Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][S:16][CH2:17][C@H:18]2[O:22][C@@H:21]([N:23]4[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]4=[O:25])[CH2:20][C@@H:19]2[OH:32])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[N:33]1C=C[CH:36]=[CH:35][CH:34]=1.C(N(C(C)C)CC)(C)C.[CH:48]([N:51]([CH:59]([CH3:61])[CH3:60])[P:52](Cl)[O:53]CCC#N)([CH3:50])[CH3:49]>O1CCCC1>[C:34]([CH2:35][CH2:36][PH:52]([O:32][C@@H:19]1[C@@H:18]([CH2:17][S:16][CH2:15][C:13]2[C:12]3[C:7]([CH:6]=[C:5]4[C:14]=2[CH:1]=[CH:2][CH:3]=[CH:4]4)=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:22][C@@H:21]([N:23]2[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[CH2:20]1)([N:51]([CH:48]([CH3:49])[CH3:50])[CH:59]([CH3:60])[CH3:61])[OH:53])#[N:33]
Reactant: CC(C)N(C(C)C)P(Cl)OCCC#N
Reactant: c1ccncc1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CSCc3c4ccccc4cc4ccccc34)O2)c(=O)[nH]c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn([C@H]2C[C@H](O[PH](O)(CCC#N)N(C(C)C)C(C)C)[C@@H](CSCc3c4ccccc4cc4ccccc34)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 79 %

Procedure:
74 mg (0.165 mmol) of 5'-[(anthracen-9-yl)methylthio]-5'-deoxythymidine [prepared as described in (a) above] were dried by azeotropic distillation with pyridine and then dissolved in 1 ml of tetrahydrofuran. 0.115 ml (0.659 mmol) of N,N-diisopropyl-N-ethylamine was added to the solution. 49 μl (0.22 mmol) of 2-cyanoethyl N,N-diisopropylchlorophosphoramidite were then added dropwise to the mixture, under an atmosphere of argon. The resulting mixture was stirred at room temperature for 1.75 hours under the same atmosphere. The tetrahydrofuran was then removed by distillation under reduced pressure. The resulting residue was dissolved in 10 ml of ethyl acetate, and the solution was washed with a 10% w/v aqueous solution of sodium carbonate and with a saturated aqueous solution of sodium chloride, in that order. The solution was dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through 10 g of silica gel (70-230 mesh), using ethyl acetate as the eluent, to give 85 mg (yield 79%) of the title compound as a foam-like substance.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][Li]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]C
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: CC1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of 1-benzyl-4-piperidone (5.6 mL, 30.0 mmol) in 50 mL THF was added a solution of methyllithium in THF (24.0 mL, 36 mmol) dropwise at 0° C. over 15 min. The reaction mixture was allowed to warm to room temperature over 3 h and then quenched with 30 mL of sat. NH4Cl solution. The organic layer was extracted with diethyl ether (2×100 mL) and the combined organic layer was washed with brine (100 mL). The organic layer was separated, dried over Na2SO4, filtered and the solvent was removed in vacuo to obtain yellow gum. It was purified by column chromatography over silica gel with 9:1 EtOAc-MeOH as the eluting system to obtain 1-benzyl-4-methyl-4-piperidinol as a yellow thick oil (3.6 g, 59% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7]/[C:6]/1=[N:12]\[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1ccccc1
Yield: 34.5 %

Procedure:
The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.45 mL, 3.2 mmol) and benzoyl chloride (Aldrich, 0.16 mL, 1.4 mmol) in 15 mL THF were processed using the method described in Example 129 to afford the title compound (0.11 g, 0.38 mmol, 35% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.24 (s, 3H), 2.27 (d, J=0.7 Hz, 3H), 3.32 (s, 3H), 3.82 (t, J=5.3 Hz, 2H), 4.41 (t, J=5.3 Hz, 2H), 7.38-7.51 (m, 3H), 8.27-8.34 (m, 2H); MS (DCI/NH3) m/z291 (M+H)+; Anal. calculated for C15H18N2O2S: C, 62.04; H, 6.25; N, 9.65. Found: C, 62.02; H, 6.05; N, 9.56.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:9])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:8][C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(N)cccc1F
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(F)c1C
Temperature: 100 °C

Procedure:
To the solution of 3-fluoro-2-methylphenylamine (40 mmol) in toluene (50 mL) was added acetic anhydride (47 mmol). The mixture was heated to 100° C. for 1 h, then concentrated to give N-(3-fluoro-2-methylphenyl)acetamide as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>ClCCl>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:1][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[OH:9])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Nc1cc(Cl)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)ccc2O)CC1
Reaction time: 18 h
Yield: 82 %

Procedure:
2-Amino-4-chloro-phenol (30.0 g, 209 mmol) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (46.0 g, 231 mmol) were set stirring in dichloromethane (600 mL). Sodium triacetoxyborohydride (58.0 g, 274 mmol) was added in portions over 10 min. Acetic acid (12 mL, 210 mmol) was then added and the mixture left to stir for 18 h. Saturated NaHCO3 was added and the organics seperated. The organics were dried (MgSO4) and evaporated to give 56 g (82%) of a light beige solid. TLC (silica, 50% EtOAc/hexanes): Rf=0.66. MS (electrospray): exact mass calculated for C16H23ClN2O3, 326.14. m/z found, 349.1 [M+Na]+. 1H NMR (400 MHz, DMSO-d6): 6.70 (d, J=8.3 Hz, 1H), 6.63 (s, 1H), 6.47 (d, J=8.2 Hz, 1H), 3.97 (d, J=12.2 Hz, 2H), 3.55-3.50 (m, 1H), 2.93 (br s, 2H), 1.93 (d, J=11.1 Hz, 2H), 1.48 (s, 9H), 1.35 (d, J=11.2 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCCCCC>[C:10]1([N:9]=[CH:7][C:3]2[S:4][CH:5]=[CH:6][C:2]=2[CH3:1])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccsc1C=O
Reactant: Nc1ccccc1
Solvent: CCCCCC
Product: Cc1ccsc1C=Nc1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 84.9 %

Procedure:
3-methylthiophene-2-aldehyde (103 g, 0.816 mol) was mixed with hexane (100 ml), to which aniline (74.4 ml, 0.816 mol) was added and stirred at room temperature for 7 hours. After separating deposited crystalline solids by filtration, and washing with hexane, 139.5 g (yield: 85%) of 3-methylthiophene-2-aldehyde phenylimine was obtained. After concentrating the liquid filtrate and stirring at room temperature for a further 12 hours, 7.30 g (yield: 4%) of 3-methylthiophene-2-aldehyde phenylimine was obtained by post treatment in the same manner as above. 1H-NMR spectra (chemical shift, ppm: in CDCl3); 2.47 (3H, s), 6.92 (1H, d, J=4.9 Hz), 7.15-7.30 (3H), 7.30-7.45 (3H), 8.61 (1H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)[CH3:3].CN(CCC1CC=CC=1)C.[Cl-:26].[Cl-].[Cl-].[CH:29]1([Zr+3:34])[CH:33]=[CH:32][CH:31]=[CH:30]1.[Cl-].[Cl-].[Cl-].C[Zr](C)(C)(C)(C)C1C=CC=C1>>[Cl-:26].[Cl-:26].[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[Zr+2:34][CH:29]1[CH:33]=[CH:32][CH:31]=[CH:30]1)[CH3:3]
Reactant: CN(C)CCCC1C=Cc2ccccc21
Reactant: [Zr+3]C1C=CC=C1
Agent: C[Zr](C)(C)(C)(C)C1C=CC=C1
Agent: CN(C)CCC1=CC=CC1
Agent: [Cl-]
Product: CN(C)CCCC1C([Zr+2]C2C=CC=C2)=Cc2ccccc21
Yield: 40 %

Procedure:
Example 1 was repeated in the same manner as described except that 1-(N,N-dimethylaminopropyl)indene was substituted for (N,N-dimethylaminoethyl)cyclopentadiene and that cyclopentadienylzirconium trichloride was substituted for pentamethylcyclopentadienylzirconium trichloride. The yield was 40.0%. The physical properties of the product are as follows:
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[OH:24].C[O:26][C:27](=[O:35])[CH:28](Br)[CH2:29][CH:30]1[CH2:33][CH2:32][CH2:31]1>>[CH:30]1([CH2:29][CH:28]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:24][C:18]3[C:17]([F:16])=[CH:22][CH:21]=[CH:20][C:19]=3[F:23])[CH:6]=[N:5]2)[C:27]([OH:26])=[O:35])[CH2:33][CH2:32][CH2:31]1
Reactant: COC(=O)C(Br)CC1CCC1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: Oc1c(F)cccc1F
Product: O=C(O)C(CC1CCC1)n1ncc(Oc2c(F)cccc2F)cc1=O

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2,6-difluoro-phenol and alkylating with 2-bromo-3-cyclobutyl-propionic acid methyl ester (Intermediate 16) afforded 3-cyclobutyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid as a white solid (520.5 mg, 82% for the final step); ES+-HRMS m/e calcd for C17H16N2O4F2 [M+H+] 351.1151, found 351.1152. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-1.56 (m, 1H), 1.57-1.87 (m, 4H), 1.87-2.01 (m, 1H), 2.03-2.27 (m, 3H), 5.17-5.28 (m, 1H), 6.07 (d, J=2.7 Hz, 1H), 7.32-7.43 (m, 2H), 7.43-7.58 (m, 1H), 8.26 (d, J=2.7 Hz, 1H), 13.05 (br s, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=O)O.N[C@H]([C:13]([OH:15])=[O:14])C>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][C:13](=[O:14])[OH:15]
Reactant: C[C@H](N)C(=O)O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
A4Glu, Asp, Pro, or Ala;
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][C:7]([B:9]1[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]1)=[CH2:8])C=C>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.ClCCl>[O:4]1[CH2:1][CH:8]=[C:7]([B:9]2[O:10][C:11]([CH3:16])([CH3:17])[C:12]([CH3:14])([CH3:15])[O:13]2)[CH2:6][CH2:5]1
Reactant: C=CCOCCC(=C)B1OC(C)(C)C(C)(C)O1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
Add Grubbs Catalyst, 2nd Generation (benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro(tricyclohexylphosphine)ruthenium, 2.58 g, 0.03 eq) to a solution of 2-(3-allyloxy-1-methylene-propyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (23.4 g, 98.26 mmol) in dichloromethane (280 mL) and stir for 16 hours. Concentrate in vacuo and add hexanes (120 mL) to the residue. Stir for one hour and filter. Concentrate the filtrate in vacuo to give 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a tan solid (20.4 g, 99%). 1H NMR (300 MHz, CDCl3) δ 6.50 (m, 1H), 4.17 (q, J=2.7 Hz, 2H), 3.73 (t, J=5.4 Hz, 2H), 2.20 (m, 2H), 1.24 (s, 12H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.CC(C)([O-])C.[K+:17]>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O-:9].[K+:17]
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: [O-]c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
A mixture of 1.94 g (12 mmol) of 3-(trifluoromethyl)phenol and 1.344 g (12 mmol) of potassium t-butoxide was stirred under argon for 30 min. A solution was resulted, and the by-product, t-butanol, was removed under vacuum and heat to give a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[OH2:14].O[N:16]1[C:20]2[CH:21]=CC=[CH:24][C:19]=2[N:18]=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[NH2:18][C@@H:19]1[CH2:24][O:14][CH2:21][C@@H:20]1[NH:16][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13]
Reactant: O
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: N[C@@H]1COC[C@@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 50 °C
Yield: 54.7 %

Procedure:
5-Chloroindole-2-carboxylic acid (0.29 g), 1-hydroxybenzotriazole monohydrate (0.2 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g) were successively added to a solution of the compound (0.5 g) obtained in Referential Example 171 in N,N-dimethylformamide (10 ml), and the mixture was heated and stirred at 50° C. for a day. The reaction mixture was concentrated, and the resultant residue was diluted with a mixed solvent composed of chloroform and methanol (9:1) and washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium chloride. After the resultant organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resultant residue was purified by column chromatography on silica gel (chloroform:methanol=95:5) to obtain the title compound (0.2 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28]CC)=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][CH:34]([C:39]2[CH:44]=[CH:43][C:42]([C:45]#N)=[CH:41][C:40]=2[N:47]2[CH:51]=[CH:50][C:49]([CH3:52])=[N:48]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.O[Li].[OH2:55].Cl.C[OH:58]>O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[O:17])[C@H:13]([C:26]([OH:28])=[O:27])[CH2:12]3)[CH2:31][CH2:32]2)[CH:5]=[C:4]([O:33][CH:34]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([OH:58])=[O:55])=[CH:41][C:40]=2[N:47]2[CH:51]=[CH:50][C:49]([CH3:52])=[N:48]2)[C:35]([F:37])([F:36])[F:38])[N:3]=1
Reactant: CO
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(OC(c4ccc(C#N)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Reactant: O
Agent: Cl
Agent: [Li]O
Product: Cc1ccn(-c2cc(C(=O)O)ccc2C(Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)O)N(C(=O)OCc3ccccc3)C4)nc(N)n2)C(F)(F)F)n1
Temperature: 50 °C

Procedure:
To a solution of (3S)-2-benzyl 3-ethyl 8-(2-amino-6-(1-(4-cyano-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (0.35 g, 0.50 mmol, see Ex. 14) in MeOH (5 mL) and water (1 mL) was added LiOH—H2O (0.20 g, 5 mmol). The mixture was heated to 50° C. overnight. The reaction was then cooled to RT, and the reaction was acidified with 6N HCl to pH=1. Concentration in vacuo followed by reverse phase HPLC purification (MeOH/water/HOAc) provided (3S)-8-(2-amino-6-(1-(4-carboxy-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]2[N:16]([CH3:17])[CH:15]=[N:14][CH:13]=2)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19]>ClC1C=CC=CC=1Cl>[CH3:17][N:16]1[C:12]2[C:3]3[CH:4]=[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:10]4=[CH:11][C:2]=3[NH:1][C:18](=[O:19])[C:13]=2[N:14]=[CH:15]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1cncc1-c1cc2ccccc2cc1N
Solvent: Clc1ccccc1Cl
Product: Cn1cnc2c(=O)[nH]c3cc4ccccc4cc3c21
Temperature: 180 °C
Yield: 41.2 %

Procedure:
A mixture of 5-(3-amino-2-naphthyl)-1-methylimidazole (Preparation 17) (0.48 g, 2.14 mmol) and 1,1′-carbonyidiimidazole (0.42 g, 2.57 mmol) in o-dichlorobenzene (22 mL) was heated at 180° C. for 5 hours. The suspension was cooled to RT, filtered, and dried under vacuum, affording the title compound as a light yellow solid (0.22 g, 42%). 1H NMR(DMSO): 11.57(s, 1H), 8.71(s, 1H), 8.15(s, 1H), 8.10(d, J=8.4, 1H), 7.89(d, J=8.4, 1H), 7.84(s, 1H), 7.53(m, 1H), 7.46(m, 1H), 4.30(s, 3H). (ESI) m/z (M+H)+=250.08.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]([CH2:6][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH2:8])=[CH:4]1.C(N(CC)CC)C.[F:26][C:27]1[CH:37]=[CH:36][C:30]([CH:31]=[CH:32][C:33](O)=[O:34])=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:26][C:27]1[CH:28]=[CH:29][C:30]([CH:31]=[CH:32][C:33]([NH:8][C@H:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6][C:5]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:3]([CH3:2])[CH:4]=2)=[O:34])=[CH:36][CH:37]=1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Reactant: COC(=O)[C@@H](N)Cc1cn(C)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cn(C)c2ccccc12)NC(=O)C=Cc1ccc(F)cc1
Yield: 95.4 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 20 (2.0 g), triethylamine (1.1 mL), 4-fluorocinnamic acid (1.4 g), WSC.HCl (1.6 g), and methylene chloride (80 mL), to give the captioned compound (2.7 g, 94%) as an oily product.
Reaction SMILES: [C:1]([N:4]1[CH:8]([C:9]2[N:18]=[C:17]([C:19]([O:21]C)=O)[C:16]([O:23]CC3C=CC(OC)=CC=3)=[C:15]3[C:10]=2[CH:11]=[CH:12][CH:13]=[N:14]3)[CH2:7][CH2:6][N:5]1[CH3:33])(=[O:3])[CH3:2].O.[C:35](O)([C:37]([F:40])(F)F)=O>C(#N)C>[C:1]([N:4]1[CH:8]([C:9]2[N:18]=[C:17]([C:19]([NH:14][CH2:15][C:10]3[CH:11]=[CH:35][C:37]([F:40])=[CH:8][CH:9]=3)=[O:21])[C:16]([OH:23])=[C:15]3[C:10]=2[CH:11]=[CH:12][CH:13]=[N:14]3)[CH2:7][CH2:6][N:5]1[CH3:33])(=[O:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1nc(C2CCN(C)N2C(C)=O)c2cccnc2c1OCc1ccc(OC)cc1
Solvent: O
Solvent: CC#N
Product: CC(=O)N1C(c2nc(C(=O)NCc3ccc(F)cc3)c(O)c3ncccc23)CCN1C
Temperature: 120 °C

Procedure:
A solution of the above acetylpyrazolidine (50 mg, Step 1), water (0.25 mL), and TFA (0.15 mL) in acetonitrile (5 mL) was stirred at room temperature for 6 hours. The resultant mixture was concentrated under vacuum. Residual water and TFA was removed by co-evaporation with additional acetonitrile (3×5 mL). Without further purification, the residual oil was treated with 4-fluorobenzylamine (0.2 mL) in a mixture of methanol (1 mL) and toluene (8 mL) in a sealed tube was heated in an oil bath at 120° C. for 2 hours. The product mixture was concentrated under vacuum. The residue was dissolved in DMSO, and subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:17]>C(Cl)(Cl)Cl>[CH3:11][O:10][C:8]([C:3]1[C:2]([CH3:1])=[N+:7]([O-:17])[CH:6]=[CH:5][N:4]=1)=[O:9]
Reactant: COC(=O)c1nccnc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ncc[n+]([O-])c1C
Temperature: 70 °C

Procedure:
In a 1-L flask, the methyl 3-methylpyrazine-2-carboxylate (step 1, 16.08 g, 106 mmol) was suspended in CHCl3 (300 mL). 3-chlorobenzoperoxoic acid (Aldrich, 24.62 g, 143 mmol) was added. The reaction mixture was heated to 70° C. for 16 h. The reaction mixture was quenched with saturated NaHCO3 (200 mL). The layers were separated, and the aqueous layer was further extracted with DCM (2×100 mL). The combined organic layers were dried over MgSO4, and the filtrate was concentrated to afford the title compound. MS m/z=169 [M+H]+. Calculated for C7H8N2O3: 168.
Reaction SMILES: [O:1]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([CH:22]=[CH2:23])=[O:21])=[CH:15][CH:14]=1)[C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[NH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+].[C:46]([O:50][C:51](=O)[O:52]C(C)(C)C)([CH3:49])([CH3:48])[CH3:47]>CC(C)=O.O.C(O)(C)C>[C:46]([O:50][C:51](=[O:52])[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:23][CH2:22][C:20](=[O:21])[NH:19][C:16]1[CH:15]=[CH:14][C:13]([O:1][CH:2]2[CH:3]([OH:4])[CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([CH2:11][OH:12])[O:10]2)=[CH:18][CH:17]=1)([CH3:49])([CH3:48])[CH3:47]
Reactant: C=CC(=O)Nc1ccc(O[C@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)cc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: NCCCCCCNC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N(CCCCCCNC(=O)c1ccccc1)CCC(=O)Nc1ccc(OC2OC(CO)C(O)C(O)C2O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound 4 (0.88 g, 2.7 mmol) and 6 (0.71 g, 3.2 mmol) in a solution of isopropanol (30 ml) and H2O (4 ml) is stirred at 65° C. (oil bath) in a capped 100 ml RBF for 48 hrs. TLC on silica shows that at least 85% of 4 is converted to the Michael addition product (Rf=0, 30:1 acetone-concentrated ammonium hydroxide). The reaction is allowed to cool to ambient temperature, followed by the addition of powdered K2CO3 (0.44 g, 3.2 mmol) and di-tert-butylcarbonate (0.84 mg, 3.8 mmol, Aldrich). The mixture is stirred at ambient temperature for 3 hr. TLC should show at least 80% of Michael addition product was converted to the desired product (Rf=0.17, 10:1 acetone-concentrated ammonium hydroxide). The solid is collected by vacuum filtration and is washed with 30 ml of MeOH. The filtrates are combined, and solvent is removed by rotary evaporation to give an oily residue. MeOH (6.5 ml) is added to dissolve the residue, and the pH is adjusted to ˜3-4 (moist pH paper) by addition of trifluoroacetic acid with chilling on ice. The desired product is purified by 10 runs of preparative HPLC: 50% MeOH in H2O, at a flow rate of 6 ml/min; tR=27 min. Product fractions are pooled, and most of the solvent is removed by rotary evaporation at ambient temperature. The remaining solvent is removed by lyophilization, and the resulting residue is dissolved in 20 ml of MeOH. Solvent is removed by rotary evaporation, and the oily residue is dried in vacuum to give a white solid (1.1 g, 63%). ESI-MS (M+H)+: 646.6; 1H-NMR (1:2.5 D2O/acetone-d6) δ 7.80˜7.75 (2H, m, COCCH), 7.55˜7.35 (5H, m, COCHCHCH and NHCCH), 7.05 (2H, d, J=9.0 Hz, NHCCHCH), 5.39 (1H, d, J=3.4 Hz, H-1), 4.00˜3.57 (6H, m, H-2,3,4,5,6,6′), 3.51 (2H, t, J=6.8 Hz, COCH2CH2), 3.30 (2H, t, J=7.0 Hz, CONHCH2), 3.16 (2H, t, J=7.0 Hz, CONH(CH2)5CH2), 2.55 (2H, t, J=6.4 Hz, COCH2), 1.70-1.20 (17H, m, O-tert-C4H9 and NHCH2(CH2)4).
Reaction SMILES: COC([NH:5][CH:6]([CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][OH:8])=O.[C:32]([O:36][C:37]([O:39]C([O-])=O)=O)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([NH:5][CH:6]([CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][OH:8])=[O:39])([CH3:33])([CH3:34])[CH3:35]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)NC(=O)OC
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)NC(=O)OC(C)(C)C
Yield: 93.4 %

Procedure:
2-tert-Butoxycarbonylamino-3-octadecylcarbamoyloxypropanol V e2 is prepared by the same manner as described in (41) by using tert-butyldicarbonate instead of methyl chloroformate.