Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[O:6].[N+:11]([CH:13](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:14])#[C-:12].C([O-])([O-])=O.[K+].[K+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][CH:12]=[N:11][C:13]=2[CH3:14])[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccc(C=O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ccc(-c2ocnc2C)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
A mixture of 3-fluoro-4-methylbenzaldehyde (1.38 g, 10.0 mmol), 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (2.09 g, 10.0 mmol), and K2CO3 (1.66 g, 12.0 mmol) in 50 mL methanol was heated at reflux 3 hr, then cooled to room temperature and stirred overnight. The reaction mixture was concentrated and the residue taken up in 25 mL H2O and 25 mL Et2O. The water layer was extracted with Et2O, and the organic layers were combined, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (Analogix® SF40-115 g column) with 15% EtOAc/hexanes to yield 1.56 g (82%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.45-7.30 (m, 3H), 2.36 (s, 3H), 2.27 (d, J=1.9, 3H).
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:9][CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].Cl[CH2:11][CH:12]=[CH:13][CH3:14]>>[CH2:11]([N:6]1[CH2:7][CH2:8][NH:9][C:5]1=[CH:4][N+:1]([O-:3])=[O:2])[CH:12]=[CH:13][CH3:14]
Reactant: O=[N+]([O-])C=C1NCCN1
Reactant: CC=CCCl
Product: CC=CCN1CCNC1=C[N+](=O)[O-]

Procedure:
Method B, 2-(nitromethylene)imidazolidine was reacted with 1-chloro-2-butene. Melting point: 82° - 85°.
Reaction SMILES: [H-].[Na+].Br.Cl[C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8]2=[N:15][N:16]=[C:17]([NH2:18])[N:7]2[N:6]=1.[CH3:19][CH2:20][CH:21]([OH:24])[CH2:22][CH3:23]>CN(C=O)C>[CH2:20]([CH:21]([O:24][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8]2=[N:15][N:16]=[C:17]([NH2:18])[N:7]2[N:6]=1)[CH2:22][CH3:23])[CH3:19]
Reactant: CCC(O)CC
Reactant: Nc1nnc2c3c(c(Cl)nn12)CCCC3
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)Oc1nn2c(N)nnc2c2c1CCCC2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
3-Pentanol (20 ml) was initially charged under argon, admixed with sodium hydride (946 mg) and stirred at 50° C. for 1 h. Subsequently, 6-chloro-7,8,9,10-tetrahydro-[1,2,4]triazolo[3,4-a]-phthalazin-3-ylamine hydrobromide (W2.018, 1.88 g), dissolved in 3-pentanol (20 ml) and DMF (100 ml), was slowly added dropwise within 1 h. After stirring for 1 h, the mixture was concentrated, and the residue was admixed with water and extracted four times with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified using a 40 g silica gel cartridge (0-10% dichloromethane-methanol gradient in 50 min). The clean product fractions were combined and dried. 0.8 g of the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([C:7](O)=[O:8])[N:6]=1.CN(C=O)C.C(Cl)(=O)C([Cl:24])=O>C(Cl)Cl>[CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([C:7]([Cl:24])=[O:8])[N:6]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(C(=O)Cl)c(-c2ccccc2)s1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a suspension of 2-methyl-5-phenyl-1,3-thiazole-4-carboxylic acid (1.47 g, 6.70 mmol) in CH2Cl2 (30 mL) cooled at 0° C. was added DMF (26 μL, 0.34 mmol) and oxalyl chloride (0.73 mL, 8.38 mmol). The reaction was allowed to warm to ambient temperature and stirred for 4 h. The solution was concentrated in vacuo to provide 2-methyl-5-phenyl-1,3-thiazole-4-carbonyl chloride as a yellow-orange oil which gave a mass ion (ES+) of 236.3. 1H NMR δ (ppm) (CDCl3): 7.42-7.46 (5H, m), 2.78 (3H, s).
Reaction SMILES: C1(C)C=CC=CC=1.C([N:10](CC)CC)C.[F:15][CH:16]1[CH2:23][C@@:22]2(C(O)=O)[C@H:18]([C:19](=[O:35])[N:20]([C@@H:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH3:28])[CH2:21]2)[CH2:17]1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(OCC)(=O)C>[NH2:10][C@:22]12[CH2:23][CH:16]([F:15])[CH2:17][C@@H:18]1[C:19](=[O:35])[N:20]([C@@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])[CH2:21]2
Reactant: C[C@H](c1ccccc1)N1C[C@@]2(C(=O)O)CC(F)C[C@H]2C1=O
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H](c1ccccc1)N1C[C@@]2(N)CC(F)C[C@@H]2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
Toluene (10 mL) and triethylamine (565 μL, 4.05 mmol) were added to (1R,5R)-7-fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octan-1-ylcarboxylic acid (590 mg, 2.03 mmol). Then, diphenylphosphoryl azide (567 μL) was added, and the mixture was stirred at room temperature for 30 minutes. Thereafter, the reaction solution was heated to reflux for one hour and blended with a mixture of ethyl acetate-saturated sodium bicarbonate water. The organic layer was dried over magnesium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was dissolved in dioxane (10 mL). 6N hydrochloric acid (10 mL) was added, and the mixture was heated with stirring at 70° C. for two hours. After washing with ether, the aqueous layer was made basic with a 10 M sodium hydroxide solution, followed by extraction with toluene five times. The extract was dried over magnesium sulfate and filtered, and then the solvent was evaporated under reduced pressure to give 476 mg (90%) of the title compound as a colorless oil. The product was used for the next step without purification.
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4].[C:16]1(O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4]
Reactant: Oc1ccccc1
Reactant: N=C(N)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: N=C(N)NC[C@H]1CC[C@H](C(=O)Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride (11.8 g), phenol (5.6 g), and dicyclohexylcarbodiimide (12.4 g) in pyridine (75 ml) was stirred overnight at room temperature. After evaporation of solvent, the residue was treated with 0.1 N hydrochloric acid (200 ml), the insoluble materials removed by filtration and the filtrate was washed with ethylacetate. The aqueous layer was concentrated to 100 ml, the resulting crystals were filtered and washed with isopropylalcohol/isopropylether to give phenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride (12.5 g, 80.2%), m.p. 150°-153° C. This compound was recrystallized from methanol to give white crystal, phenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride, m.p. 159.5°-161.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:15]([Mg]Br)=[CH2:16]>C1COCC1>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([CH:5]([OH:6])[CH:15]=[CH2:16])[C:7]([C:10]([F:12])([F:13])[F:11])=[CH:8][CH:9]=1
Reactant: O=Cc1c(C(F)(F)F)ccc(Cl)c1F
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)c1c(C(F)(F)F)ccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.3 %

Procedure:
To a solution of 3-chloro-2-fluoro-6-(trifluoromethyl)benzaldehyde (2.052 g, 9.06 mmol) in THF (30 mL) under nitrogen at −78° C. was added dropwise vinyl magnesium bromide (1 M in THF) (11.77 mL, 11.77 mmol). The mixture was stirred for 15 minutes at this temperature then the cooling bath was removed allowing the solution to warm to ambient temperature where it was stirred for 1 h. The reaction was cooled to 0° C. and quenched with 20 mL of aqueous NH4Cl (saturated) and the solvent was removed under a stream of nitrogen. The solid residue was taken up in water/ethyl acetate and phases were separated. The aqueous layer was extracted twice with ethyl acetate and the combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to give an oil. The oil was then purified using silica gel chromatography. The desired fractions were combined together to give 1-(3-chloro-2-fluoro-6-(trifluoromethyl)phenyl)prop-2-en-1-ol (1.322 g, 57%) as a faint yellow colored oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:21])[N:16]([CH:18]([CH3:20])[CH3:19])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:30][OH:31].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:21])[N:16]([CH:18]([CH3:20])[CH3:19])[CH:17]=2)=[N:30]\[OH:31])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C(C)C)c1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C(C)C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-isopropyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless foam, MS (ESI+): m/z=453.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[CH2:13]([N:15]([CH2:26][CH3:27])[CH2:16][CH2:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[CH3:14]>C1COCC1.CC(O)C>[CH2:26]([N:15]([CH2:13][CH3:14])[CH2:16][CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([NH:23][C:2]2[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=2)=[CH:24][CH:25]=1)[CH3:27]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: CNc1nc(Cl)ncc1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc(Nc2ncc([N+](=O)[O-])c(NC)n2)cc1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
To a solution of 1.89 g (10 mmol) of 2-chloro-4-(methylamino)-5-nitropyrimidine in 100 mL THF at −78° C. is added a solution of 2.48 g (12 mmol) of 4-[2-(diethylamino)ethoxy]aniline in 100 mL of 2-propanol, and the resulting mixture is allowed to warm slowly to room temperature. The precipitate is collected, washed with 2-propanol, and dissolved in water. After being filtered through celite, the aqueous solution is basified with aqueous ammonia, and the resulting precipitate is collected, washed with water, and dried, to give 2.88 g (80%) of the title compound: mp (EtOH)163–164° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[N:7]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH2:16])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[O:18]=[C:19]1[NH:23][C:22](=[O:24])[CH:21]([CH2:25][C:26]2[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32](O)=[O:33])=[CH:28][CH:27]=2)[S:20]1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>O1CCCC1>[C:1]([O:5][C:6](=[O:17])[N:7]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:32](=[O:33])[CH2:31][O:30][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH:21]2[S:20][C:19](=[O:18])[NH:23][C:22]2=[O:24])=[CH:36][CH:35]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 64.4 %

Procedure:
To a mixture of N-(2-amino-5-chlorophenyl)-N-methylcarbamic acid t-butyl ester (2.50 g) (obtained in Reference Example 2), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (3.01 g) (obtained in Reference Example 6), triethylamine (1.49 ml) and anhydrous tetrahydrofuran (50 ml) was added diethyl cyanophosphonate (1.75 g) and the resulting mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The resulting residue was chromatographed on a silica gel column using n-hexane/ethyl acetate (2/1) as the eluant to give the desired product (3.26 g). Rf=0.41 (thin-layer chromatography on a silica gel plate using n-hexane/ethyl acetate (2/3) as the eluant).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][CH:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])=[CH:6][CH:5]=1.Br[C:20]1[S:21][C:22]([C:26]([NH:28][CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[O:27])=[C:23]([CH3:25])[N:24]=1>>[CH3:25][C:23]1[N:24]=[C:20]([N:11]2[CH2:12][CH2:13][CH:9]([CH2:8][C:7]3[CH:15]=[CH:16][C:4]([O:3][C:2]([F:17])([F:1])[F:18])=[CH:5][CH:6]=3)[C:10]2=[O:14])[S:21][C:22]=1[C:26]([NH:28][CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)=[O:27]
Reactant: Cc1nc(Br)sc1C(=O)NCc1cccnc1
Reactant: O=C1NCCC1Cc1ccc(OC(F)(F)F)cc1
Product: Cc1nc(N2CCC(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 34 %

Procedure:
Following the procedure as described in Example 8, making variations as required to use 3-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one in place of 3-(4-fluorobenzyl)pyrrolidin-2-one to react with 2-bromo-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide, the title compound was obtained as a white solid in 34% yield: mp 158-160° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.49 (d, J=4.0 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.31-7.06 (m, 5H), 6.43 (t, J=5.7 Hz, 1H), 4.58 (d, J=5.7 Hz, 2H), 4.06 (ddd, J=11.5, 8.0, 3.1 Hz, 1H), 3.86 (td, J=11.5, 8.0 Hz, 1H), 3.23 (dd, J=13.9, 4.4 Hz, 1H), 3.08-2.94 (m, 1H), 2.83-2.74 (m, 1H), 2.60 (s, 3H), 2.34-2.19 (m, 1H), 1.94-1.87 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 174.6, 162.5, 155.4, 153.2, 149.3, 148.9, 148.0, 138.1, 136.9, 135.7, 133.9, 130.3, 123.7, 121.2, 118.3, 45.9, 44.3, 41.5, 35.7, 24.3, 17.3; MS (ES+) m/z 491.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([C:9](OCC)=[O:10])[C:3]=1[CH3:14].[BH4-].[Na+].Cl>CO>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([CH2:9][OH:10])[C:3]=1[CH3:14]
Reactant: CCOC(=O)c1ncc(C)c(Cl)c1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cnc(CO)c(C)c1Cl
Yield: 85 %

Procedure:
4-Chloro-2-ethoxycarbonyl-3,5-Lutidine (1 equivalent) was dissolved in methanol (4 volumes). The solution was cooled in an ice bath and while stirring sodium borohydride (1-4 eq.) was added in portions. The mixture was stirred and heated to reflux (80-85ℑC.). At the end of the reaction, the solvent was evaporated, water (2 volumes) was added and the product was extracted with toluene (2×4 volumes). The combined organic layers were stirred in an ice bath and HCl gas (1.2 eq.) was bubbled in solution. The 4-Chloro-2-hydroxymethyl-3,5-Lutidine hydrochloride salt was filtered, washed with toluene and dried at 50ℑ C. at high vacuum. The product was obtained as a white solid in 85% yield.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[Br:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[Cl:19])[NH:15][N:14]=[C:13]2[NH:20][C:21](=[O:25])[CH2:22][CH2:23][CH3:24].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[Br:9][C:10]1[CH:11]=[C:12]2[C:16](=[C:17]([N+:7]([O-:8])=[O:6])[C:18]=1[Cl:19])[NH:15][N:14]=[C:13]2[NH:20][C:21](=[O:25])[CH2:22][CH2:23][CH3:24]
Reactant: O=[N+]=O
Reactant: CCCC(=O)Nc1n[nH]c2cc(Cl)c(Br)cc12
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2c([N+](=O)[O-])c(Cl)c(Br)cc12
Reaction time: 4 h
Yield: 1.8 %

Procedure:
418 mg of nitronium tetrafluoroborate are added to 4 g of N-(5-bromo-6-chloro-1H-indazol-3-yl)butanamide, described in Example 58, in 50 cm3 of acetonitrile at 0° C., and the mixture is stirred for 4 hours. 200 cm3 of ethyl acetate and 100 cm3 of saturated sodium hydrogen carbonate solution are added to the reaction medium. The organic phase is washed with 2×40 cm3 of saturated sodium hydrogen carbonate solution and then with 40 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.) to give 840 mg of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) and then dried (90 Pa; 45° C.) to give 20 mg of N-(5-bromo-6-chloro-7-nitro-1H-indazol-3-yl)butanamide in the form of a yellow solid melting above 260° C.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([O:9]CC)=[O:8])[CH:4]=[C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:2]=1.Cl>C(O)C.[OH-].[K+]>[C:12]([C:3]1[CH:4]=[C:5]([C:7]([OH:9])=[O:8])[CH:6]=[N:1][CH:2]=1)([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cncc(C(=O)OCC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cncc(C(=O)O)c1
Reaction time: 0.5 h

Procedure:
To a solution of 10 g (0.045 mol) of diethyl 3,5-pyridinedicarboxylate in 75 ml of ethyl alcohol, 25 ml of 2N alcoholic KOH were added while stirring. Stirring was continued for 1/2 hour at room temperature. To the mixture, 12.5 ml of 4N HCl were added while stirring. The solid which separated was filtered and washed with alcohol. The combined filtrate and washings were distilled on rotovap and the residue was washed with water, filtered and crystallized from ethanol. Yield 7.5 g (86%), m.p. 180°-182° C., NMR (CDCl3 /DMSO-d6) δ 10.56 (bs, 1H, COOH), 9.26 (d, 2H, J=2 Hz, C2 and C6 pyridine protons), 8.75 (t, 1H, J=2 Hz, C4 pyridine protons), 4.4 (q, 2H, J=7 Hz, O--CH2), 1.42 (t, 3H, J=7 Hz, CH3).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].B(F)(F)F.[CH3:18]COCC.CCOCC>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:18])=[O:8]
Reactant: CCOCC
Reactant: O=C(O)c1cc(O)ccc1[N+](=O)[O-]
Agent: FB(F)F
Solvent: CO
Product: COC(=O)c1cc(O)ccc1[N+](=O)[O-]

Procedure:
5-Hydroxy-2-nitrobenzoic acid (47 g) in 750 ml methanol was treated with 160 ml BF3 -ether, ether distilled off until pot temperature reached 60°, and refluxed overnight. The procedure was repeated with 100 ml BF3 -ether. The mixture was poured into 3 volumes of water, extracted with ethyl acetate, the ethyl acetate washed with water, KHCO3 solution, water, dried and concentrated to give 48.4 g product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([CH2:11][NH2:12])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[Cl:26][C:27]1[S:31][C:30]([S:32](Cl)(=[O:34])=[O:33])=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([CH2:11][NH:12][S:32]([C:30]2[S:31][C:27]([Cl:26])=[CH:28][CH:29]=2)(=[O:34])=[O:33])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cc(CN)nc(-c2ccccn2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1cc(CNS(=O)(=O)c2ccc(Cl)s2)nc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
A mixture of C-(4-Methanesulfonyl-[2,2′]bipyridinyl-6-yl)-methylamine (40.0 mg, 0.153 mmol), triethylamine (58.0 μL, 0.459 mmol), 5-chlorothiophene-2-sulfonyl chloride (42.0 mg, 0.184 mmol) and DCM (2 mL) was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the crude purified by column chromatography on silica gel (0-10% methanol in dichloromethane) to afford 5-chloro-thiophene-2-sulfonic acid (4-methanesulfonyl-[2,2′]bipyridinyl-6-ylmethyl)-amide as a white solid (20.0 mg, 30%).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:9]([CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])=[CH:8][N:7]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:29][C:30]=3[CH3:31])=[CH:20][CH:19]=2)[N:6]=1)([CH3:3])[CH3:2].[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH:1]([O:4][C:5]1[C:9]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][N:7]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[O:29][C:30]=3[CH3:31])=[CH:20][CH:19]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(OC(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A mixture of ethyl 3-[3-isopropoxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazole-4-yl]propionate (440 mg), 1 N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for one hour, diluted with 1 N hydrochloric acid (5 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-isopropoxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid was obtained (380 mg, yield: 91%). This was recrystallized from acetone-isopropyl ether. Melting point: 106–107° C.
Reaction SMILES: [Se](=O)=[O:2].[CH3:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6]>O1CCOCC1.O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]([CH:4]=[O:2])=[O:6])=[CH:8][CH:9]=1
Reactant: O=[Se]=O
Reactant: CC(=O)c1ccc(F)cc1
Solvent: O
Solvent: C1COCCO1
Product: O=CC(=O)c1ccc(F)cc1
Reaction time: 12 h
Yield: 71.1 %

Procedure:
Selenium dioxide (6.70 g, 61.0 mmol) was added to a solution of 4-fluoroacetophenone (8.43 g, 61.0 mmol) in dioxane (100 mL) and water (3 mL), and the resulting mixture was heated at 55° C. until complete dissolution of selenium dioxide had occurred. The reaction mass was then refluxed for 5-6 hrs. After completion of the reaction (TLC), the mixture was filtered and the filtrate was concentrated in vacuo affording a viscous oil. Water (50 mL) was added and the resulting mixture was stirred for 12 hrs, after which time the solid was collected on a filter, washed with water (25 mL) and dried in vacuo, affording 4-fluorophenylglyoxal (6.60 g, 85%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18][N:19]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:20]3=[O:30])=[C:13]([Cl:31])[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO.C(OCC)(=O)C>[Cl:31][C:13]1[CH:12]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=2)[CH:16]=[C:15]([Cl:17])[C:14]=1[CH2:18][N:19]1[CH2:23][CH2:22][CH:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:20]1=[O:30]
Reactant: COC(=O)c1ccc(-c2cc(Cl)c(CN3CCC(N4CCCCC4)C3=O)c(Cl)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(-c2cc(Cl)c(CN3CCC(N4CCCCC4)C3=O)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.8 %

Procedure:
Treat a solution of 3′,5′-Dichloro-4′-(2-oxo-3-piperidin-1-yl-pyrrolidin-1-ylmethyl)-biphenyl-4-carboxylic acid methyl ester (0.190 g, 0.41 mmol) in methanol (15 mL) with 5N NaOH (0.82 mL), heat to reflux, and cool and stir at room temperature for 16 hours. Remove the solvent in vacuo to give a residue and neutralize with 1N HCl. Dilute the mixture with ethyl acetate and wash with water. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, purify with a 0 to 10% methanol in CH2Cl2 gradient to afford 0.106 g (58%) of the titled product. Rf=0.50 (4/1 CH2Cl2/methanol). ES MS (m/z): 447 (M+).