Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C@@H:11]([CH2:28][C:29]#N)[CH2:10]1)(=[O:8])=[O:7].[OH-:31].[Na+].[OH2:33].CCO.[ClH:37]>O>[ClH:37].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=2)[C@@H:11]([CH2:28][C:29]([OH:33])=[O:31])[CH2:10]1)(=[O:8])=[O:7]
Reactant: [OH-]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CC#N)cc1)C(F)(F)F
Reactant: O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CC(=O)O)cc1)C(F)(F)F
Reaction time: 1 h

Procedure:
A solution of 2-((2S)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)acetonitrile (1.10 g, 2.40 mmol) and 5 M NaOH (3 mL) in 2:1 water-EtOH (10 mL) was heated to 150° C. and stirred for 1 h. Afterwards, the mixture was diluted with water (30 mL) and then neutralized with concentrated HCl to a pH of about 2 to 3. The aqueous solution was extracted with 3×EtOAc (20 mL). The organic layer was dried over is MgSO4, filtered, and concentrated. The crude product was then dissolved in 1 N NaOH. The basic solution was extracted with 2×EtOAc. The basic aqueous solution was then neutralized with concentrated HCl and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was dissolved in EtOAc (30 mL) and the solution was slowly acidified with 1 N HCl in diethyl ether. The resulting precipitate was collected and dried to give ((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)acetic acid hydrochloride (0.655 g).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:10][N:11]([CH3:16])[CH:12]=[CH:13][CH:14]=[O:15].C=O.[C:19](O)(=O)C>C(O)C>[CH3:10][N:11]([CH3:16])/[CH:12]=[C:13](\[CH2:19][N:7]1[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]1)/[CH:14]=[O:15]
Reactant: CC(C)N1CCNCC1
Reactant: CN(C)C=CC=O
Reactant: CC(=O)O
Agent: C=O
Solvent: CCO
Product: CC(C)N1CCN(C/C(C=O)=C\N(C)C)CC1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 90 %

Procedure:
1-Isopropylpiperazine (4.4 ml, 30.6 mmol) was added to a solution of 3-(dimethylamino)acrolein (2.82 g, 25.5 mmol) in ethanol (100 ml), followed by formaldehyde (37% solution in water, 2.3 ml, 30.6 mmol) and acetic acid (100 μl). The mixture was stirred at 50° C. for 3.5 hours, then room temperature for 15 hours. The solution was concentrated in vacuo, re-dissolved in ethanol (25 ml) and then formaldehyde (2.3 ml) and acetic acid (100 μl) were added. The mixture was stirred at 60° C. for 4 hours then concentrated in vacuo to yield the title compound as a pale yellow oil (6.10 g, 90%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][CH:16]=2)[NH:13][CH2:12][CH2:11][CH2:10]3)[CH:2]=1.[C:17]([N:25]=C=O)(=[O:24])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][CH:16]=2)[N:13]([C:17]([NH2:25])=[O:24])[CH2:12][CH2:11][CH2:10]3)[CH:2]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: c1cncc(-c2cnc3c(c2)CCCN3)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)N1CCCc2cc(-c3cccnc3)cnc21
Temperature: 50 °C
Yield: 55.7 %

Procedure:
6-Pyridin-3-yl-1,2,3,4-tetrahydro-[1,8]naphthyridine (50 mg, 0.24 mmol) and benzoyl isocyanate (58 mg, 0.36 mmol) are dissolved in 1.5 mL of DCM. The mixture is heated at 50° C. for 5 hrs. Then the solvent is removed in vacuum and the residue is dissolved in 1.5 mL of EtOH. K2CO3 (56 mg, 0.40 mmol) is added and the mixture is heated at 80° C. for 55 min. Then the solvent is removed and the residue is partitioned between water (35 mL) and EtOAc (55 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. To the crude product is added EtOAc (1 mL) and the white solid formed is filtered, rinsed with EtOAc/heptane (1:1) mixture and dried to give 34 mg of the titled product.
Reaction SMILES: [C:1]([C:4]1[CH:9]([CH2:10][CH:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16](OC)[CH:17]=3)[C:12]2=[O:23])[CH:8]=[CH:7][N:6]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])[CH:5]=1)(=[O:3])[CH3:2].C(C1C(=O)C([Cl:45])=C(Cl)[C:39](=[O:40])C=1C#N)#N>C(#N)C>[Cl-:45].[C:1]([C:4]1[CH:5]=[N+:6]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:32])([F:34])[F:33])[CH:7]=[CH:8][C:9]=1[CH2:10][C:11]1([O:40][CH3:39])[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)CCC(CC1C=CN(Cc3ccccc3C(F)(F)F)C=C1C(C)=O)C2=O
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC#N
Product: COC1(Cc2cc[n+](Cc3ccccc3C(F)(F)F)cc2C(C)=O)CCc2ccccc2C1=O
Product: [Cl-]
Reaction time: 24 h

Procedure:
To a solution of compound 67 (30.0 mg, 0.064 mmol) in acetonitrile (1 mL) was added DDQ (1 equiv) in one portion at room temperature. After completion of the reaction, acetonitrile was removed under reduced pressure and the residue was taken up in dichloromethane (10 mL). The organic layer was successively washed with aqueous solution of HCl 1M and brine, dried over magnesium sulfate, filtered and concentrated to dryness. The obtained solid was placed in presence of anion exchange resin (Amberlyst Cl−) in acetonitrile for 24 h. After filtration and concentration, the title compound 83 was obtained as a yellow solid (Yield 19.3 mg, 60%).
Reaction SMILES: CC(C)([O-:4])C.[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14](F)[CH:15]=1)[C:11]#[N:12].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C@H:24]([OH:46])[C@@H:25]([C:32]2[CH:45]=[CH:44][C:35]([C:36]([NH:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:37])=[CH:34][CH:33]=2)[CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:20][CH:19]=1.CC(C1NC(=O)C(CCSC)NC(=O)C(NC(C(NC(C(NC(C(NC(C(N)CC(O)=O)=O)C(O)C)=O)CCSC)=O)CCCNC(N)=N)=O)CSSCC(C(NC(C(NC(C(NC(C(O)=O)C(C)C)=O)CCC(O)=O)=O)CC2C3C(=CC=CC=3)NC=2)=O)NC(=O)C2N(CCC2)C(=O)C(CCCNC(N)=N)NC(=O)C(CC2C=CC(O)=CC=2)NC(=O)C(C(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)CNC1=O)C>CN(C=O)C.CCOC(C)=O>[NH2:12][C:11]([C:10]1[CH:13]=[C:14]([CH:15]=[C:8]([Cl:7])[CH:9]=1)[O:46][C@@H:24]([C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=1)[C@@H:25]([C:32]1[CH:45]=[CH:44][C:35]([C:36]([NH:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:37])=[CH:34][CH:33]=1)[CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[O:4]
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1cc(F)cc(Cl)c1
Reactant: O=C(O)CCNC(=O)c1ccc([C@@H](CCC(F)(F)F)[C@@H](O)c2ccc(Cl)cc2)cc1
Agent: CSCCC1NC(=O)C(NC(=O)C(CCCNC(=N)N)NC(=O)C(CCSC)NC(=O)C(NC(=O)C(N)CC(=O)O)C(C)O)CSSCC(C(=O)NC(Cc2c[nH]c3ccccc23)C(=O)NC(CCC(=O)O)C(=O)NC(C(=O)O)C(C)C)NC(=O)C2CCCN2C(=O)C(CCCNC(=N)N)NC(=O)C(Cc2ccc(O)cc2)NC(=O)C(C(C)C)NC(=O)C(CCCNC(=N)N)NC(=O)CNC(=O)C(C(C)C)NC1=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(Cl)cc(O[C@@H](c2ccc(Cl)cc2)[C@H](CCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)c1

Procedure:
Sodium tert-butoxide (92 mg, 0.96 mmol) was added to a solution of 3-chloro-5-fluorobenzonitrile (67.9 mg, 0.359 mmol) and N-(4-{(1R)-1-[(R)-(4-chlorophenyl)(hydroxy)methyl]-4,4,4-trifluorobutyl}benzoyl)-β-alanine (prepared using the procedures from INTERMEDIATE 1 and the saponification step of EXAMPLE 1, 100 mg, 0.239 mmol) in DMF (3 mL), then the resulting brown mixture was stirred at 80° C. for 16 hours. The mixture was diluted with EtOAc, then washed with 2 N HCl(aq), then washed twice with water. The organic layer was then concentrated, and the resulting yellow residue was purified by reverse phase HPLC eluting with 30-100% MeCN/water+0.1% TFA. Following lyophilization, this afforded the title compound. LC3 3.35 min. (M+H)+ 577.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:18]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7]
Reactant: C1CCNC1
Reactant: CCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCN1CCCC1
Temperature: 55 °C
Yield: 64.1 %

Procedure:
47 g pyrrolidine, 149.5 g 1-bromododecane and 83 g potassium carbonate were added to 560 mL acetone. The reaction mixture was heated at 55° C. for 24 hr, then filtered. Solvent was removed from the filtrate, yielding 92 g N-dodecylpyrrolidine. 80 g N-dodecylpyrrolidine and 52.6 g 1-bromo-3-chloropropane were dissolved in 133 mL methanol and the reaction mixture was heated at 65° C. for 18 hr. After cooling to room temperature, methanol was removed under reduced pressure. The residue was poured into 2 L diethylether with stirring and the mixture was allowed to stand for another 6 hr. The white precipitate thus formed was filtered and was dried at 40° C. under a vacuum for 24 hr yielding 85 g (3-chloropropyl)dodecylpyrrolidinium bromide as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[CH2:10][CH2:9]1)#[N:2].CCN(CC)CC.Cl[C:47]([O:49][CH3:50])=[O:48]>C(Cl)Cl>[CH3:50][O:49][C:47](=[O:48])[O:35][C:32]1[CH:33]=[CH:34][C:29]([N:7]([CH2:6][C:5]2[CH:36]=[CH:37][CH:38]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:26])[CH2:10][CH2:9]2)=[CH:30][CH:31]=1
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(O)cc2)CC1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Oc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)cccc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To a solution of COMPOUND 117 (43 mg, 0.083 mmol) in CH2Cl2 (2 mL) were added Et3N (0.04 mL, 0.29 mmol) followed by methyl chloroformate (14 μL, 0.19 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 139 as a white solid (41 mg, 86%) following work-up and purification. 1H NMR (CDCl3) δ 0.91-1.14 (m, 2H), 1.00 (d, 3H, J=6.0 Hz), 1.50-1.55 (m, 1H), 1.70-1.74 (m, 3H), 2.15 (t, 1H, J=12.0 Hz), 2.31 (s, 6H), 2.55 (t, 1H, J=10.8 Hz), 2.74-2.91 (m, 3H), 3.24-3.32 (m, 1H), 3.57-3.63 (m, 1H), 3.78 (s, 2H), 3.86 (s, 3H), 3.86-3.90 (m, 1H), 6.51 (d, 2H, J=8.1 Hz), 6.92-7.05 (m, 5H), 7.43-7.53 (m, 4H), 8.37-8.38 (m, 1H). 13C NMR (CDCl3) δ 13.80, 19.54, 29.34, 30.72, 31.34, 40.23, 43.96, 48.84, 52.54, 55.68, 57.14, 60.94, 112.96, 114.36, 119.30, 122.04, 127.69, 128.78, 129.65, 130.33, 130.94, 131.25, 134.49, 139.04, 142.38, 143.01, 146.78, 155.24, 170.23. ES-MS m/z 569 (M+H). Anal. Calcd. for C34H40N4O4.0.5H2O: C, 70.69; H, 7.15; N, 9.70. Found. C, 70.64; H, 7.02; N, 9.65.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[N:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[S:13][CH3:14])[N:4]([CH:15]2[CH:22]3[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:24][CH:16]2[CH2:17]4)[CH2:21]3)[C:3]1=[O:25].[OH2:27].[OH:28]O.O>CO.[Cl-].[Cl-].[Cl-].[Cl-].[Cl-].[Ta+5]>[CH3:1][C:2]1([CH3:26])[N:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[S:13]([CH3:14])(=[O:28])=[O:27])[N:4]([CH:15]2[CH:16]3[CH2:17][CH:18]4[CH2:19][CH:20]([CH2:21][CH:22]2[CH2:23]4)[CH2:24]3)[C:3]1=[O:25]
Reactant: O
Reactant: OO
Reactant: CSc1ccccc1CN1N(C2C3CC4CC(C3)CC2C4)C(=O)C1(C)C
Agent: [Ta+5]
Agent: [Cl-]
Solvent: CO
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccccc1S(C)(=O)=O
Reaction time: 36.5 h
Yield: 32.1 %

Procedure:
A solution of 4,4-dimethyl-1-[2-(methylthio)benzyl]-2-(adamantan-2-yl)-1,2-diazetidin-3-one (7.20 mg, 0.0186 mmol) prepared in Example 60 in methanol was added sequentially with tantalum pentachloride (3.30 mg, 0.00930 mmol) and hydrogen peroxide water (5.70 mg, 0.0558 mmol) at room temperature, and the resultant was stirred at the same temperature for 36.5 hours. The reaction solution was added with water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained residue was purified using Preparative Thin-Layer chromatography (hexane:ethyl acetate=1:5), and the title compound (2.40 mg, 32.0%) was obtained as a white crystalline powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH3:29][S:30][C:31](SC)=[N:32][C:33]#[N:34].CCOCC>C(O)(C)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:24]([O:26][CH3:27])=[O:25])=[C:8]([CH3:28])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][C:31](=[N:32][C:33]#[N:34])[S:30][CH3:29])=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CSC(=NC#N)SC
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: CCOC(=O)C1=C(COCCNC(=NC#N)SC)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reaction time: 4 h

Procedure:
2-[2-Aminoethoxymethyl]-3-ethoxycarbonyl-4-(2-chlorophenyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (4.3 g) and dimethyl N-cyanoimidodithiocarbonate (2 g) in isopropanol (15 ml) were allowed to stand at room temperature for 4 hours. Ether (30 ml) was then added and the mixture was stood at room temperature overnight. The crystalline precipitate was filtered, washed with ether and dried, yield of the title compound 5.0 g, m.p. 177°-179°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.[OH-].[K+].Cl>CO.C(#N)C1C=CC=CC=1>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: N#Cc1ccccc1
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 53.2 %

Procedure:
To a mixture of 306 mg (purity: 99.0%; 1.84 mmol) of 4-hydroxy-3,6-dichloropyridazine and 826 mg (5.48 mmol) of 2-cyclopropyl-6-methylphenol were added benzonitrile (2.76 g) and 323 mg (5.48 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 271 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 53%) was obtained.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[C:24]([OH:25])=[CH:23][C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)=[C:21]([F:33])[CH:20]=1)[C:14](=[O:34])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][C:43]#[N:44].O>CN(C=O)C>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[CH:20]=[C:21]([F:33])[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)=[CH:23][C:24]=1[O:25][CH2:42][C:43]#[N:44])[C:14](=[O:34])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1ccc2cc(SCc3ccccc3)ccc2n1-c1cc(F)c(-c2cccc(F)c2)cc1O
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCOc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Yield: 107 %

Procedure:
6-(Benzylthio)-1-(2,3′-difluoro-5-hydroxy-[1,1′-biphenyl]-4-yl)quinolin-2(1H)-one (528 mg, 1.120 mmol) was dissolved in DMF (2240 μl). Then potassium carbonate (155 mg, 1.120 mmol) was added followed by 2-bromoacetonitrile (86 μl, 1.232 mmol). The whole was stirred at rt for 1d. Water (1 mL) was added. White precipitate was collected with an aid of water, and dried to afford 2-((4-(6-(benzylthio)-2-oxoquinolin-1(2H)-yl)-3′,6-difluoro-[1,1′-biphenyl]-3-yl)oxy)acetonitrile (612 mg, 107% yield). m/z (ESI): [M+H]+=511.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.25 (s, 2 H) 5.14-5.31 (m, 2 H) 6.59 (d, J=8.80 Hz, 1 H) 6.71 (d, J=9.59 Hz, 1 H) 7.19-7.40 (m, 6 H) 7.44 (dd, J=8.80, 2.15 Hz, 1 H) 7.53-7.68 (m, 5 H) 7.81 (d, J=2.15 Hz, 1 H) 7.95 (br. s., 1 H) 7.99 (d, J=9.49 Hz, 1 H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)[C:7](/[CH:10]=[C:11]2\[NH:12][C:13](=[O:20])[N:14]([CH2:17][O:18][CH3:19])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[ClH:38].[Cl:39][CH2:40][C:41]1[N:42]=[C:43]([CH3:46])[S:44][CH:45]=1.Cl>CN(C=O)C.C(OCC)(=O)C.CCOCC>[ClH:39].[ClH:38].[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:40][C:41]3[N:42]=[C:43]([CH3:46])[S:44][CH:45]=3)[C:13](=[O:20])[N:14]([CH2:17][O:18][CH3:19])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1nc(CCl)cs1
Reactant: CCCCc1ncc(/C=C2\NC(=O)N(COC)C2=O)n1Cc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCc1ncc(/C=C2/C(=O)N(COC)C(=O)N2Cc2csc(C)n2)n1Cc1ccc(C(=O)OC)cc1
Reaction time: 48 h

Procedure:
To a solution of methyl Z-4-[[2-butyl-5-[[1-(methoxymethyl)-2,5-dioxo-4-imidazolidinylidene) methyl]-1H-imidazol-1-yl]methyl]benzoate (0.307 g, 0.721 mmol) in DMF (4 mL) is added K2CO3 (0.500 g, 3.62 mmol). After stirring for 5 minutes 4-chloromethyl-2-methylthiazole hydrochloride (0.265 g, 1.44 mmol) is added. The mixture is stirred for 48 hours. A pale brown slurry results which was diluted with ethyl acetate and washed with water and brine and then dried over MgSO4. Chromatography eluting with 1-% methanol in chloroform and evaporation in vacuo affords a viscous oil. This oil is dissolved in ether and treated with ethereal HCl to afford a foamy solid upon evaporation in vacuo. This solid is crystallized from 2-propanol/ether.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[N:24]1[C:33]2[C:28](=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][C:6]1[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=[C:2]([C:29]2[CH:30]=[CH:31][CH:32]=[C:33]3[C:28]=2[CH:27]=[CH:26][CH:25]=[N:24]3)[N:7]=1
Reactant: OB(O)c1cccc2ncccc12
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2cccc3ncccc23)nc1-c1ccc(C)cc1
Yield: 65.8 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (100 mg; 0.300 mmol), quinolin-5-ylboronic acid (156 mg; 0.901 mmol), tetrakis(triphenylphosphine) palladium(0) (34.7 mg; 0.030 mmol) were placed in a 5 mL reaction tube and dissolved in a mixture of degassed DME (1.50 mL) and water (0.5 mL). N,N-Diisopropylethylamine (0.185 mL; 1.202 mmol) was added, the tube was sealed and irradiated in a microwave oven at 130° C. for 1 h. The reaction mixture was partitioned between brine and dichloromethane, filtered over a phase separator filter (1PS) and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (10-80%) in heptane to give 84 mg (43%) of the title compound as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([Si:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[C:11](Cl)=[O:12].[CH2:22]([NH:24][CH:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH3:23]>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([Si:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[C:11]([N:24]([CH2:22][CH3:23])[CH:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:12]
Reactant: CCCCCCC(C)NCC
Reactant: C[Si](C)(C)c1cccc(Cl)c1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCC(C)N(CC)C(=O)c1c(Cl)cccc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 31.5 %

Procedure:
Triethylamine (2.02 g, 20 mmol) was added to a mixture of the compound of Example b (2.47 g, 10 mmol) and N-ethyl-N-(1-methylhept-1-yl)amine (3.15 g, 20 mmol) in toluene (25 mL). The reaction was stirred 2.5 h at ambient temperature, then was partitioned between ethyl acetate and dilute citric acid. The organic phase was washed twice with sat aq NaHCO3, followed with brine, then was dried (MgSO4), concentrated, and kugelrohr distilled under vacuum. The fraction which distilled at 157° C. was collected to afford 1.16 g of the title compound as an amber oil, a 38% yield.
Reaction SMILES: C(O[C:6](=[O:32])[C@@H:7]1C[CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13](O)[C@@H](NC(=O)[C@H](CC(=O)N)N)C[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C)(C)C.[C:33]1(C(O)=O)C2C(=CC=CC=2)C=C[N:34]=1.O[C:47]1[C:55]2[N:54]=NN[C:51]=2[CH:50]=[CH:49][CH:48]=1>>[CH2:9]([N:8]1[CH2:7][CH2:6][O:32][CH2:13][CH2:12]1)[CH3:10].[CH:55]1([N:54]=[C:33]=[N:34][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)c1nccc2ccccc12
Product: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCN1CCOCC1

Procedure:
In a manner analogous to that described in Example 27, from 234 mg of N-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester, 90 mg of 1-isoquinolinecarboxylic acid, 70 mg of hydroxybenzotriazole. 60 mg of N-ethylmorpholine and 118 mg of dicyclohexylcarbodiimide there were obtained, after chromatography on silica gel using 10% methanol in dichloromethane for the elution, 146 mg of N-[2(R)-hydroxy-3(S)-[[N-(1-isoquinolylcarbonyl)-L-asparaginyl]amino]-4-phenylbutyl]-L-proline tert.butyl ester as a pale cream solid from ethyl acetate/n-hexane; MS: m/e 604 [M+H]+.
Reaction SMILES: CC(C)C[N:4]1[CH:8]=[CH:7][CH:6]([C:9](OCC)=O)[C:5]1=O.[CH2:16]([OH:18])[CH3:17].O.[C:20](=O)=[O:21].[Cl-].[Na+]>C(OCC)(=O)C>[CH3:9][CH:6]([CH3:5])[CH2:7][C@@H:8]1[NH:4][C:16](=[O:18])[CH2:17][C:20]1=[O:21]
Reactant: CCO
Reactant: CCOC(=O)C1C=CN(CC(C)C)C1=O
Reactant: O=C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H]1NC(=O)CC1=O
Reaction time: 0.25 h

Procedure:
Approximately 150 mmol of (S)-2,5-dihydro-4-hydroxy-5-(2-methylpropyl-2-oxo-1H-pyrrole-3-carboxylic acid, ethyl ester is added as rapidly as possible to 1 L of boiling ethanol-water (1:1, pot temperature 85°-87° C.) in a 3 L beaker with vigorous stirring. Complete solution occurs rapidly and vigorous effervescence is observed. Refluxing is continued 20 minutes until the CO2 evolution ceases. The beaker is plunged into an ice bath to rapidly cool the solution, 120 g of sodium chloride and 500 ml of ethyl acetate are added and the organic layer is separated. The aqueous layer is extracted with 2×500 ml of ethyl acetate and the organic fractions combined, dried over magnesium sulfate and evaporated to a solid. The solid is slurried in 200 ml of diethyl ether, diluted with 200 ml of ethyl acetate, and stirred approximately 15 minutes until most of the solid dissolves. The insoluble material is filtered off and the filtrate evaporated to afford 15.9 g of (S)-5-(2-methylpropyl)-2,4-pyrrolidinedione as an off-white solid; mp 94°-95° C. [α]D23 =-80° (C=1%, chloroform). TLC (ethyl acetate, silica gel, ultra violet (uv)) Rf =0.4.