Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1[CH:14]=[C:13]([O:15][CH2:16]/[CH:17]=[C:18](/[C:33]2[CH:38]=[CH:37][C:36]([S:39][CH3:40])=[CH:35][CH:34]=2)\[C:19]2[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27][N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:21][CH:20]=2)[CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9]>C(O)(=O)C.O>[CH3:40][S:39]([C:36]1[CH:35]=[CH:34][C:33](/[C:18](/[C:19]2[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27][N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:21][CH:20]=2)=[CH:17]/[CH2:16][O:15][C:13]2[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH3:3])[CH:14]=2)=[CH:38][CH:37]=1)=[O:1]
Reactant: OO
Reactant: CSc1ccc(/C(=C/COc2ccc(OCC(=O)O)c(C)c2)c2ccc(C#CCn3cccn3)cc2)cc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(OC/C=C(\c2ccc(C#CCn3cccn3)cc2)c2ccc(S(C)=O)cc2)ccc1OCC(=O)O

Procedure:
30% Aqueous hydrogen peroxide (0.0618 mL, 0.6 mmol) was added to a solution of (E)-[4-[3-[4-(methylsulfanyl)phenyl]-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetic acid (262 mg, 0.5 mmol; example 48) in glacial acetic acid (7 mL) at 5° C. under stirring. The mixture was left to stand over night at ambient temperature, diluted with water (40 mL) and extracted with ethyl acetate (2×20 mL). The combined extracts were alkalized with 15% aqueous solution of ammonium hydroxide; the solution was washed with water (10 mL) and brine (10 mL), dried with anhydrous magnesium sulphate and evaporated in vacuo. The residue was triturated with hexanes (3×15 mL) to yield the title compound as pale solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[C:17](=[O:29])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=1)C1C=CC=CC=1.[H][H]>[Pd].O1CCCC1.CO>[NH2:26][C:22]1[CH:21]=[C:20]([CH2:19][CH2:18][C:17]([C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[OH:8])=[O:29])[CH:25]=[CH:24][CH:23]=1
Reactant: [H][H]
Reactant: COc1ccc(OCc2ccccc2)c(C(=O)C=Cc2cccc([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(O)c(C(=O)CCc2cccc(N)c2)c1
Yield: 89 %

Procedure:
A mixture of 15.0 g (0.039 mole) of the title product from Example 120 and 1.5 g 5% palladium on charcoal in 300 ml tetrahydrofuran and 200 ml absolute methanol was shaken in a Parr hydrogenator under 10 psi hydrogen at ambient temperature for 3 hours. The reaction mixture was filtered through Celite and the filtrate was evaporated in vacuo to yield an oil. Column chromatography of the oil on silica gel eluting with ethyl acetate: hexanes (1:2, v/v) gave 9.42 g (90%) of the title product as an oil; 1H NMR (CDCl3): δ2.98 (t, J=8 Hz, 2H); 3.28 (t, J=8 Hz, 2H); 3.65 (s, br, 2H); 3.77 (s, 3H); 6.65 (m, 3H); 6.93 (d, J=9 Hz, 1H); 7.10 (m, 3H); 11.95 (s, 1H). Analysis calculated for C16H17NO3 : C, 70.83; H, 6.32; N, 5.16. Found: C, 70.51; H, 6.30; N, 4.97.
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:20][C@@H:21]([CH3:31])[CH2:22][O:23][CH2:24][C@H:25]([OH:30])[C:26](OC)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[Si:13]([O:20][C@@H:21]([CH3:31])[CH2:22][O:23][CH2:24][C@H:25]([OH:30])[C:26]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: COC(=O)[C@@H](O)COC[C@H](C)O[Si](C)(C)C(C)(C)C
Reactant: Cc1ccc(N)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)[C@@H](O)COC[C@H](C)O[Si](C)(C)C(C)(C)C)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78.9 %

Procedure:
Trimethylaluminium (1.966 mL, 3.93 mmol) was added slowly to 5-methylpyridin-2-amine (0.407 g, 3.76 mmol) in toluene (20 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes. (S)-methyl 3-((S)-2-(tert-butyldimethylsilyloxy)propoxy)-2-hydroxypropanoate (Intermediate AS3) (1 g, 3.42 mmol) in toluene (4 mL) was added and the reaction was allowed to warm to room temperature and then heated at reflux for 4 hours (a further 5ml toluene was added to aid stirring). The reaction mixture was concentrated in vacuo. The residue was neutralised with citric acid (1M, aq) and then diluted with water and extracted with EtOAc. The combined organics were dried (MgSO4) and evaporated to afford the product (0.994 g) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 0.07 (6H, d), 0.88 (9H, s), 1.15 (3H, d), 2.30 (3H, s), 2.79-3.11 (1H, m), 3.39-3.51 (2H, m), 3.80-3.91 (2H, m), 3.94-4.03 (1H, m), 4.31-4.36 (1H, m), 7.49-7.56 (1H, m), 8.09-8.16 (2H, m), 9.20 (1H, s); m/z (ES+) (M+H)+=369.52; HPLC tR=2.73 min.
Reaction SMILES: [CH3:1][C:2]1[N:3](O)[C:4]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][N:6]=1.C(=O)(O)[O-].[Na+].[OH-].[Na+]>CO>[CH3:1][C:2]1[NH:3][C:4]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][N:6]=1
Reactant: Cc1ncc(CCc2ccccc2)n1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ncc(CCc2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a solution of 2-methyl-5-phenethyl-imidazol-1-ol (0.20 g, 1.0 mmol) in methanol (3.5 ml) titanium(III)-chloride solution (2.5 ml, 15%) was added and the mixture was stirred overnight at room temperature. First saturated sodium bicarbonate solution then diluted sodium hydroxide solution was added to achieve a basic pH. The mixture was extracted twice with dichloromethane, the combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by column chromatography (dichloromethane/methanol=9:1) to yield a white solid (0.14 mg, 75%); MS (EI): 186.1 (M+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][CH:7]=1.[ClH:17]>>[ClH:17].[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1ccc(-c2ncc[nH]2)cc1
Agent: Cl
Product: O=C(O)c1ccc(-c2ncc[nH]2)cc1

Procedure:
160 mg (0.74 mmol) of ethyl 4-(2-1H-imidazolyl)benzoate was heated under reflux in 4 ml of hydrochloric acid and 8 ml of acetic acid Three hours after, the solvent was evaporated to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH:16]([CH2:18]O)[CH2:15][C:14]2=[O:20])=[CH:9][CH:8]=1.CS(Cl)(=O)=O.[C-:29]#[N:30].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:14](=[O:20])[CH2:15][CH:16]([CH2:18][C:29]#[N:30])[CH2:17]2)=[CH:11][CH:12]=1
Reactant: [C-]#N
Reactant: O=C1CC(CO)CN1c1ccc(OCc2cccc(F)c2)cc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Product: N#CCC1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1

Procedure:
The title compound is prepared in analogy to Example 33b) from (RS)-1-[4-(3-fluoro-benzyloxy)-phenyl]-4-hydroxymethyl-pyrrolidin-2-one, methanesulfonyl chloride and sodium cyanide. Yield: 27% of a colorless solid. MS: m/e=325.2 (M+H)+.
Reaction SMILES: [C:1]1([C:6]2[CH:11]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=3)[CH:9]=[C:8]([C:23]([F:26])([F:25])[F:24])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1>C(O)C.[Pd]>[CH:1]1([C:6]2[CH:11]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=3)[CH:9]=[C:8]([C:23]([F:26])([F:24])[F:25])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)Cc1ccc(Nc2cc(C3=CCCC3)nc(C(F)(F)F)c2)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)Cc1ccc(Nc2cc(C3CCCC3)nc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.2 %

Procedure:
To a solution of 2-(4-((2-(cyclopent-1-en-1-yl)-6-(trifluoromethyl)pyridin-4-yl)amino)phenyl)acetic acid (0.050 g, 0.14 mmol) in ethanol (5 mL) was added 10% Pd/C (0.002 g) and the mixture was stirred under an hydrogen atmosphere at rt for 48 h. After this time, the mixture was cooled and filtered through celite with ethanol washing. The filtrate was dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica, hexane/ethyl acetate) to afford the title compound (0.021 g, 43%) as a light brown solid. MW=364.36. 1H NMR (DMSO-d6, 500 MHz) δ 9.09 (s, 1H), 7.27 (d, J=8.0 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H), 7.03 (s, 1H), 6.93 (s, 1H), 3.54 (s, 2H), 3.10-3.01 (m, 1H), 2.01-1.89 (m, 2H), 1.81-1.57 (m, 6H), 1.24 (s, 1H); APCI MS m/z 365 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:17][C@H:18]([OH:23])[C:19]([F:22])([F:21])[F:20])[C:10](=[O:16])[N:11]([CH2:13][C:14]#[CH:15])[N:12]=2)=[CH:4][CH:3]=1.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[Cl:34])=[N+:25]=[N-:26]>C(#N)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:17][C@H:18]([OH:23])[C:19]([F:21])([F:22])[F:20])[C:10](=[O:16])[N:11]([CH2:13][C:14]3[N:26]=[N:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=4[Cl:34])[CH:15]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: C#CCn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Reactant: [N-]=[N+]=Nc1cccc(Cl)c1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: O=c1n(Cc2cn(-c3cccc(Cl)c3Cl)nn2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
124 mg (0.36 mmol) of the compound from Example 14A were dissolved in 2 ml of acetonitrile, and 0.6 mg (0.003 mmol) of copper(II) acetate monohydrate and 56 mg (0.30 mmol) of 1-azido-2,3-dichlorobenzene were added. The mixture was stirred at 50° C. for 2 h. For work-up, the crude mixture was allowed to cool to RT and filtered through a little silica gel. The product was eluted with ethyl acetate and the solution obtained was concentrated under reduced pressure. The crude product was then purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 1:1). This gave 61 mg (31% of theory) of the target compound.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:16][CH2:17][OH:18])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([OH:13])[C:8]=2[CH3:12])[O:3]1.[CH2:19]=[C:20]([CH3:22])[CH3:21].S(=O)(=O)(O)O>C(Cl)Cl>[CH3:1][C@@:2]1([CH2:16][CH2:17][O:18][C:20]([CH3:22])([CH3:21])[CH3:19])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([OH:13])[C:8]=2[CH3:12])[O:3]1
Reactant: C=C(C)C
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCO)O2
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCOC(C)(C)C)O2
Reaction time: 0.25 h

Procedure:
5 g of (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman were suspended in 250 ml of methylene chloride, and isobutene was passed through the suspension. After 15 minutes, 1 ml of concentrated sulfuric acid was added, and stirring was then continued for a further 4 hours at room temperature, while a gentle stream of isobutene was passed through. The mixture was then left to stand overnight in a closed vessel. The organic phase was washed with sodium bicarbonate solution and with water, and was then dried and evaporated down. The crude product was purified over silica gel, using a 5:1 hexane/acetone solvent mixture. 4.5 g of (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-tert.-butoxyethyl)-chroman were obtained as a colorless oil. [α]36520 =+4.23° (c=2, ethanol).
Reaction SMILES: I[C:2]1[NH:6][C:5]([CH3:7])=[N:4][CH:3]=1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:17]=[C:18]([C:22]#[CH:23])[CH:19]=[CH:20][CH:21]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:15][C:16]1[CH:17]=[C:18]([C:22]#[C:23][C:2]2[N:6]=[C:5]([CH3:7])[NH:4][CH:3]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: C#Cc1cccc(Cl)c1
Reactant: Cc1ncc(I)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
To a solution of 500 mg (2.40 mmol) of 5-iodo-2-methyl-1H-imidazole (CAS: [73746-45-9]) in 7 ml of DMF were added under an argon atmosphere 118 mg (0.17 mmol) of Bis(triphenylphosphine)palladium dichloride and 0.67 ml (4.81 mmol) of triethylamine. The mixture was stirred for 10 min at room temperature. Then 0.52 ml (575 mg, 4.09 mmol) of 3-chloro-1-ethynyl-benzene and 13.7 mg (0.072 mmol) of copper(I) iodide were added and the mixture was stirred for 1.5 h at 60° C. The mixture was concentrated in vaccuo, dissolved in a minimal volume of methylene chloride and purified by chromatography on 20 g of silicagel (gradient Heptane/EtOAc 85:15->EtOAc) to yield 430 mg (83%) of the title compound as an orange crystalline solid, MS: m/e=217.2, 219.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:12])[N:11]=1)[C:5]([O:7]C)=[O:6].Cl.O>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:12])[N:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(F)nc(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(F)nc(F)c1

Procedure:
22.6 g of methyl 2,6-difluoroisonicotinate are dissolved in 25 ml of dioxane and added to a mixture of 150 ml of conc. hydrochloric acid and 100 ml of water. The mixture is then refluxed for 21/4 hours, volume is reduced to about 5/8 by evaporation, and the residue is cooled. The acid which precipitates out in crystalline form is filtered off and dried.
Reaction SMILES: [C:1]1([O:11][C:12](=[O:63])[C@H:13]([CH2:36][CH2:37][CH2:38][N:39](C(OCC2C=CC=CC=2)=O)[C:40](=[NH:52])[NH:41]C(OCC2C=CC=CC=2)=O)[NH:14][C:15](=[O:35])[C@H:16]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[NH:17]C(OCC2C=CC=CC=2)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[ClH:64].O1CCOCC1.[H][H]>CN(C=O)C.[C].[Pd]>[ClH:64].[ClH:64].[C:1]1([O:11][C:12](=[O:63])[C@H:13]([CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:41])[NH2:52])[NH:14][C:15](=[O:35])[C@H:16]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH2:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N=C(NC(=O)OCc1ccccc1)N(CCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)Oc1cccc2ccccc12)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)Oc1cccc2ccccc12
Reaction time: 4 h
Yield: 78 %

Procedure:
In DMF was dissolved 935 mg of the above ester, and to the resulting solution were added 0.5 g of 10% palladium-carbon (Pd-C) and 0.98 ml of a 2 N hydrochloric acid-dioxane solution, after which hydrogen gas was passed through the resulting mixture with ice-cooling and with stirring for 4 hrs. After the reaction, the Pd-C was removed by filtration, and 300 ml of anhydrous diethyl ether was added dropwise to the filtrate, upon which a powder was precipitated. The powder was collected by filtration to obtain 450 mg (yield 78%) of L-phenylalanyl-L-arginine 1-naphthyl ester dihydrochloride, m.p. 215° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F:17][C:18](I)([F:20])[F:19].Cl>CN(C)C=O.[Zn]>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[C:18]([F:20])([F:19])[F:17])=[CH:4][C:3]=1[O:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Reactant: FC(F)(F)I
Agent: Cl
Agent: [Zn]
Solvent: CN(C)C=O
Product: OC(c1ccc(F)c(Oc2ccccc2)c1)C(F)(F)F
Yield: 56.7 %

Procedure:
A mixture of 2 g of 4-fluoro-3-phenoxy-benzaldehyde, 5 ml of dimethylforomamide, 2 g of electrolytic zinc and 15 ml of a solution of 13.5 mmols of trifluoromethyl iodide in dimethylformamide was ultrasonically irradiated for 15 minutes and the mixture was poured into aqueous N hydrochloric acid. The mixture was extracted with isopropyl ether and the organic phase was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 1-1 methylene chloride-hexane mixture to be obtain 1.5 g of 1-(4-fluoro-3-phenoxy-phenyl)-2,2,2-trifluoroethanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C@H:11]([CH2:21][C:22]2[N:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24](O)=[O:25])[O:10][C:9]1([CH3:32])[CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:34][NH2:35]>>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C@H:11]([CH2:21][C:22]2[C:23]([C:24](=[O:25])[NH:35][CH3:34])=[CH:27][CH:28]=[CH:29][N:30]=2)[O:10][C:9]1([CH3:32])[CH3:31])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccccc2F)[C@H](Cc2ncccc2C(=O)O)OC1(C)C
Reactant: CN
Agent: Cl
Product: CNC(=O)c1cccnc1C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]1Cc1ccccc1F

Procedure:
Using general reaction procedure 5 with 2-[(4R,5S)-3-tert-butoxycarbonyl-4-(2-fluoro-benzyl)-2,2-dimethyl-oxazolidin-5-ylmethyl]-nicotinic acid (0.5 g, 1.1 mmol) and methyl amine hydrochloride (0.38 mL, 5.6 mmol) gives the title compound.
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+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[O:42][N:41]=[CH:40][CH:39]=2)=[CH:34][CH:33]=1>CN(C=O)C>[O:42]1[C:38]([C:35]2[CH:36]=[CH:37][C:32]([CH2:31][N:15]3[C:14](=[O:17])[N:11]4[N:12]=[CH:13][C:8]([C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=5)=[C:9]([C:18]5[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=5)[C:10]4=[N:16]3)=[CH:33][CH:34]=2)=[CH:39][CH:40]=[N:41]1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: BrCc1ccc(-c2ccno2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(-c3ccno3)cc2)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (3.0 g, 9.27 mmol), prepared as described in Example 244, K2CO3 (2.56 g, 18.53 mmol) and 5-(4-(bromomethyl)phenyl)isoxazole (2.65 g, 11.12 mmol), in DMF (23 mL), were added. The resulting mixture was heated to 60° C. After 2 h, the reaction mixture was cooled to RT and partitioned between water and EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc (2×200 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography using hexanes/EtOAc 1:10 to give the title compound, 2-(4-(isoxazol-5-yl)benzyl)-7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, as a light yellow solid. HPLC RT: 2.64 min; MS, M+H=481; 1H NMR (CDCl3): δ 8.62-8.64 (m, 2H), 8.29 (d, J=1.8 Hz, 1H), 8.20 (s, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.22 (m, 2H), 7.09 (d, J=8.4 Hz, 2H), 6.51 (d, J=1.6 Hz, 1H), 5.25 (s, 2H).
Reaction SMILES: N12CCCN=C1CCCCC2.[CH2:12]([O:15][C:16](=[O:26])[CH2:17][C:18]1[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:19]=1[F:25])[CH:13]=[CH2:14].C(NC1C=CC(S([N:40]=[N+:41]=[N-])(=O)=O)=CC=1)(=O)C>C1COCC1>[CH2:12]([O:15][C:16](=[O:26])[C:17]([C:18]1[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:19]=1[F:25])=[N+:40]=[N-:41])[CH:13]=[CH2:14]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: C=CCOC(=O)Cc1cc(Br)ccc1F
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCOC(=O)C(=[N+]=[N-])c1cc(Br)ccc1F
Temperature: 23 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
To a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (4.2 ml, 28 mmol) in THF (24 ml) at 23° C. was added a solution of (5-bromo-2-fluoro-phenyl)-acetic acid allyl ester (intermediate B3A) (7.29 g, 27 mmol) and commercially available p-acetamidobenzenesulfonyl azide ([CAS No. 2158-14-7], 6.94 g, 28 mmol) in THF (48 ml) over 1 h. The mixture was stirred for 5 h at 23° C. Then it was quenched with sat. aqueous ammonium chloride solution, diluted with ethyl acetate, and the organic layer was washed with brine and dried over sodium sulfate. Removal of the solvent in vacuum left a yellow oil, which was purified by silica gel column chromatography with hexane/ethyl acetate to give the title compound as a yellow solid (7.344 g, 92%). MS (ISP): m/z=316.1 [(M+NH4)+] and 318.0 [(M+2+NH4)+].
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:15][C:16]1[CH:34]=[CH:33][C:19]([CH2:20][NH:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29])=[CH:18][CH:17]=1)[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[O:35]1CC(O)O[CH2:37][CH:36]1O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:30]([N:26]([CH2:27][CH2:28][CH3:29])[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:20][C:19]1[CH:33]=[CH:34][C:16]([CH2:15][N:7]([CH2:6][C:2]2[NH:3][CH:4]=[CH:5][N:1]=2)[CH2:8][C:9]2[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=2)=[CH:17][CH:18]=1)[CH2:37][CH2:36][OH:35])[CH2:31][CH3:32]
Reactant: CCCN(CCC)CCCCNCc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Reactant: OC1COC(O)CO1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCN(CCO)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 76.8 %

Procedure:
The compound (209 mg) obtained in Example 1-8 was dissolved in anhydrous methanol (8.4 ml) and added with [1,4]-dioxan-2,5-diol (54.0 mg) and sodium cyanoborohydride (56.6 mg). Then, the solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 19.5 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution (1.0 ml) and subjected to extraction with chloroform, followed by drying with magnesium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (175.8 mg) of the subject compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:12][C:11]([C:13]([O:15]CC)=[O:14])=[C:10]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>O1CCOCC1>[C:1]([O:5][C:6]([C:8]1[S:12][C:11]([C:13]([OH:15])=[O:14])=[C:10]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1sc(C(=O)OC(C)(C)C)cc1OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1cc(OC(C)(C)C)c(C(=O)O)s1
Temperature: 0 °C

Procedure:
A solution of tert-butyl-3-tert-butoxy-2-ethyloxycarbonyl-5-thiophenecarboxylate (11.5 g, 35 mmol) in dioxane with NaOH (2N) (34.5 ml, 70 mmol) was heated for 1.45 hours at 50° C. The mixture was cooled to 0° C., neutralized with HCl (2N), and the solvent evaporated. The residue was triturated with a concentrated aqueous solution of Na2CO3 (400 ml) and ether (200 ml). The aqueous phase was recovered, cooled to 0° C., acidified with HCl (5N) and extracted with ether. After drying, concentration of the etheral phase, and purification by flash silica gel chromatography, the title compound was obtained (3.45 g).
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11]Br.[C:13]([O-:16])(=[O:15])[CH3:14].[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.C(Cl)Cl>[C:13]([O:16][CH2:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Br:1])(=[O:15])[CH3:14]
Reactant: O=[N+]([O-])c1cccc(CBr)c1Br
Reactant: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(=O)OCc1cccc([N+](=O)[O-])c1Br
Yield: 51.1 %

Procedure:
A stirred solution of 2-bromo-1-bromomethyl-3-nitrobenzene (20.2 g, 0.0685 mole), potassium acetate (10.08 g, 0.103 mole), and tetrabutylammonium chloride (1.5 g) in 150 ml of acetonitrile was heated at reflux for six hours. The reaction mixture was cooled, filtered, and extracted with methylene chloride. The extract was evaporated to give a residue which was redissolved in methylene chloride and washed twice with 150 ml portions of saturated aqueous sodium chloride solution. The organic phase was passed through phase separation filter paper and evaporated to give a dark solid. The solid was purified by column chromatography on silica gel, elution with toluene, to give (2-bromo-3-nitrophenyl)methyl acetate as a yellow solid (9.6 g, mp 60°-63°).