CNC1CCN(Cc2ccccc2)CC1
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)N(C)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Dimethylcarbamoyl chloride (2.7 g) was added slowly to a stirred, cooled solution of 1-benzyl-4-(methylamino)piperidine dihydrochloride (7 g) in dry chloroform (50 ml) and triethylamine (7.7 g). The mixture was then stirred at room temperature for 3 hours and heated under reflux for a further 7 hours. The cooled mixture was treated with water (50 ml), separated, and the chloroform layer dried (MgSO4) and evaporated in vacuo to give 1-(1-Benzylpiperid-4yl)-1,3,3-trimethyl urea (6.5 g) as a mobile oil.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[O:14])[C:10]2([C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][CH2:28][CH2:27]2)[CH2:9]1)C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[C:21]1([CH:18]2[CH2:17][CH2:16][N:15]([C:13]([CH:11]3[CH2:12][NH:8][CH2:9][C:10]43[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][CH2:28][CH2:27]4)=[O:14])[CH2:20][CH2:19]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(C1CN(Cc2ccccc2)CC12CCCc1ccccc12)N1CCC(c2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C(C1CNCC12CCCc1ccccc12)N1CCC(c2ccccc2)CC1
Reaction time: 2 h

Procedure:
N-benzyl-4′-[(4-phenylpiperidin-1-yl)carbonyl]-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidine] (0.15 g, 0.323 mmol) in EtOH (20 ml) was added Pearlman's Catalyst (0.075 g, 0.107 mmol) and hydrogenated with a balloon for 2 hours. Filtered through celite and concentrated.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:13]([OH:15])=[O:14])([O-:3])=[O:2].[CH:16](OC)(OC)OC.S(=O)(=O)(O)O>CO>[C:13]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH3:16])=[O:8])([OH:15])=[O:14]
Reactant: COC(OC)OC
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1C(=O)O
Temperature: 62 °C
Yield: 94.7 %

Procedure:
A mixture of 3-nitrophtalic acid [NPA] (660 kg), trimethyl orthoformate (400 kg), concentrated sulfuric acid (115 kg) and methanol (1180 kg) was stirred under reflux at 59-65° C. for about 15-20 hours. The reaction solution was cooled and concentrated under reduced pressure at not more than 40° C. The residue was cooled to not more than 30° C., to which was added water (900 L), and the solution was cooled to not more than 5° C. The precipitated crystals were centrifuged, washed with water and dried at 50° C. for about 50 hours to give methyl 2-carboxy-3-nitrobenzoate [MNA] (666.8 kg, 94.7%).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[F:23][C:24]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:25]=1[CH2:26][N:27]1[C:31]2=[CH:32][N:33]=[C:34]([C:36]([OH:38])=O)[CH:35]=[C:30]2[CH:29]=[CH:28]1.C(N(CC)CC)C.[CH2:51]([O:58][NH2:59])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>CN(C=O)C.O>[CH2:51]([O:58][NH:59][C:36]([C:34]1[CH:35]=[C:30]2[CH:29]=[CH:28][N:27]([CH2:26][C:25]3[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:24]=3[F:23])[C:31]2=[CH:32][N:33]=1)=[O:38])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)c1cc2ccn(Cc3ccc(F)cc3F)c2cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NOCc1ccccc1)c1cc2ccn(Cc3ccc(F)cc3F)c2cn1
Reaction time: 1 h
Yield: 63.6 %

Procedure:
1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide hydrochloride (EDC, 126 mg, 0.67 mmol) and 1-hydroxybenzotriazole (HOBt, 56 mg, 0.56 mmol) was added to a the stirred solution of 1-(2,4-difluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid (70 mg, 0.24 mmol) in DMF (8 mL). The mixture was stirred for 1 h, and then triethylamine (0.33 ml, 2.37 mmol) and O-benzylhydroxylamine (231 mg, 1.80 mmol) were added. The resulting mixture was stirred for 24 h at ambient temperature, and then water (50 mL) was added. The precipitates were collected, and dried to give the title compound (60 mg, 63%). 1H NMR (DMSO-d6) δ: 11.71 (s, 1H), 8.81 (s, 1H), 8.20(s, 1H), 7.74 (s, 1H), 7.15-7.45 (m, 7H), 7.02 (m, 1H), 6.68 (s, 1H), 5.60 (s, 2H), 4.88 (s, 2H). HRMS calcd for C22H8F2N3O2 (M+H) 394.1367, found 394.1388.
Reaction SMILES: I[C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:13]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:18]=CC=C[CH:14]=1.[Cl-].C([Al+]CC)C.[C]=[O:39]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][C:5]1[CH:4]=[C:3]([CH3:12])[C:2]([C:14](=[O:39])[CH2:13][CH3:18])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Cc1cc(C)c(C(=O)O)cc1I
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: [C]=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[Al+]CC
Agent: [Cl-]
Solvent: COCCOC
Product: CCC(=O)c1cc(C(=O)O)c(C)cc1C
Temperature: 25 °C
Yield: 80 %

Procedure:
Into a 100-mL autoclave (30 atm), was placed a solution of 5-iodo-2,4-dimethylbenzoic acid (compound 1.3, 2.00 g, 7.24 mmol) in ethylene glycol dimethyl ether (20 mL). Triphenylphosphine (190 mg, 0.73 mmol), Pd(PPh3)2Cl2 (500 mg, 0.71 mmol) and diethylaluminum chloride (2M, 10.8 mL, 21.6 mmol) were added to the reaction mixture. The resulting mixture was stirred under pressure with carbon monoxide (gas, 30 atm) at 80° C. for 15 h. (CAUTION: Highly toxic gas at high pressure. All necessary safety precautions were performed). After cooling to room temperature, the mixture was carefully purged, then quenched with 20 mL of water. Aqueous HCl (2M) was added carefully to adjust the pH to 5-6 and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine (2×100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:40-1:20) as the eluent to yield the title compound as a light yellow solid (1.2 g, 80%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8](Br)[C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].[Si:22]([C:26]#[CH:27])([CH3:25])([CH3:24])[CH3:23].N(C(C)C)C(C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:27]#[C:26][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cc(C#C[Si](C)(C)C)c(F)c(F)c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
A mixture of 5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (4) (101 mg, 0.268 mmol), TMS-acetylene (0.045 mL, 0.31 mmol), Pd(PPh3)2Cl2 (18.7 mg, 0.0261 mmol), CuI (5.1 mg, 0.027 mmol), and i-Pr2NH (0.075 mL, 0.53 mmol) in THF (1.5 mL) was stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and diluted with EtOAc. The organic layer was washed with saturated aqueous NH4Cl and brine, dried over MgSO4, and concentrated. Purification by flash column chromatography using the Biotage system (100% hexane to 1% EtOAc in hexane) gave 81.3 mg (77% yield) of the desired product (5).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([NH:41]C(=O)OC(C)(C)C)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[C:23](/[N:25]=[C:26]1\[S:27][C:28]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:29][N:30]\1[CH2:31][C@H:32]1[CH2:36][CH2:35][CH2:34][O:33]1)=[O:24])(C(C)(C)C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:41][C@H:10]([CH2:9][OH:8])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=1[C:23](/[N:25]=[C:26]1\[S:27][C:28]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:29][N:30]\1[CH2:31][C@H:32]1[CH2:36][CH2:35][CH2:34][O:33]1)=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@H](COc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1)CO[Si](C)(C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OC[C@H](N)CO)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
A solution of Example 69A (500 mg, 0.7 mmol) in CH2Cl2 (10 mL) at 0° C. was treated with trifluoroacetic acid (0.27 mL, 3.5 mmol). The mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was concentrated under reduced pressure, diluted with saturated NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated under reduced pressure. Purification by chromatography (SiO2, eluted with CH2Cl2-MeOH: 6:1) afforded 260 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.33 (s, 9 H), 1.58-1.73 (m, 1H), 1.75-2.04 (m, 3 H), 2.25-2.43 (m, 1 H), 3.08 (q, J=5.6 Hz, 1 H), 3.36-3.53 (m, 3 H), 3.59-3.69 (m, 1 H), 3.74-3.86 (m, 1 H), 3.94-4.01 (m, 1 H), 4.05-4.12 (m, 1 H), 4.19-4.36 (m, 3 H), 4.68 (t, J=5.2 Hz, 1 H), 7.24-7.34 (m, 2 H), 7.76 (dd, J=8.9, 2.2 Hz, 1 H), 8.07 (d, J=2.4 Hz, 1 H); MS (DCI/NH3) m/z 502 (M+H)+. Anal calculated for C23H30F3N3O4S.0.75H2O: C, 53.63; H, 6.16; N, 8.16. Found: C, 53.40; H, 6.06; N, 8.16.
Reaction SMILES: [C:1]([NH:4][CH:5]([PH:17]([OH:19])=[O:18])[CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2].[H-].[Na+].[CH2:22](I)[CH:23]([CH3:25])[CH3:24].C(O)(=O)C>CS(C)=O>[C:1]([NH:4][CH:5]([PH:17]([OH:19])=[O:18])[C:6]([CH2:22][CH:23]([CH3:25])[CH3:24])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(C)CI
Reactant: CCOC(=O)C(C(=O)OCC)C(NC(C)=O)[PH](=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(CC(C)C)(C(=O)OCC)C(NC(C)=O)[PH](=O)O
Temperature: 10 °C
Yield: 44 %

Procedure:
12.0 g of diethyl 2-[(acetamido)(hydroxyphosphinyl)methyl]malonate were dissolved in 100 ml of dry dimethyl sulphoxide and the solution was cooled to 10° C. while stirring under a nitrogen atmosphere. 3.2 g of 60% sodium hydride in mineral oil were added, the mixture was stirred at room temperature for 2 hours and then 8 g of isobutyl iodide were added. The mixture was stirred at room temperature in the dark for 20 hours and 20 ml of glacial acetic acid were added. The volatiles were removed by evaporation in a high vacuum and the resulting semi-solid residue was dissolved in 100 ml of water containing 15 ml of 50% hypophosphorous acid. The solution was extracted eight times with ethyl acetate and the combined extracts were dried over sodium sulfate and evaporated. The residue was dissolved in dichloromethane and the solution was washed in sequence with water and saturated sodium chloride solution. The dichloromethane solution was dried over sodium sulfate and evaporated, and the residue was crystallized from diethyl ether/n-hexane to give 6.28 g of diethyl 2-[(acetamido)-(hydroxyphosphinyl)methyl]-2-isobutylmalonate in the form of a white solid; MS: 352 (M+H)+.
Reaction SMILES: C(=O)(OC(C)(C)C)[O:2][N:3]([CH2:9][CH2:10][C:11]([C:13]#[N:14])=[CH2:12])[C:4]([O:6][CH2:7][CH3:8])=[O:5].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CN(C)C=O>[C:13]([CH:11]1[CH2:12][O:2][N:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:9][CH2:10]1)#[N:14]
Reactant: C=C(C#N)CCN(OC(=O)OC(C)(C)C)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)N1CCC(C#N)CO1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A solution of (3-cyano-3-butene-1-yl)(ethoxycarbonyl)azanyl 1,1-dimethylethyl carbonate (i.e. the product of Step G) and trifluoroacetic acid (3 mL) in dichloromethane (40 mL) was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure to a tan oil. The oil was combined with potassium carbonate (3.6 g, 0.026 mol) in N,N-dimethylformamide (30 mL) and stirred at 80° C. for 24 h. The reaction mixture was concentrated under reduced pressure to near dryness. Methanol and dichloromethane were added and the precipitated solids were removed by filtration. The resulting solid was adsorbed onto Celite® (diatomaceous filter aid), and then purified by silica gel chromatography to provide the title compound as a pale-tan oil (0.645 g).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[C:4](=[O:9])/[CH:5]=[CH:6]\[CH2:7][CH3:8].[I-].[Na+]>C(O)(=O)C>[CH3:11][O:10][CH:3]([O:2][CH3:1])[C:4](=[O:9])/[CH:5]=[CH:6]/[CH2:7][CH3:8]
Reactant: CC/C=C\C(=O)C(OC)OC
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC/C=C/C(=O)C(OC)OC

Procedure:
The crude product produced in Example III is dissolved in 6 ml of acetic acid with 0.1 g of sodium iodide. By GLC analysis on Carbowax (polyethylene glycol) it is clear that the 1,1-dimethoxy-cis-3-hexene-2-one is converted to a new material of later retention time. After one-half hour less than 5 percent of "cis" material remains.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH2:16]=O.CNC.[P:21]([O:28]CC)([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24]>CN(C)C=O>[C:11]([C:7]1[CH:8]=[C:9]([CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])[CH2:16][P:21](=[O:28])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: C=O
Reactant: CCOP(OCC)OCC
Agent: CNC
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)OCC
Temperature: 105 °C

Procedure:
20.63 g (100 mmol) of 2,6-di-tert-butylphenol, 5.22 g (174 mmol) of paraformaldehyde, 6.1 g (45 mmol) of 33% ethanolic dimethylamine and 26 ml (=24.7 g) of N,N-dimethylformamide are heated at 50° C. under nitrogen for 1 hour in a sulfonation flask fitted with a reflux condenser and mechanical stirrer. 33.23 g (200 mmol) of triethyl phosphite are added to this mixture. It is heated under reflux at a reaction temperature of 105° C.; the conversion to the final product is 82% (HPLC). Working-up: extraction (water/methylcyclohexane) and recrystallization (methylcyclohexane). Yield: 23.0 g (65%), melting point 120° C., purity (HPLC): 98%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][C:14]([N:16]1[CH2:20][C@H:19](O)[CH2:18][C@H:17]1[CH2:22][O:23][CH2:24][C:25]([OH:27])=[O:26])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl>O1CCCC1.O>[CH2:6]([O:13][C:14]([N:16]1[CH2:20][C@H:19]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:18][C@H:17]1[CH2:22][O:23][CH2:24][C:25]([OH:27])=[O:26])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(O)COC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)[C@@H]1C[C@@H](COCC(=O)O)N(C(=O)OCc2ccccc2)C1
Reaction time: 1 h

Procedure:
A solution of methanesulfonyl chloride (10 ml) in tetrahydrofuran (20 ml) was dropwise added to a solution of (2S,4R)-1-benzyloxycarbonyl-2-carboxymethyloxymethyl-4-hydroxypyrrolidine (19.95 g) and triethylamine (27 ml) in tetrahydrofuran (200 ml) at -10°~-5° C. and the mixture was stirred at the same temperature for 1 hour. The mixture was poured into water (200 ml), adjusted to pH 2.5 with 6N hydrochloric acid and extracted with ethyl acetate (150 ml×2). The organic layer was washed with brine (200 ml×2), dried over magnesium sulfate and concentrated under reduced pressure to give (2S,4R)-1-benzyloxycarbonyl-2-carboxymethyloxymethyl-4-methanesulfonylpyrrolidine (24.85 g).