Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]([CH3:24])([CH3:23])[CH2:11][C:12]([OH:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[CH:13]=O.[NH2:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[N:29][NH:30][C:31]2=[O:36]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:22][C:12]1([C:15]([F:20])([F:21])[C:16]([F:18])([F:19])[F:17])[CH2:11][C:10]([CH3:23])([CH3:24])[C:4]2[C:5](=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=2[O:2][CH3:1])[CH:13]1[NH:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[N:29][NH:30][C:31]2=[O:36]
Reactant: COc1cc(C)ccc1C(C)(C)CC(O)(C=O)C(F)(F)C(F)(F)F
Reactant: Nc1cccc2c(=O)[nH]ncc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C)cc2c1C(C)(C)CC(O)(C(F)(F)C(F)(F)F)C2Nc1cccc2c(=O)[nH]ncc12
Yield: 2.3 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 250 mg of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)pentanal and 118 mg of 5-amino-phthalazin-1-one. As in Example 3, 65 mg of the imine is reacted by reaction with 0.38 ml of titanium tetrachloride (1 M in dichloromethane) in 6 ml of dichloromethane, and 8 mg of the title compound is obtained.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([O:41][Si](CC)(CC)CC)[CH2:6][S:7][C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[C:14]([C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[S:13][C:12]=12)=[N+:2]=[N-:3].Cl.C(=O)([O-])O.[Na+]>C1COCC1.O>[N:1]([CH2:4][C@@H:5]([OH:41])[CH2:6][S:7][C:8]1[N:9]=[CH:10][N:11]2[CH:15]=[C:14]([C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[S:13][C:12]=12)=[N+:2]=[N-:3]
Reactant: CC[Si](CC)(CC)O[C@H](CN=[N+]=[N-])CSc1ncn2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SC[C@H](O)CN=[N+]=[N-])c4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-[7-((2R)-3-azido-2-triethylsilyloxypropyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (560 mg) was dissolved in 10 ml of THF and 10 ml of water. The solution was adjusted to pH 2.5 by the addition of 1 N hydrochloric acid. The mixture was stirred at room temperature for 30 min, and was then adjusted to pH 7.0 by the addition of an aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate twice. The organic layers were combined, were washed with brine, and were dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) to prepare 455 mg of 4-nitrobenzyl (1S,5R,6S)-2-[7-((2R)-3-azido-2-hydroxypropyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]2[N:10]=[C:11]([O:21][CH3:22])[C:12]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[C:8]2[CH:7]=[CH:6][CH:5]=1.Br[CH2:24][CH:25]1[CH2:27][CH2:26]1.C(OCC)(=O)C>CN(C)C=O>[Br:3][C:4]1[N:9]2[N:10]=[C:11]([O:21][CH3:22])[C:12]([N:13]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[C:8]2[CH:7]=[CH:6][CH:5]=1
Reactant: COc1nn2c(Br)cccc2c1NC(=O)OC(C)(C)C
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1nn2c(Br)cccc2c1N(CC1CC1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in oil; 24.6 mg) was added to a solution of tert-butyl N-(7-bromo-2-methoxypyrazolo[1,5-a]pyridin-3-yl)carbamate (140 mg) in N,N-dimethylformamide (10 mL) at room temperature and the reaction mixture was stirred for 30 minutes. (Bromomethyl)cyclopropane (0.06 mL) was added thereto at the same temperature, and the reaction mixture was stirred for 1 hour at 60° C. After completion of the reaction, the reaction mixture was gradually added to ice, extraction was performed with ethyl acetate, the organic extract was washed with water and brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure to afford a crude product of tert-butyl N-(7-bromo-2-methoxypyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethylcarbamate.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2].[C:22]1([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1.C1C=CC=CC=1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[O:21][C:30](=[O:31])[CH2:29][CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OC(=O)CCc1ccccc1
Yield: 62.3 %

Procedure:
Add 13β-ethyl-17β-hydroxy-gon-4-en-3-one (0.11 g.) in dry pyridine (0.35 cc.) at -20° to 3-phenylpropionyl chloride (0.11 g.) in benzene (0.3 cc.). Keep this at -10° for 16 hours, add ice-cold water and extract with a mixture of equal volumes of ether and benzene. Wash the extracts in turn with 2N potassium hydroxide solution, water, 2N hydrochloric acid solution, and brine, and dry. Evaporate solvent to give a residue and recrystallize from a mixture of ether and ethyl acetate to obtain the title compound (0.10 g.), m.p. 135°-40°; infrared absorption peaks at 5.81, 5.99, 8.51, 13.3, 14.3 μ, showing no absorption due to hydroxyl.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:34])([F:33])[C:5]1[CH:6]=[C:7]([N:15]([CH3:32])[C:16]([N:18]([C@H:20]2[C@H:24]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=3)[CH2:23][NH:22][CH2:21]2)[CH3:19])=[O:17])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.[CH3:35][O:36][C:37]([NH:39][C@H:40]1[CH2:45][CH2:44][C@H:43]([C:46](O)=[O:47])[CH2:42][CH2:41]1)=[O:38]>>[F:34][C:4]([F:3])([F:33])[C:5]1[CH:6]=[C:7]([N:15]([CH3:32])[C:16]([N:18]([CH3:19])[C@H:20]2[C@H:24]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=3)[CH2:23][N:22]([C:46]([C@H:43]3[CH2:42][CH2:41][C@H:40]([NH:39][C:37](=[O:38])[O:36][CH3:35])[CH2:45][CH2:44]3)=[O:47])[CH2:21]2)=[O:17])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1
Reactant: CN(C(=O)N(C)[C@@H]1CNC[C@H]1c1ccc(F)cn1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cl
Product: COC(=O)N[C@H]1CC[C@H](C(=O)N2C[C@@H](N(C)C(=O)N(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](c3ccc(F)cn3)C2)CC1

Procedure:
By reaction and purification in the same manner as in the method described in Example 4 and using the compound obtained in Example 191 and trans-4-[(methoxycarbonyl)amino]cyclohexanecarboxylic acid, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N:11]=[C:12]=[O:13].[NH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)[CH:19]=[C:18]2[CH:33]=[C:34]1[S:38][C:37](=[O:39])[NH:36][C:35]1=[O:40]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12](=[O:13])[NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)[CH:19]=[C:18]2[CH:33]=[C:34]1[S:38][C:37](=[O:39])[NH:36][C:35]1=[O:40]
Reactant: COc1ccc(N=C=O)c(OC)c1
Reactant: Nc1ccc2c(c1)c(C=C1SC(=O)NC1=O)cn2Cc1ccc(Cl)c(Cl)c1
Product: COc1ccc(NC(=O)Nc2ccc3c(c2)c(C=C2SC(=O)NC2=O)cn3Cc2ccc(Cl)c(Cl)c2)c(OC)c1

Procedure:
The title compound was prepared by General Procedure 7 with 2,4-dimethoxyphenyl isocyanate and the amino compound from Example 47 as reactants. Nmr and ms data were consistent; ms m/e 598 (M+1). HPLC (System 1): purity greater than 80%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][CH:12]([NH2:16])[C:13]([OH:15])=[O:14])[C:3]1=[O:17].[Cl:18][C:19]1[CH:36]=[CH:35][C:22]([C:23](N2C3C=CC=CC=3OC2=S)=[O:24])=[CH:21][CH:20]=1>CN1CCCC1=O>[Cl:18][C:19]1[CH:36]=[CH:35][C:22]([C:23]([NH:16][CH:12]([CH2:11][CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[C:3]2=[O:17])[C:13]([OH:15])=[O:14])=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(c1ccc(Cl)cc1)n1c(=S)oc2ccccc21
Reactant: CN1C(=O)C(CC(N)C(=O)O)c2ccccc21
Solvent: CN1CCCC1=O
Product: CN1C(=O)C(CC(NC(=O)c2ccc(Cl)cc2)C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2 Grams of 3-(1-methyloxindol-3-yl)-2-aminopropionic acid prepared in Reference Example 5 was suspended in 50 ml of 1-methyl-2-pyrrolidone, then 2.2 g of 3-(4-chlorobenzoyl)benzoxazolin-2-thione was added thereto, and the reaction mixture was stirred at a room temperature for 3 days. The reaction mixture was poured into an ice-water, and the crystals formed were collected by filtration, then the crystals were dissolved in 1N-sodium hydroxide aqueous solution, then the resulting solution was acidified by using 10%-hydrochloric acid, and the crystals formed were collected by filtration. The crystals were dried, washed with chloroform, there was obtained 1.1 g of 2-(4-chlorobenzoylamino)-3-(1-methyloxindol-3-yl)propionic acid. White powdery substance. Melting point: 115°-120° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([NH2:23])=[S:22])[CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:25]I>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[NH:23])[S:22][CH3:25])[CH:15]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2cccc(NC(N)=S)c2)CCCCC1
Reactant: CI
Product: CSC(=N)Nc1cccc(C2(NC(=O)OC(C)(C)C)CCCCC2)c1
Yield: 70 %

Procedure:
Using the compound obtained in Example 140 as a starting material and also using methyl iodide as a reagent, reaction was performed as in Example 29 to give 85 mg of the titled compound (yield, 70%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:34](O)[CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40]/[CH:41]=[CH:42]\[CH2:43]/[CH:44]=[CH:45]\[CH2:46]/[CH:47]=[CH:48]\[CH2:49]/[CH:50]=[CH:51]\[CH2:52][CH3:53].[C:55]([OH:58])(=[S:57])[CH3:56]>C1COCC1.CCCCCCC>[C:55](=[O:58])([S:57][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40]/[CH:41]=[CH:42]\[CH2:43]/[CH:44]=[CH:45]\[CH2:46]/[CH:47]=[CH:48]\[CH2:49]/[CH:50]=[CH:51]\[CH2:52][CH3:53])[CH3:56]
Reactant: CC(O)=S
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCSC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
Triphenylphosphine (21.0 g, 80 mmol) was dissolved in dry THF (170 mL) at 0° C. under inert atmosphere and added DIAD (15.8 mL, 80 mmol) dropwise. After 40 minutes at 0° C. the white suspension was added dropwise to a solution of (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-ol (11.5 g, 40 mmol) and thioacetic acid (5.7 mL, 80 mmol) in dry THF (50 mL) during 15 minutes. The resulting turbid mixture was stirred at 0° C. for 30 minutes, followed by ambient temperature for 1.5 hour. Heptane was added (200 mL), the mixture was stirred for ten minutes and the precipitated white solid removed by filtration and rinsed with heptane (150 mL). The residue was concentrated to remove most of the THF and stirred at ambient for 18 hours. The mixture was filtered, concentrated and added heptane (200 mL). The resulting mixture was stirred for 2 hours, filtered and evaporated. The residue was purified by flash chromatography on silica gel, using EtOAc:Heptane (2:98), followed by EtOAc:Heptane (4:96) and finally EtOAc:Heptane (5:95). Concentration of the appropriate fractions provided 11.0 g (79% yield) of the title compound as oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:31]([N:34]=[C:35]=[O:36])([CH3:33])[CH3:32]>C(Cl)Cl>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])[C:35]([NH:34][CH:31]([CH3:33])[CH3:32])=[O:36])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCCCNCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CC(C)N=C=O
Solvent: ClCCl
Product: CC(C)NC(=O)N(CCCCCO)CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Temperature: 0 °C

Procedure:
Part D. A solution of the amine prepared in Part C above (2.92 g, 6.89 mmol) in methylene chloride (50 mL) was cooled to 0° C., and a solution of isopropylisocyanate (0.70 mL, 7.1 mmol) in methylene chloride (20 mL) was added dropwise. The mixture was allowed to stir and slowly warm over 18 hours, then was evaporated. The residual oil was separated by flash chromatography (1:4 ethyl acetate-hexane) to afford the product, 1-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-1-(5-hydroxypentyl)-3-(1-methylethyl)-urea, as a low-melting solid (3.00 g, 5.90 mmol, 86%). 1H NMR (CDCl3): 11.34 (1H, br s); 7.60 (2H, br d, J=7 Hz); 7.48 (2H, br d, J =7 Hz); 7.38-7.20 (6H, m); 4.21 (1H, br d, J=6.6 Hz); 4.02 (1H, br s); 3.82 (1H, octet, J=6.6 Hz); 3.65 (2H, br t, J=7 Hz); 3.32 (2H, t, J=6.4 Hz); 3.12 (2H, t, J=7.5 Hz); 3.01 (2H, t, J=6.6 Hz); 1.81-1.36 (12H, m); 1.06 (6H, d, J=6.6 Hz).
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][OH:14])[CH2:7][CH2:6][C:5]2([CH2:12][CH2:11][CH2:10][O:9][CH2:8]2)[O:4]1)[CH3:2].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]Cl.[H-].[Na+]>>[CH2:1]([C:3]1([CH2:13][O:14][CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)[CH2:7][CH2:6][C:5]2([CH2:12][CH2:11][CH2:10][O:9][CH2:8]2)[O:4]1)[CH3:2]
Reactant: ClCc1ccccn1
Reactant: CCC1(CO)CCC2(CCCOC2)O1
Agent: [H-]
Agent: [Na+]
Product: CCC1(COCc2ccccn2)CCC2(CCCOC2)O1

Procedure:
Following procedures similar to Embodiments I-V above, 2-ethyl-1,7-dioxaspiro[4.5]decane-2-methanol was treated with 2-picolinyl chloride in the presence of sodium hydride to yield the desired product as a pale amber oil, b.p. 123° C. (0.006 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:41])([F:40])[F:42])=[CH:35][N:34]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(CCl)nc1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cnn12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(C(F)(F)F)cn2)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 65 °C
Yield: 55.9 %

Procedure:
A solution of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (32.4 mg, 0.1 mmol), prepared as described in Example 244, K2CO3 (56 mg, 0.4 mmol), and 2-chloromethyl-5-trifluoromethylpyridine hydrochloride (37 mg, 0.4 mmol) in DMF (0.4 mL) was heated at 65° C. for 2 h. Using a similar procedure as described in Example 247, the crude product was obtained. The crude product was purified by reverse phase HPLC to give the title compound, 7-(4-chlorophenyl)-8-(pyridin-4-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (27 mg) as a yellow solid. HPLC RT: 2.78 min; M+H=483; 1H NMR (CDCl3): δ 8.82 (s, 1H), 8.62 (m, 2H), 8.24 (s, 1H), 7.91 (m, 1H), 7.38-7.10 (m, 7H), 5.45 (2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:10]([CH2:20][OH:21])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:29])C(=O)C1.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>CC#N.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C@H:10]([CH2:20][OH:21])[CH2:9]2)=[CH:4][C:3]=1[Br:29]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2ccc(N)nc2)C[C@H]1CO
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](c2cnc(N)c(Br)c2)C[C@H]1CO
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
A solution of (2S,4R)-tert-butyl 4-(6-aminopyridin-3-yl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (230 mg, 0.784 mmol) in MeCN (10 mL) was treated with NBS (147 mg, 0.823 mmol). After 10 min, the reaction was complete. The reaction was treated with 10 mL 1:1 sat. aq. NaHCO3:sat.aq. Na2S2O3 and the mixture was stirred vigorously for 10 min. The mixture was diluted with ethyl acetate (30 mL) and the layers were separated. The organics were washed with brine, dried over magnesium sulfate and concentrated to provide (2S,4R)-tert-butyl 4-(6-amino-5-bromopyridin-3-yl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (290 mg, 100% yield). LCMS (m/z): 372.1/374.0 (MH+), 0.55 min.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[CH:13]1([CH3:23])[CH2:18][CH2:17][CH:16]([CH:19]([CH3:21])[CH3:20])[CH:15](O)[CH2:14]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([O:8][C@H:15]1[C@H:16]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:18][C@@H:13]([CH3:23])[CH2:14]1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC1CCC(C(C)C)C(O)C1
Reactant: CC(=O)c1ccccc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1ccccc1C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Reaction time: 70 h
Yield: 13 %

Procedure:
A solution of 11.36 g (50.0 mmol) 2-acetylbenzoic acid, 4.88 g (40.0 mmol) DMAP and 23.40 g (150.0 mmol) (−)-menthol in 80 ml dichloromethane was cooled in an ice bath before adding a solution of 11.36 g (55.0 mmol) DCC in 40 ml dichloromethane for 15 min. The reaction mixture was maintained with stirring at 40° for 70 h. The precipitate formed during the reaction was filtered and the filtrate washed with HCl (10%, 2×) then with a saturated Na2CO3 solution (2×). The organic phase was dried (Na2SO4), concentrated, chromatographed (SiO2, toluene) and recrystallised in hexane to give 1.96 g (13%) (1R, 3R, 4S)-3-p-menthanyl 2-acetylbenzoate in the form of white crystals.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](=[O:43])[CH:37]=[CH:36]2.[Cl:44][C:45]1[CH:46]=[C:47]([NH:52][C:53]2[N:54]=[CH:55][C:56]([CH2:59]O)=[N:57][CH:58]=2)[CH:48]=[CH:49][C:50]=1[Cl:51]>C1COCC1>[Cl:44][C:45]1[CH:46]=[C:47]([NH:52][C:53]2[N:54]=[CH:55][C:56]([CH2:59][O:32][C:33]3[CH:34]=[C:35]4[C:40](=[CH:41][CH:42]=3)[NH:39][C:38](=[O:43])[CH:37]=[CH:36]4)=[N:57][CH:58]=2)[CH:48]=[CH:49][C:50]=1[Cl:51]
Reactant: OCc1cnc(Nc2ccc(Cl)c(Cl)c2)cn1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1ccc2cc(OCc3cnc(Nc4ccc(Cl)c(Cl)c4)cn3)ccc2[nH]1
Reaction time: 0.17 h
Yield: 13.1 %

Procedure:
A solution of Ph3P (0.07 g, 0.267 mmol) in THF (1.7 mL) was cooled to 0° C. under N2 and DEAD (0.076 ml, 0.481 mmol) was added dropwise. The mixture was stirred for 10 min, then 6-hydroxyquinolin-2(1H)-one (0.072 g, 0.444 mmol) was added. After stirring for 5 min, a solution of (5-((3,4-dichlorophenyl)amino)pyrazin-2-yl)methanol (0.1 g, 0.370 mmol) in THF (2 mL) was added. The reaction was stirred at room temperature overnight. The mixture was concentrated and partially purified by flash chromatography on silica gel using 30-100% ethyl acetate in hexanes, then 5-10% methanol in ethyl acetate. The desired fractions were concentrated to a solid, which was redissolved in DMF. Water was added to the vigorously stirred solution until a suspension formed. After stirring 18 h, the off-white solid was filtered, washed with methanol, and dried to yield 6-((5-(3,4-dichlorophenylamino)pyrazin-2-yl)methoxy)quinolin-2(1H)-one (0.02 g, 13%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.67 (1H, s), 9.97 (1H, s), 8.40 (1H, d, J=1.00 Hz), 8.28 (1H, d, J=1.51 Hz), 8.20 (1H, d, J=2.26 Hz), 7.86 (1H, d, J=9.79 Hz), 7.49-7.64 (2H, m), 7.37 (1H, s), 7.17-7.32 (2H, m), 6.51 (1H, dd, J=9.54, 2.01 Hz), 5.12 (2H, s). LCMS: R.T.=4.09; [M+H]+=412.93.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:32])=[C:4]([N:8]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:32])=[C:4]([N:8]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:23])=[O:24])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:33]=[N:34][NH:35][N:21]=3)[CH:15]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2cccc(C#N)c2)c2cccc(Cl)c2C)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2cccc(-c3nn[nH]n3)c2)c2cccc(Cl)c2C)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 25.2 %

Procedure:
300 mg of N2-(3-chloro-2-methylphenyl)-N-(3-cyanobenzyl)-N2-[(4-methylphenyl)sulfonyl]glycinamide was dissolved in 5.00 mL of DMF, and 125 mg of sodium azide and 103 mg of ammonium chloride were added thereto, followed by stirring at 100° C. for 6 hours. The reaction liquid was concentrated under reduced pressure, and to the obtained residue was added water, followed by extraction with chloroform. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by preparative thin layer chromatography (chloroform:methanol=80:20). The obtained product was recrystallized from ethanol/diisopropyl ether to obtain 82.6 mg of N2-(3-chloro-2-methylphenyl)-N2-[(4-methylphenyl)sulfonyl]-N-[3-(2H-tetrazol-5-yl)benzyl]glycinamide.
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[C:18](=O)([O-])[O-].[K+].[K+]>CO>[C:1]1([C:7]2([C:10]([O:12][CH3:18])=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C1(c2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Product: COC(=O)C1(c2ccccc2)CC1

Procedure:
To a solution of 1-phenylcyclopropanecarboxylic acid (9.8 g) in methanol (121 ml) was added conc. sulfuric acid (0.1 ml) and the mixture was refluxed under heating for 8 hr. The reaction mixture was neutralized by adding an aqueous potassium carbonate solution and concentrated under reduced pressure. The concentrate was extracted with ethyl acetate. The extract was washed with an aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound (8.5 g) as a colorless oil.