Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[NH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+]>>[OH:30][C:6]1[C:5]([C:3]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:4])=[N:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:10](=[O:23])[N:11]2[C@H:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16]
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2[C@@H](C)c2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: C[C@@H](c1ccccc1)n1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)NCCC(=O)O)ncc21
Temperature: 25 °C
Yield: 75.8 %

Procedure:
A mixture of (S)-5-hydroxy-2-oxo-3-phenyl-1-(1-phenyl-ethyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.075 mmol), β-alanine (535 mg, 6.0 mmol) and NaOMe solution (9 mL, 4.5 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 26 mg of the title compound. MS: (+) m/z 458.36 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:21])[C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH:5]=[CH:4][C:3]=1[C:22]#[N:23].[CH3:24][O-:25].[Na+]>CO>[C:22]([C:3]1[CH:4]=[CH:5][C:6]([N:8]([CH3:21])[C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)=[N:7][C:2]=1[O:25][CH3:24])#[N:23]
Reactant: CN(c1ccc(C#N)c(Cl)n1)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(N(C)[C@@H]2CCN(C(=O)OC(C)(C)C)C2)ccc1C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (R)-tert-butyl 3-((6-chloro-5-cyanopyridin-2-yl)(methyl)amino)pyrrolidine-1-carboxylate (0.45 mmol) in MeOH (20 mL) was added the solution of NaOMe (0.9 mmol) in MeOH (2 mL). The reaction mixture was stirred at room temperature for 3 hours, then heated to 50° C., stirred for another 2 hours, then stirred at reflux overnight. The mixture was concentrated, diluted with EtOAc, washed with brine, dried, filtered, and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:39])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH2:33][C:34]([O:36]CC)=[O:35])[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[C:34]([CH2:33][O:32][C:31]1[C:19]2[CH2:18][C:17](=[CH:16][CH2:15][CH2:14][N:11]3[CH2:10][CH2:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)([OH:39])[CH2:13][CH2:12]3)[C:27]3[C:22]([O:21][C:20]=2[CH:28]=[CH:29][CH:30]=1)=[N:23][CH:24]=[CH:25][CH:26]=3)([OH:36])=[O:35]
Reactant: CCOC(=O)COc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a solution of product of example 48 (3.0 g) in methanol (50 ml) was added 1N sodium hydroxide solution (8 ml) and the mixture stirred at room temperature for 1 hour. The reaction mixture was distilled off under reduced pressure. The residue was dissolved with water and neutralized with iN hydrochloric acid. The precipitation was filtered and washed with water to give the titled compound (2.6 g).
Reaction SMILES: C[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:15])=[CH:7][C:8]([C:12]([OH:14])=O)=[N:9]2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[CH2:37]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:48]([CH:50]([NH2:60])[CH2:51][CH2:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[O:49])[CH2:44][CH2:43]1)=[O:41])[CH3:38]>C(Cl)Cl.CN(C=O)C.C(Cl)Cl>[CH2:37]([O:39][C:40]([N:42]1[CH2:43][CH2:44][N:45]([C:48]([CH:50]([NH:60][C:12]([C:8]2[CH:7]=[C:6]([OH:15])[C:5]3[C:10](=[CH:11][CH:2]=[CH:3][CH:4]=3)[N:9]=2)=[O:14])[CH2:51][CH2:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[O:49])[CH2:46][CH2:47]1)=[O:41])[CH3:38]
Reactant: Cc1ccc2c(O)cc(C(=O)O)nc2c1
Reactant: CCOC(=O)N1CCN(C(=O)C(N)CCC(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccccc3n2)CC1
Reaction time: 0.17 h

Procedure:
To a suspension of 7-methyl-4-hydroxy-2-carboxyquinoline (0.81 g, 4 mmol) in methylene chloride: DMF (4:1, 25 mL) was added 1-hydoxybenzotriazole (HOBT) (0.64 g, 4.8 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (1.09 g, 4.8 mmol) and the reaction mixture was stirred for 10 minutes. A solution of 4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (1.37 g, 4 mmol) in methylene chloride (10 mL) was added to the reaction mixture and the resulting mixture was stirred at ambient temperature for 6 hours. The solvent was evaporated in vacuo and the resulting residue was partitioned in ethyl acetate and water. The organic layers were combined and washed with water, brine and concentrated to afford an off-white foam, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-hydroxyquinoline; (1.44 g, 68%).
Reaction SMILES: [N+:1](=[C:3]([C:14]([CH3:16])=[O:15])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])=[N-:2].C(N(CC)CC)C.[CH3:24][Si:25](Cl)([CH3:27])[CH3:26].[I-].[Na+]>C(#N)C>[N+:1](=[C:3]([C:14]([O:15][Si:25]([CH3:27])([CH3:26])[CH3:24])=[CH2:16])[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5])=[N-:2]
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)C(=[N+]=[N-])C(=O)OCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(O[Si](C)(C)C)C(=[N+]=[N-])C(=O)OCc1ccccc1
Yield: 84.3 %

Procedure:
To 1.5 ml of dry acetonitrile were added 83 mg (0.380 millimole) of benzyl 2-diazoacetoacetate, 64.8 μl (0.465 millimole) of triethylamine and 59 μl (0.465 millimole) of trimethylsilyl chloride. A solution obtained by dissolving 70 mg (0.467 millimole) of sodium iodide in 0.5 ml of dry acetonitrile was added dropwise thereto at a room temperature. After agitation for an hour, the reaction mixture was concentrated under a reduced pressure. After addition of 5 ml of hexane, insoluble materials were filtered off and the hexane was distilled off under a reduced pressure to give 93 mg (yield 84.1 %) of the desired compound in a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([NH:10][C:11](=[S:13])[N:12]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.OO>CO>[F:1][C:2]1[C:3]2[N:4]([N:10]=[C:11]([S:13][S:13][C:11]3[N:12]=[C:3]4[N:4]([C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]4[F:1])[N:10]=3)[N:12]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(F)c2nc(=S)[nH]n12
Agent: OO
Solvent: CO
Product: COc1ncc(F)c2nc(SSc3nc4c(F)cnc(OC)n4n3)nn12
Temperature: 43 °C
Yield: 81.8 %

Procedure:
A heterogeneous mixture composed of 76.0 g (0.380 mol) of 8-fluoro-5-methoxy[1,2,4]triazolo[1,5-c]pyrimidine-2(3H)-thione and 400 g of methanol at 24° C. was prepared and 45.3 g (0.400 mol) of ice cold 30 percent by weight hydrogen peroxide solution was added with stirring. An exothermic reaction took place raising the temperature to 43° C. The mixture was allowed to react for about 75 min and then another 13.0 g (0.115 mol) of ice cold 30 percent by weight hydrogen peroxide solution was added with stirring. The mixture was allowed to react for another 30 min and then the solids present were recovered by vacuum filtration. These solids were dried and were then slurried with methanol. The slurry was heated to reflux, cooled to 35°-45° C., and filtered to recover the insoluble solids. The solids were dried under reduced pressure at 40° C. to obtain 61.9 g of the title compound (80 percent of theory) as an off-white solid. The compound is a white powder melting at 201°-208° C. (dec.).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[O:15][C@@H:14]([CH3:16])[CH2:13][N:12](CC2C=CC(OC)=CC=2OC)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OC(Cl)C)=O.CO>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@H:10]1[O:15][C@@H:14]([CH3:16])[CH2:13][NH:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2C[C@@H](COCc3ccccc3)O[C@@H](C)C2)c(OC)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: C[C@H]1CNC[C@@H](COCc2ccccc2)O1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,6S)-rel-2-[(benzyloxy)methyl]-4-(2,4-dimethoxybenzyl)-6-methylmorpholine (Intermediate 495, 0.6 g, 1.6 mmol) in DCM (15 mL) was added 1-chloroethyl chloroformate (0.6 mL, 6.9 mmol) and mixture was heated at 50° C. for 10 hour. To the reaction mixture methanol was added and heating was continued for 1 hour. After cooling, the mixture was concentrated give product as solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1F.[CH2:20]([NH2:23])[CH2:21][NH2:22].O>CN(C)C(=O)C>[NH2:22][CH2:21][CH2:20][NH:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[Cl:1])[N:9]([CH:12]1[CH2:14][CH2:13]1)[CH:8]=[C:7]([C:15]([OH:17])=[O:16])[C:6]2=[O:18]
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: NCCN
Solvent: CC(=O)N(C)C
Solvent: O
Product: NCCNc1cc2c(=O)c(C(=O)O)cn(C3CC3)c2cc1Cl
Temperature: 115 °C
Reaction time: 8.5 h
Yield: 10 %

Procedure:
7-Chloro-1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-quinoline-3-carboxylic acid (56.3 g) and ethylenediamine (36 g) were dissolved in N,N-dimethylacetamide (650 mL) at 100° C. and stirred for 8.5 h at 115° C. Water (700 mL) was added to the reaction mixture cooled at room temperature. The reaction mixture was stirred at room temperature for 2 h, cooled at 0-5° C. and stirred for 1 h. The precipitate obtained was filtered, washed with cold water, cold EtOH, and dried at 110° C. under reduced pressure for 1 h. The crude product was treated with HCl (6% aqueous solution) heating for 1 h in the presence of charcoal. After filtration, the solution was cooled to 35-40° C. and a first precipitation happened. The precipitate was filtered, washed with water and dried at 110° C. for 1 h. The title compound (6.4 g) was obtained as the hydrochloride salt. The hydrochloride salt was then converted to the free base using standard conditions; ESMS m/z 320 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:20]#[N:21])[C:14]=2[CH2:13][CH2:12][CH2:11]1)=[O:9].C([Sn](CCCC)=O)CCC.[Si]([N:41]=[N+:42]=[N-:43])(C)(C)C>COCCOC>[NH:41]1[C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:14]=2[CH2:13][CH2:12][CH2:11][N:10]3[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][O:4][C:3]2[CH:22]=[CH:23][CH:24]=[C:25]([CH3:26])[C:2]=2[CH3:1])=[N:21][N:43]=[N:42]1
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(C#N)cccc32)c1C
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: COCCOC
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4nnn[nH]4)cccc32)c1C
Yield: 83.8 %

Procedure:
A solution of 1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinoline-5-carbonitrile (0.020 g, 0.057 mmol), dibutylstannanone (2.86 mg, 0.011 mmol) and TMS-N3 (0.030 mL, 0.230 mmol) in DME (0.3 mL) was stirred at 100° C. for 3 days, and then concentrated in vacuo. The resulting residue was purified by preparative HPLC (PHENOMENEX® Axia Luna column, 5μ, C18, 30×75 mm; 10 min gradient from 75% A:25% B to 0% A:100% B (A=90% H2O/10% MeCN+0.1% TFA); (B=90% MeCN/10% H2O+0.1% TFA); detection at 220 nm) to afford the title compound (18.7 mg, 82% yield) as an off-white solid. LCMS, [M+H]+=392.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C@:13]3([CH3:22])[C:18]([F:20])([F:19])[CH2:17][O:16][C:15]([NH2:21])=[N:14]3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])#[CH:24].C(N(CC)CC)C>O1CCCC1.[Cu]I.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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:19][C:18]1([F:20])[CH2:17][O:16][C:15]([NH2:21])=[N:14][C@:13]1([CH3:22])[C:11]1[CH:10]=[N:9][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:24]#[C:23][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:3]=2)[CH:12]=1
Reactant: C[C@]1(c2cnn(-c3cccc(Br)c3)c2)N=C(N)OCC1(F)F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@]1(c2cnn(-c3cccc(C#C[Si](C)(C)C)c3)c2)N=C(N)OCC1(F)F
Temperature: 70 °C
Reaction time: 20 h
Yield: 44.2 %

Procedure:
A solution of (R)-4-(1-(3-bromophenyl)-1H-pyrazol-4-yl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-2-amine (227 mg, 612 μmol) (intermediate K7.1) in tetrahydrofuran (5 ml) was treated consecutively with ethynyltrimethylsilane (120 mg, 169 μl, 1.22 mmol), triphenylphosphine (4.81 mg, 18.3 μmol) and triethylamine (186 mg, 256 μl, 1.83 mmol). The mixture was degassed by bubbling argon through the solution, then copper(I) iodide (1.16 mg, 6.12 μmol) and bis(triphenylphosphine)palladium(II) chloride (21.5 mg, 30.6 μmol) were added. The reaction mixture was stirred at 70° C. in a sealed tube. In order to complete the reaction, ethynyltrimethylsilane (120 mg, 169 μl, 1.22 mmol) and bis(triphenylphosphine)palladium(II) chloride (21.5 mg, 30.6 μmol) were added again and stirring continued at 70° C. for 20 hours. Thereafter, the reaction mixture was evaporated and the residue purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 0:100 as the eluent. The (R)-5,5-difluoro-4-methyl-4-[1-(3-trimethylsilanylethynyl-phenyl)-1H-pyrazol-4-yl]-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (105 mg, 44% yield) was obtained as a brown, amorphous material. MS (ISP): m/z=389.3 [M+H]+.
Reaction SMILES: [C-:1]#[N:2].[Na+].O1CCCCC1[O:10][CH2:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16]Cl>CS(C)=O.[Cl-].[Na+].O>[C:1]([CH2:16][CH2:15][CH2:14][C:13]#[C:12][CH2:11][OH:10])#[N:2]
Reactant: ClCCCC#CCOC1CCCCO1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCC#CCO
Reaction time: 8 h
Yield: 58.4 %

Procedure:
To a stirred slurry of sodium cyanide (15 g, 306 mmol) in dimethyl sulphoxide (100 ml) preheated to 85° C., was added 1-tetrahydropyranyloxy-6-chloro-hex-2-yne (66.2 g, 306 mmol) at such a rate as to keep the temperature between 85° C. and 100° C. One hour after the addition was completed, the cooled mixture was slowly added to brine (600 ml) and extracted with ether (3×200 ml). The combined ether extracts were washed with further brine (200 ml) and dried over sodium sulphate. After removal of the solvent under reduced pressure, the reddish-brown oil was distilled and the fraction boiling between 140° and 160° C. (0.25 m.m.) collected and dissolved in methanol (200 ml). This solution was stirred overnight with 5 MH2SO4 (30 ml) and neutralised with solid potassium carbonate. The methanol was removed under reduced pressure and the residue partitioned between ether (200 ml) and brine (300 ml). The aqueous layer was extracted with further ether (2×300 ml). The combined organic extracts were washed with brine (2×100 ml) and dried over sodium sulphate. Removal of the solvent under reduced pressure, and distillation of the oil obtained gave 6-cyano-hex-2-yn-1-ol (22.0 g, 58%) as a colourless oil.
Reaction SMILES: [OH:1][C:2]([P:8]([OH:10])[OH:9])([CH3:7])[CH2:3][CH2:4][CH2:5][CH3:6].[CH3:11][O:12][CH2:13][CH2:14]O.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1.CCOCC>[OH:1][C:2]([PH:8](=[O:10])[O:9][CH2:14][CH2:13][O:12][CH3:11])([CH3:7])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(C)(O)P(O)O
Reactant: COCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCC(C)(O)[PH](=O)OCCOC
Reaction time: 3 h

Procedure:
1-Hydroxy-1,4-dimethylbutylphosphonous acid prepared as described in Example 8 (0.166 g. 0.001M), 2-methoxyethanol (0.076 g. 0.001M) and dimethylaminopyridine (0.01 g.) are stirred in THF (5 ml.) at 5° C. Dicyclohexylcarbodiimide (0.23 g., 0.001M) is added portionwise and the mixture is stirred for 3 hours. Ether (10 ml.) is added and the dicyclohexylurea is filtered off. The filtrate is evaporated and the residue is dissolved in chloroform and washed with water. Evaporation of the chloroform gives an oil which is purified on silica using ethyl acetate as eluant. There is obtained 2-methoxyethyl (1-hydroxy-1,4-dimethylbutyl)phosphinate.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@@:8]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:16])[CH2:10][CH2:9]1)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C>[N:28]([CH2:6][CH2:7][C@@:8]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:16])[CH2:10][CH2:9]1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H](N1CC[C@](CCOS(C)(=O)=O)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](N1CC[C@](CCN=[N+]=[N-])(c2ccc(F)cc2)OC1=O)C(C)(C)C
Yield: 92.4 %

Procedure:
To a solution of 2-((S)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl methanesulfonate (273 mg, 0.68 mmol) in DMF (5 mL) was added NaN3 (133 mg, 2.04 mmol), and the mixture was refluxed overnight. The reaction was quenched with H2O, and the pH of the mixture was adjusted to >9 with 1N aq NaOH. The mixture was extracted with EtOAc (3×). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated to give (S)-6-(2-azidoethyl)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (219 mg, 93%). 1H NMR (CDCl3): 0.61-0.69 (s, 9H), 1.02-1.08 (d, 3H), 1.98-2.14 (m, 3H), 2.23-2.32 (m, 1H), 2.51-2.61 (m, 1H), 2.91-3.02 (m, 1H), 3.06-3.13 (m, 1H), 3.41-3.52 (m, 1H), 4.33-4.42 (m, 1H), 6.98-7.03 (m, 2H), 7.21-7.24 (m, 2H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].O.C[N:16]([CH:18]=O)C>>[C:1]1([S:7][C:4]2[CH:5]=[CH:6][C:1]([S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:2]([C:18]#[N:16])[C:3]=2[C:18]#[N:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1c(Sc2ccccc2)ccc(Sc2ccccc2)c1C#N
Reaction time: 1 h
Yield: 52 %

Procedure:
Thiophenol (11.75 g, 107 mmol), potassium carbonate (14.74 g, 107 mmol) and ditosylated dicyanohydroquinone (25.00 g, 53.0 mmol) in DMF (80 mL) were reacted as described above. Water (100 mL) was added and the mixture stirred for 1 hour then filtered. The filter cake was purified by flash column chromatography (gradient elution 10%-30% ethyl acetate:isohexane) to give the title compound as a yellow solid (5.53 g, 16.1 mmol, 52%). [Found: C, 69.6%; H, 3.5%; N, 8.2%; S, 18.3%; C20H12N2S2 requires C, 69.8%; H, 3.5%; N, 8.1%; S, 18.6%]; MS (EI+) 344 (M+, 100%).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:15](=[O:29])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[O:23])[CH:17]=2)[CH2:10][C@H:9]1[C:30]([N:32]1[CH2:36][CH2:35][S:34][CH2:33]1)=[O:31])=O)(C)(C)C.Cl.O1CCOCC1>CO>[CH3:28][S:25]([NH:24][C:22]([C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[C:15]([NH:14][CH2:13][C@H:11]1[CH2:10][C@@H:9]([C:30]([N:32]2[CH2:36][CH2:35][S:34][CH2:33]2)=[O:31])[NH:8][CH2:12]1)=[O:29])=[O:23])(=[O:26])=[O:27]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2cccc(C(=O)NS(C)(=O)=O)c2)C[C@H]1C(=O)N1CCSC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CS(=O)(=O)NC(=O)c1cccc(C(=O)NC[C@@H]2CN[C@H](C(=O)N3CCSC3)C2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of Example 32C (372.1 mg, 0.69 mmol) in methanol (5 mL) was slowly added a solution of 4 M HCl in dioxane (1.6 mL, 6.4 mmol) at 0° C. over 10 minutes via addition funnel. The mixture was allowed to stir for 5 hours at room temperature and then was concentrated under reduced pressure to provide the titled compound. MS (ESI) m/e 441 (M+H)+, 439 (M−H)−; 1H NMR (400 MHz, CD3OD) δ ppm 1.80 (m, 1H), 2.74 (m, 1H), 2.84 (m, 1H), 3.09 (m, 1H), 3.16 (t, 1H), 3.24 (m, 1H), 3.52 (dd, 2H), 3.55 (m, 1H), 3.74 (m, 1H), 3.88 (m, 1H), 4.51 (m, 1H), 4.65 (d, 1H), 4.70 (d, 1H), 7.63 (m, 1H) 8.06 (d, 1H) 8.10 (d, 1H) 8.39 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[CH2:1]([O:3][P:4]([C:9]1[CH:10]=[N+:11]([O-:23])[CH:12]=[CH:13][CH:14]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOP(=O)(OCC)c1cccnc1
Solvent: ClCCl
Product: CCOP(=O)(OCC)c1ccc[n+]([O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.5 g of 3-diethylphosphonopyridine, Bull. Chem. Soc. Jap. 55, 909 (1982), in 20 ml of methylene chloride is treated with 2.33 g m-chloroperbenzoic acid at room temperature. The reaction mixture is allowed to stir at room temperature overnight, then concentrated under vacuum. The residue is partitioned between ether and water, the aqueous layer is concentrated under vacuum to afford 3-(diethylphosphono)-pyridine-N-oxide as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH2:13][CH2:14][CH2:15]O)=[CH:10][CH:11]=2)[N:6]([CH3:17])[C:5]1=[O:18].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:33][S:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])=[O:35]>O1CCOCC1>[CH3:1][C:2]([CH3:20])([CH3:19])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH2:13][CH2:14][CH2:15][N:40]3[CH2:41][CH2:42][N:37]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:38][CH2:39]3)=[CH:10][CH:11]=2)[N:6]([CH3:17])[C:5]1=[O:18]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(CCCO)nc21
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(CCCN3CCN(S(C)(=O)=O)CC3)nc21
Temperature: 100 °C

Procedure:
To a stirred solution of 37-2 (0.05 g, 0.18 mmol) in dioxane (1 mL) was added triethylamine (0.10 mL, 0.72 mmol) and methanesulfonyl chloride (0.017 mL, 0.21 mmol). To this resulting mixture was added 1-methanesulfonyl-piperazine (0.09 g, 0.54 mmol) and the reaction was heated to 100° C. for 3 days. The reaction was concentrated and flash column separation using a 0-5% methanol/dichloromethane gradient gave 37-3. (0.025 g, 33%). HRMS (M+H)+: observed=424.2378, calculated=424.2377