Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].CN(C)C.Cl[C:15]([O:17][CH2:18][C:19]#[CH:20])=[O:16].C(Cl)Cl.O>C(Cl)Cl>[C:1]([O:6][CH2:7][CH2:8][O:9][C:15]([O:17][CH2:18][C:19]#[CH:20])=[O:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCO
Reactant: C#CCOC(=O)Cl
Agent: CN(C)C
Solvent: O
Solvent: ClCCl
Product: C#CCOC(=O)OCCOC(=O)C(=C)C
Yield: 73.6 %

Procedure:
A flask equipped with a stirrer, thermometer, nitrogen gas tube and reflux condenser was charged with 13.0 g of 2-hydroxyethyl methacrylate and 11.5 g of trimethylamine in 50.0 g of methylene chloride. To the flask was added 13.0 g of propargyl chloroformate dropwise over one hour. The mixture was allowed to react for 6 hours at 30° C. After the reaction, the mixture was treated with methylene chloride-water mixture. The organic phase was separated and dried over magnesium sulfate. After filtering, the filtrate was evaporated in a rotary evaporator. The resulting residue was applied on a 200 mesh silica gel column and developed with ethyl acetate-hexane mixture. The title compound was obtained as colorless liquid. Yield was 73.6% of theory.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([N+:14]([O-])=O)[C:5]=1[P:17](=[O:30])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-])=O.O1CCOCC1>Cl>[NH2:14][C:6]1[CH:7]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:9]=[C:4]([NH2:1])[C:5]=1[P:17](=[O:30])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1P(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cc(C(F)(F)F)cc(N)c1P(=O)(c1ccccc1)c1ccccc1
Temperature: 10 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
Into a 500 mL Erlenmeyer flask equipped with a stir bar was placed (2,6-dinitro-4-trifluoromethylphenyl)diphenylphosphine oxide (6.48 g, 0.0149 mol) and 1,4-dioxane (100 mL). The mixture was cooled in an ice bath to ˜10° C. A solution of stannous chloride dihydrate (31.22 g, 0.1384 mol) in concentrated hydrochloric acid (130 mL) was added dropwise over ˜1 hour. Once the addition was complete, the mixture was allowed to warm to room temperature with stirring. After ˜16 hours, the crude amine salt was collected via filtration, added to ice water and basified to a pH of ˜10 with ammonium hydroxide. The crude solid was isolated by filtration, washed with water, and air dried at room temperature to afford 5.11 g (91% crude yield) of a white powder. The solid exhibited a sharp endothermic peak at 172° C. as determined by differential scanning calorimetry (DSC) at a heating rate of 10° C./min. Recrystallization from ˜50% aqueous ethanol afforded tan plates (3.86 g, 69% yield) exhibiting a sharp endothermic peak at 174.17° C. by DSC.
Reaction SMILES: [Br-].[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:10][C:5]=2[O:4][CH2:3]1.[C:31]([C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH:42]([CH3:45])[CH:43]=O)=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32].CC(O)=O>C1COCC1>[C:31]([C:35]1[CH:36]=[CH:37][C:38]([CH2:41][CH:42]([CH3:45])[CH:43]=[CH:11][C:9]2[CH:8]=[CH:7][C:6]3[O:2][CH2:3][O:4][C:5]=3[CH:10]=2)=[CH:39][CH:40]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Reactant: c1ccc([P+](Cc2ccc3c(c2)OCO3)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C=Cc1ccc2c(c1)OCO2)Cc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
Potassium t-butylat (1 Min THF, 11 mL, 11.0 mmol, 1.1 equiv.) was added to a solution of (benzo[d][1,3]dioxol-5-ylmethyl)triphenylphosphonium bromide (4.77 g, 10.0 mmol, 1.0 equiv.) in THF (20 mL) at 25° C. After the dark red suspension was stirred at 25° C. for 10 min, 3-(4-tert-butylphenyl)-2-methylpropanal (2.04 g, 10.0 mmol, 1.0 equiv.) in THF (10 mL) was added, and the mixture was stirred at 70° C. for 1.5 h. After addition of 20% aq. AcOH-solution (10 mL) at 25° C., the aqueous layer was extracted with hexanes, the combined organic phases were dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (hexanes/EtOAc 19:1) to yield 2.83 g (88%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>>[NH:26]1[C:27]2[C:23](=[C:22]([O:21][C:16]3[N:15]=[C:14]([NH:13][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=4)[CH:19]=[N:18][CH:17]=3)[CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:25]1
Reactant: Oc1cccc2[nH]ccc12
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Product: COc1cc(Nc2cncc(Oc3cccc4[nH]ccc34)n2)cc(OC)c1OC
Yield: 17 %

Procedure:
Using Method X with 150 mg of 2-(3,4,5-trimethoxyphenylamino)-6-chloropyrazine and 4-hydroxyindole, the title compound was obtained (34 mg). Yield: 17%. 1H NMR (250 MHz, DMSO-d6) δ 3.24 (s, 6H), 3.49 (s, 3H), 6.10-6.12 (m, 1H), 6.66 (s, 2H), 6.79 (d, 1H, J=7.1 Hz), 7.07 (t, 1H, J=7.8 Hz), 7.25-7.29 (m, 2H), 7.79 (s, 1H), 7.92 (s, 1H), 9.44 (s, 1H), 11.26 (s, 1H). 13C NMR (62.9 MHz, DMSO-d6) δ 55.12, 59.96, 95.43, 98.04, 108.42, 109.87, 120.50, 120.91, 121.37, 125.36, 127.87, 131.91, 136.34, 138.13, 146.33, 150.59, 152.58, 157.84. m/z 393.1 [(M+H)+ calcd for C21H20N4O4 392.1].
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([NH:10][CH:11]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:12]2[CH:17]=[CH:16][C:15]([P:18](=[O:25])([O:22]CC)[O:19]CC)=[CH:14][CH:13]=2)=[O:9])=[CH:6][N:5]=[C:4]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[N:3]=1.C[Si](Br)(C)C>ClCCl>[OH:1][C:2]1[C:7]([C:8]([NH:10][CH:11]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:12]2[CH:13]=[CH:14][C:15]([P:18](=[O:19])([OH:22])[OH:25])=[CH:16][CH:17]=2)=[O:9])=[CH:6][N:5]=[C:4]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[N:3]=1
Reactant: CCOP(=O)(OCC)c1ccc(C(NC(=O)c2cnc(-c3ccccn3)nc2O)c2ccc(OC)cc2)cc1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: COc1ccc(C(NC(=O)c2cnc(-c3ccccn3)nc2O)c2ccc(P(=O)(O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of ethyl phosphate (1-1-1, 260 mg, 0.47 mmol) in dichloromethane (10 ml) was added TMSBr (2.18 g, 14.2 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature for 3 days. The mixture was concentrated under vacuum and methanol (20 ml) was added. The mixture was stirred for 15 mins at room temperature and concentrated. The residue was purified on prep-HPLC to provide the product, 1-1-2. (100 mg, 43%). 1H NMR (DMSO-d6, 300 MHz,): δ 8.81 (d, 1H, J=6 Hz), 8.40 (m, 1H), 8.10 (m, 1H), 7.60 (m, 4H), 7.35 (m, 2H), 7.25 (m, 2H), 6.95 (m, 2H), 6.23 (d, 1H, J=6 Hz), 3.71 (s, 3H). (M−H)−=491.1.
Reaction SMILES: [C:1]([NH:4][C:5]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[S:6])(=[O:3])[NH2:2].BrBr.O.CO>C(OCC)(=O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([NH:7][C:5]2[S:6][NH:2][C:1](=[O:3])[N:4]=2)=[O:16])=[CH:10][CH:11]=1
Reactant: NC(=O)NC(=S)NC(=O)c1ccc(Cl)cc1
Agent: BrBr
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1nc(=O)[nH]s1)c1ccc(Cl)cc1
Yield: 70 %

Procedure:
N—(Carbamoylcarbamothioyl)-4-chloro-benzamide (350 mg) from step (i) above was mixed with 50 mL of ethyl acetate. Bromine (224 mg) in 5 mL of ethyl acetate was added. After 30 minutes 10 mL of water and 10 mL of methanol was added. The mixture was concentrated and the residue was triturated with water/methanol and dried in vacuum to give the product as a white solid, 0.25 g, 0.98 mmol, 70% yield.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[C:9]=2[C:8]1=[O:28].[N:38]1([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:46]3[CH2:47][CH2:48][CH:43]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)[CH2:44][CH2:45]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[C:9]=2[C:8]1=[O:28]
Reactant: COc1ccccc1-c1cc(Cl)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Reactant: C1CCN(C2CCNCC2)C1
Product: COc1ccccc1-c1cc(N2CCC(N3CCCC3)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Yield: 38.5 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-methoxyphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (82.0 mg) was reacted with 4-(pyrrolidine-1-yl)piperidine (69.5 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methoxyphenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (38.4 mg, 39%).
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH:14]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:16])[CH3:15].[C:25]1([P:31](Cl)(Cl)=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CCCCCC.C1CCCCC1>[CH:14]([N:17]1[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[P:31]1(=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:16])[CH3:15]
Reactant: CC(C)NCc1ccccc1
Reactant: O=P(Cl)(Cl)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCCCC1
Product: CC(C)N1Cc2ccccc2P1(=O)c1ccccc1
Temperature: 26 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
Under a static nitrogen atmosphere at 0° C., a solution of n-butyllithium (7.87 g, 0.123 mol) in hexane was added to a solution of tetramethylethylenediamine (14.3 g, 0.123 mol) in 60 ml. of anhydrous cyclohexane with constant stirring. While maintaining the temperature of the reaction at 0° C., a solution of N-isopropylbenzylamine (9 g, 0.06 mol) in 60 ml. of anhydrous cyclohexane was added to the reaction mixture to produce a suspension containing a dilithio compound. This suspension was stirred for 2 hours at 26° C. and then cooled to -40° C. using a solid carbon dioxide-acetone bath. A solution of phenylphosphonic dichloride (12.5 g, 0.064 mol) in 60 ml. of anhydrous cyclohexane was rapidly added to the suspension causing the temperature of the reaction to increase to 10° C. The reaction mixture was stirred for 1.5 hours at 26° C., after which time the reaction mixture was cooled to 0° C. and then quenched with the rapid addition of 12 ml. of acetic acid. After stirring for 15 minutes, the cyclohexane was removed on a rotary evaporator, and the resulting residue was partitioned between methylene chloride and water. The layers were separated and the methylene chloride layer was washed with water, dried over magnesium sulfate and concentrated in vacuo to yield an oil. This oil was distilled at 160° C. and 0.2 torr and the resulting residue was crystallized at 0° C. from diethyl ether and petroleum ether to yield 2-(1-isopropyl)-1-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (4.5 g, 28% yield) having a melting point of 92°-94° C. and the following analysis:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[CH:22][N:23]=2)[CH:20]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[N:23]1[CH:22]=[CH:21][N:19]2[CH:20]=[C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])[CH:16]=[CH:17][C:18]=12
Reactant: Brc1ccc2nccn2c1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3nccn3c2)C1=O
Yield: 44.3 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847 mmol) was reacted with 6-bromo-imidazo[1,2-a]pyridine (249.5 mg, 1.27 mmol), 1,4-dioxane (10 mL), copper iodide (16.13 mg, 0.0847 mmol), trans-1,2-diamino cyclohexane (0.03 mL, 0.254 mmol) and potassium phosphate (539 mg, 2.54 mmol) to afford the crude product. Purification by column chromatography on silica gel (5% MeOH in CHCl3) afforded 110 mg of the product (44.35% yield).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13]C)=[O:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=1.[SH-:16].[Na+]>O>[C:11]([C:9]1[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=[C:2]([SH:16])[N:7]2[N:8]=1)([OH:13])=[O:12]
Reactant: COC(=O)c1nc2nc(C)cc(Cl)n2n1
Reactant: [SH-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(S)n2nc(C(=O)O)nc2n1
Temperature: 60 °C
Yield: 63.4 %

Procedure:
The product obtained in Step 1 (17 g) was added at a time, in a nitrogen atmosphere, to a solution of sodium hydrosulfide (16 g) in 280 ml of water at room temperature with stirring, and the mixture was heated to 60° C. with stirring continued. The resultant yellow solution was cooled to room temperature, the insoluble matters were filtered off, the filtrate was acidified with concentrated hydrochloric acid to pH 2.0, and the crystals thus formed were collected by filtration and washed twice with 20 ml of water, affording 10 g of the objective compound as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(=O)([O-])[O-].[K+].[K+].O.C[N:17]([CH:19]=O)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[C:4]([C:19]#[N:17])[C:3]=1[C:19]#[N:17]
Reactant: Sc1ccccc1Cl
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1c(Sc2ccccc2Cl)ccc(Sc2ccccc2Cl)c1C#N
Reaction time: 1 h

Procedure:
2-Chlorothiophenol (12.50 g, 86.5 mmol), potassium carbonate (11.94 g, 86.5 mmol) and ditosylated dicyanohydroquinone (20.36 g, 43.5 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 (eluting 30% ethyl acetate:isohexane) to give the title compound as a yellow solid (5.53 g, 13.4 mmol, 31%) [Found: C, 58.1%; H, 2.7%; N, 6.9%; S, 15.4%; Cl 16.6%; C20H10N2S2Cl2 requires C, 58.1%; H, 2.4%; N, 6.8%; S, 15.5%; Cl 17.2%]; MS (EI+) 412 (M+, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:5]([NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)=[O:6].[CH2:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:5]([NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:30][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:12])=[O:6]
Reactant: COc1ccc(C(=O)Nc2ccccc2C(=O)O)cc1Cl
Reactant: NCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)Nc2ccccc2C(=O)NCCc2ccccc2)cc1Cl
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A solution of 42B (50 mg, 0.16 mmol) in DMF (5 mL) was treated with phenethylamine (150 μL, 1.6 mmol), diisopropylethylamine (42 mL, 0.32 mmol), and EDCI (31 mg, 0.32 mmol) at room temperature. After 2 hours Bop reagent (100 mg, 0.22 mmol) was added. After 30 minutes, the reaction was concentrated and purified by chromatography (SiO2, 30% EtOAc in hexanes) to afford 42C (47 mg, 70%). HPLC retention time: 2.79 minutes (YMC S-5 Combiscreen 4.6×50 mm, 10% to 90% MeOH/H2O w/0.2% H3PO4, 4 minute gradient).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH3:7].[CH3:20][C:21]([NH2:34])([CH3:33])[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[OH:1][C@H:2]([CH2:3][NH:34][C:21]([CH3:33])([CH3:20])[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)[CH2:4][O:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH3:7]
Reactant: COC(=O)CCc1ccccc1[C@@H](C)OC[C@H]1CO1
Reactant: CC(C)(N)Cc1ccc2ccccc2c1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: COC(=O)CCc1ccccc1[C@@H](C)OC[C@H](O)CNC(C)(C)Cc1ccc2ccccc2c1
Yield: 107.4 %

Procedure:
Methyl 3-[2-[(1R)-1-(((2R)-oxiranyl)methoxy)ethyl]phenyl]propionate (286 mg) obtained in Step 3 was dissolved in acetonitrile (10 ml), [2-methyl-1-(naphthalen-2-yl)propan-2-yl]amine (218 mg) and lithium perchlorate (157 mg) were successively added, and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give the title compound (539 mg).
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:7][CH2:6][C:5](=[O:8])[N:4]1[CH2:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([O:19]CCCC)=[O:18])[N:14]=1.[F:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1([C:33](=[O:41])[CH2:34]P(=O)(OC)OC)[CH2:32][CH2:31][CH2:30]1>>[F:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1([C@H:33]([OH:41])/[CH:34]=[CH:2]/[C@H:3]2[CH2:7][CH2:6][C:5](=[O:8])[N:4]2[CH2:9][C:10]2[S:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[N:14]=2)[CH2:30][CH2:31][CH2:32]1
Reactant: CCCCOC(=O)CCc1csc(CN2C(=O)CC[C@@H]2CO)n1
Reactant: COP(=O)(CC(=O)C1(CCCCF)CCC1)OC
Product: O=C(O)CCc1csc(CN2C(=O)CC[C@@H]2/C=C/[C@@H](O)C2(CCCCF)CCC2)n1

Procedure:
By the same procedure as a series of reactions of Example 5→Example 6→Example 7→Example 8 using the compound 75 instead of the compound 4 and using dimethyl {2-[1-(4-fluorobutyl)cyclobutyl]-2-oxoethyl}phosphonate instead of dimethyl (3,3-dimethyl-2-oxoheptyl)phosphonate, the title compound having the following physical data was obtained.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-:14])=[O:13])[CH:5]=[N:4][CH:3]=1.[CH3:15][O:16][C:17]1[C:18]([O:34][CH2:35][O:36][CH3:37])=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].[OH-].[K+]>C(COC)OC.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.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>[CH3:15][O:16][C:17]1[C:18]([O:34][CH2:35][O:36][CH3:37])=[C:19]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[N+:12]([O-:14])=[O:13])[CH:5]=[N:4][CH:3]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: O=[N+]([O-])c1cccc2cncc(Br)c12
Reactant: COCOc1c(B2OC(C)(C)C(C)(C)O2)ccc(OC)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: COCCOC
Solvent: O
Product: COCOc1c(-c2cncc3cccc([N+](=O)[O-])c23)ccc(OC)c1OC
Temperature: 25 °C
Yield: 99.9 %

Procedure:
Isoquinoline 3 (3.36 g; 0.0143 mol), pinacol boronate ester 2 (5.562 g; 0.0172 mol), and 1.0 g (6 mol %) of tetrakis(triphenylphosphine)palladium(0) were suspended in 100 ml of dimethoxyethane (DME). Potassium hydroxide (3.6 g; 0.064 mol), and 0.46 g (10 mol %) of tetrabutylammonium bromide were dissolved in 14.5 ml of water and added to the DME mixture. The resulting suspension was degassed for 30 minutes with argon and then heated at reflux for four hours. The resulting black solution was allowed to cool to room temperature, poured into 500 ml of water, extracted with diethyl ether (3×500 ml), dried (Na2SO4), and concentrated. The product was then purified by column chromatography (silica gel, 50% ethyl acetate: hexane) giving 5.29 g of yellow crystals (80.1%): mp 138-140° C.; 1H NMR: (300 MHz, CDCl3): 9.33 (s, 1H); 8.61 (s, 1H); 8.24 (dd, 1H, J=7.2, 0.9 Hz); 8.0 (dd, 1H, J=6.3, 1.2 Hz); 7.67 (t, 1H, J=7.8 Hz); 7.03 (d, 1H, J=9.6 Hz); 6.81 (d, 1H, J=8.1 Hz); 4.86 (d, 1H, J=6 Hz); 4.70 (d, 1H, J=5.4 Hz); 3.92 (s, 3H); 3.89 (s, 3 H); 2.613 (s, 3 H). CIMS mlz: 371 (M+H+, 100%). Anal Calc'd for C19H18N2O6: C, 61.62; H, 4.90; N, 7.56. Found: C, 61.66; H, 4.90; N, 7.56.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:14](Cl)[C:15]#[CH:16]>CS(C)=O>[CH2:16]([S:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[C:15]#[CH:14]
Reactant: Sc1ccncc1
Reactant: C#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C#CCSc1ccncc1
Temperature: 60 °C
Yield: 40.2 %

Procedure:
In 200 ml dimethyl sulfoxide (DMSO) was dissolved 25.0 g (0.225 mole) 4-mercaptopyridine. To this solution were added 15.5 g (0.112 mole) anhydrous potassium carbonate and 16.5 g (0.25 mole) propargyl chloride. This mixture was heated at 60° C. for 3 hours. The reaction mixture was then cooled to room temperature and filtered. The filtrate was added to an equal volume of water. This mixture was extracted with ether. After removal of the ether under reduced pressure, there remained 20.0 g crude product. Distillation gave 13.5 g 4-(2-propynylthio)pyridine. Yield 39% theory; b.p. 79°-81° C. (1.0 mm); mp 55°-56° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[NH:4][CH2:5][C@H:6]([CH2:11][C:12](=[O:22])[NH:13][C@H](C1C=CC=CC=1)C)[CH2:7][CH:8]([CH3:10])[CH3:9].O1CCCC1.N.[Na]>O>[CH3:1][O:2][C:3](=[O:23])[NH:4][CH2:5][C@H:6]([CH2:11][C:12](=[O:22])[NH2:13])[CH2:7][CH:8]([CH3:9])[CH3:10]
Reactant: COC(=O)NC[C@H](CC(=O)N[C@@H](C)c1ccccc1)CC(C)C
Agent: N
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)NC[C@H](CC(N)=O)CC(C)C
Yield: 60.5 %

Procedure:
A 2 l, four-necked flask, equipped with a mechanical stirrer, thermometer pocket and a liquid ammonia inlet, was charged with {(S)-4-methyl-2-[((S)-1-phenylethylcarbamoyl)-methyl ]pentyl}carbamic acid methyl ester (26) (25 g, 0.078 mole), tetrahydrofuran (175 ml), and water (25 ml). The reaction mixture was cooled to −40° to −60° C. and liquid ammonia (1000 ml) was added followed by addition of small pieces of sodium metal (7.2 g). The resultant reaction mixture was stirred vigorously for 4-10 hours until the ammonia had evaporated. Water (100 ml) was added to the reaction mass under N2 atmosphere at 5°-10° C., followed by separating the phases. The organic layer was separated and dried over anhydrous sodium sulphate and the solvent was stripped off. The residue was crystallized from diisopropyl ether to get 10.2 g (60% yield) of {(S)-2-carbamoylmethyl-4-methylpentyl)carbamic acid methyl ester with purity of 73% as measured by HPLC.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[O:19]
Reactant: [H][H]
Reactant: CS(=O)(=O)NNC(=O)[C@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)NNC(=O)[C@H]1CC[C@@H]2CN1C(=O)N2O
Yield: 98.8 %

Procedure:
To a solution of (2R,5R)-6-(benzyloxy)-N′-(methylsulfonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 188 (0.37 g, 1.044 mml) in methanol (35 mL) was added 5% Pd/C (0.40 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered through Celite and the filtrate was evaporated to give (2R,5R)-6-hydroxy-N′-(methylsulfonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 189 (0.276 g, 99%) as a colorless foam.