Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:6]=1[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])#[N:4].S(OCC)(O[CH2:29][CH3:30])(=O)=O.O>CN(C=O)C>[C:3]([C:5]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:6]=1[N:7]([CH2:29][CH3:30])[S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])#[N:4]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc([N+](=O)[O-])cc2C#N)cc1
Reactant: CCOS(=O)(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(c1ccc([N+](=O)[O-])cc1C#N)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.4 %

Procedure:
To a suspension of sodium hydride (60%, 0.12 g (3.00 mmol)) in 3.0 ml of DMF, 2′-cyano-4′-nitro-p-toluenesulfonanilide (0.80 g (2.52 mmol)) was added with′stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, diethyl sulfate (0.40 ml (3.05 mmol)) was added dropwise and the mixture was heated at 80° C. for 2 hours and at 100° C. for 2 hours with stirring. The reaction mixture was then cooled to room temperature, poured into water and extracted with diethyl ether. The extract was washed three times with 1% aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:2) as eluent, to give 0.23 g (26%) of the title compound as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH3:13][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)Cc1ccc(F)cc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
A solution of the compound of Example 14A (23.2 g, 0.138 mol) in dry tetrahydrofuran (30 mL) was added dropwise over 30 min to a −78° C. solution of lithium hexamethyldisilazide (prepared from hexamethyldisilazane (35 mL, 0.165 mol) and n-butyllithium in hexane (2.5 M, 58 mL, 0.145 mol)) in dry tetrahydrofuran (100 mL). The solution was stirred at −78° C. for 1 h, and then a large excess of methyl iodide was added. The solution was stirred at −78° C. for 30 min and was then warmed to ambient temperature for 18 h. The solution was quenched by addition of saturated ammonium chloride solution and diluted with water. The mixture was concentrated in vacuo to remove tetrahydrofuran and then extracted with ethyl acetate. The organic layer was extracted with water (2×) and saturated NaCl solution, followed by drying (Na2SO4) and concentration in vacuo. The residue was distilled under reduced pressure (70-75° C./0.5 mm Hg) to afford the title compound (21.9 g, 87%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 1.49 (d, J=7.35 Hz, 3 H) 3.70 (m, 4 H) 7.01 (m, 2 H) 7.27 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([O:10][CH3:11])[N:3]=1)[CH:8]=[O:9]
Reactant: COc1cc(CO)cc(Cl)n1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc(C=O)cc(Cl)n1

Procedure:
To a solution of (2-chloro-6-methoxypyridin-4-yl)methanol (1.73 g, 9.97 mmole) from the protocol immediately above in CH2Cl2 (40 mL) was added PCC (2.58 g, 11.96 mmole) all at once at RT. After 60 hr the mixture was diluted with Et2O and filtered through a plug of Celite®. The filtrate was concentrated to give the titled compound as a tan-yellow solid which was sufficiently pure for use in the next step. 1H-NMR (500 MHz, CDCl3) δ 9.96 (s, 1 H), 7.32 (s, 1 H), 7.06 (s, 1 H), 4.00 (s, 3 H).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=2)=[O:12])[C:4](=[O:28])[CH:3]=1.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[CH:25][CH:26]=2)=[O:12])[C:4](=[O:28])[CH:3]=1
Reactant: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1Br
Reactant: OB(O)c1cc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1Br
Reaction time: 8 h

Procedure:
Under argon (in a flask dried by heating), 113 mg (0.25 mmol) of tert-butyl 4-{[2-(4-bromo-5-methoxy-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate (racemate), 70 mg (0.30 mmol, 1.2 eq.) of 2-bromo-5-chlorophenylboronic acid, 103 mg (0.74 mmol, 3.0 eq.) of potassium carbonate and 20 mg (0.03 mmol, 0.1 eq.) of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were suspended in 5.0 ml of dioxane and stirred overnight in an oil bath already preheated to 110° C. A further 10 mg (0.01 mmol, 0.05 eq.) of [1,1-bis-(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct and 29 mg (0.12 mmol, 0.5 eq.) of 2-bromo-5-chlorophenylboronic acid were added and the reaction mixture was stirred at 110° C. for a further night and then filtered through Celite. The residue was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The residue was triturated with water, filtered off, dried under reduced pressure and purified by flash chromatography (silica gel 50, cyclohexane/ethyl acetate gradient). Yield: 72 mg (purity 73%, 38% of theory)
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH2:17])[C:15](=[O:18])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.[NH2:19][N:20]1[C:25]([NH2:26])=[CH:24][C:23]([NH2:27])=[N:22][C:21]1=[S:28].CO.N>C(#N)C>[NH2:17][CH:16]1[C:15](=[O:18])[N:10]2[C:11]([C:12]([O-:14])=[O:13])=[C:6]([CH2:5][S:28][C:21]3[N:22]=[C:23]([NH2:27])[CH:24]=[C:25]([NH2:26])[N+:20]=3[NH2:19])[CH2:7][S:8][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: Nc1cc(N)n(N)c(=S)n1
Agent: N
Solvent: CC#N
Solvent: CO
Product: Nc1cc(N)[n+](N)c(SCC2=C(C(=O)[O-])N3C(=O)C(N)[C@H]3SC2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
Under an anhydrous condition, a solution containing 2.72 g of 3-acetoxymethyl-7-amino-3-cephem-4-carboxylic acid and 1.50 g of 1,4,6-triamino-2(1H)-pyrimidinethione suspended in 20 ml of dry acetonitrile was cooled to 0° C.; and 4.8 ml of boron trifluoride diethylether was added. The temperature of the reaction solution was increased to 50° C; the solution was stirred for two hours; and then 10 ml of methyl alcohol was added. The resultant solution was stirred for 10 minutes and was added with 30 ml of ice water. The pH of the solution was adjusted to 7.1 by adding aqueous ammonia solution. After concentration under a reduced pressure, e.g., about 20 mmHg, the solution was adjusted to pH 3.7 with 2N-aqueous hydrochloric acid; and allowed to stand at a room temperature for 24 hrs. The precipitates resulted from the reaction solution were filtered, washed with 10 ml of distilled water and with 10 ml of methyl alcohol, and dried to give 2.55 g of the title compound as a solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(O)(O)(=O)=O.[NH2:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1.C(N(CC)CC)C>ClCCl.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[NH:16]1[CH:17]=[CH:18][N:19]=[C:15]1/[N:14]=[CH:1]/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncc[nH]1
Reactant: O=Cc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C(=N/c1ncc[nH]1)\c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of benzaldehyde (1.92 ml, 18.8 mmol) in dichloromethane (15 ml) were added sequentially 2-aminoimidazole sulfate (3.77 g, 14.3 mmol), tetraisopropyl orthotitanate (6.83 ml, 23.3 mmol) and triethylamine (3.90 ml, 2.81 mmol). The reaction mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was taken up in ethyl acetate and water and the mixture filtered. The filtrate phases were separated and the organic phase dried over sodium sulfate and concentrated in vacuo to yield the title compound as a yellow solid which was used in the next step without further purification (3.03 g, 95%); MS (ISP): 172.1 ([M+H]+).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]([N:17]2[CH2:22][CH:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[O:16])[C@@H:4]([C:29]([O:31][CH3:32])=[O:30])[CH2:3]1.O1CCCC1.[N:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:23]1([C:20]2[CH2:21][CH2:22][N:17]([C:15]([C@@H:5]3[C@@H:4]([C:29]([O:31][CH3:32])=[O:30])[CH2:3][C@H:2]([O:1][C:41]4[CH:42]=[CH:43][N:38]=[CH:39][CH:40]=4)[CH2:7][N:6]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:16])[CH2:18][CH:19]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Oc1ccncc1
Reactant: COC(=O)[C@H]1C[C@@H](O)CN(C(=O)OC(C)(C)C)[C@@H]1C(=O)N1CC=C(c2ccccc2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](Oc2ccncc2)CN(C(=O)OC(C)(C)C)[C@@H]1C(=O)N1CC=C(c2ccccc2)CC1
Temperature: 70 °C

Procedure:
To a solution of 1-tert-butyl 3-methyl(2S,3S,5R)-5-hydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidine-1,3-dicarboxylate (100 mg, 0.0002 mol) in tetrahydrofuran (0.912 mL, 0.0112 mol) was added 4-pyridinol (25.7 mg, 0.000270 mol), triphenylphosphine (70.8 mg, 0.000270 mol), followed by diisopropyl azodicarboxylate (0.0532 mL, 0.000270 mol). The mixture was heated at 70 Celsius overnight. After concentrated to dry, the mixture was purified on silica gel, eluting with 0 to 40% EtOAc in hexane, to afford the desired ether compound (56 mg, 50%). MS (ESI): (M+H)+=522.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH:11]([F:13])[F:12])=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].P(OC)(OC)(O[CH3:17])=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH:11]([F:12])[F:13])=[N:8][N:9]([CH3:17])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]nc1C(F)F
Reactant: COP(=O)(OC)OC
Product: CCOC(=O)c1cn(C)nc1C(F)F
Temperature: 180 °C
Reaction time: 18 h
Yield: 63.7 %

Procedure:
A mixture of 5.7 g of 3-difluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (30 mmol) and 25 ml of trimethyl phosphate (214 mmol) is stirred at a temperature of 180° C. for 18 hours. 250 ml of an ice-water mixture are then added. The resulting reaction product is filtered, washed with water and dissolved in 50 ml of ethyl acetate. The organic phase is washed with 50 ml of saturated sodium chloride solution and dried over sodium sulfate and concentrated by evaporation. 3.9 g (64% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester are obtained in the form of crystals (m.p. 59-60° C.).
Reaction SMILES: [NH2:1][NH2:2].[O:3]1[CH2:8][CH2:7][N:6]([S:9]([C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14](OC)=[O:15])(=[O:11])=[O:10])[CH2:5][CH2:4]1>CO>[O:3]1[CH2:8][CH2:7][N:6]([S:9]([C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([NH:1][NH2:2])=[O:15])(=[O:11])=[O:10])[CH2:5][CH2:4]1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N1CCOCC1
Reactant: NN
Solvent: CO
Product: NNC(=O)c1ccccc1S(=O)(=O)N1CCOCC1
Temperature: 70 °C
Yield: 36.9 %

Procedure:
Hydrazine (22.46 mg, 0.701 mmol) was added to the methyl 2-(morpholinosulfonyl)benzoate (100 mg, 0.350 mmol) in methanol and refluxed for 12 h at 70° C. Following cooling, Reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by flash chromatography afforded the title compound 2-(morpholinosulfonyl)benzohydrazide (40 mg, 0.129 mmol, 36.8% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 7.86 (m, 1H), 7.66-7.56 (m, 2H), 7.52 (dd, 1H, J=1.2 & 7.6 Hz), 7.40 (m, 1H), 4.09 (m, 2H), 3.70 (m, 4H), 3.15 (m, 4H). ESI-MS: 286.1[M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:15][C:16](=[O:19])[CH2:17]Cl)([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:9])[NH:15][C:16](=[O:19])[CH2:17][N:11]3[N:12]=[CH:13][CH:14]=[C:10]23)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(NC(=O)CCl)(c1cccc(Br)c1)c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(c2cccc(Br)c2)NC(=O)Cn2nccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
A solution of rac-N-[1-(3-bromo-phenyl)-1-(1H-pyrazol-3-yl)-ethyl]-2-chloro-acetamide (1.22 g, 3.56 mmol) in THF (40 mL) was added dropwise to a suspension of sodium hydride (0.28 g, 7.12 mmol) in THF (40 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 1 hour. The mixture was diluted with water and the product extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; AcOEt in DCM 50/50 to 100/0). The desired fractions were collected and concentrated in vacuo to yield rac-4-(3-bromo-phenyl)-4-methyl-4,5-dihydro-pyrazolo[1,5-a]pyrazin-6-one (0.7 g, 64% yield) as a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:10][CH2:9]1.N1C=CC=CC=1>C1C=CC=CC=1>[Cl:3][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:10][CH2:9]1
Reactant: OCCN1CCN(c2ccccc2F)CC1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: Fc1ccccc1N1CCN(CCCl)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
Thionyl chloride (1 mL) was added dropwise to an ice-cooled solution of 1-(2-hydroxyethyl)-4-(2-fluorophenyl)piperazine (300 mg) and pyridine (1 mL) in benzene (20 mL). After 30 minutes the solution was brought to room temperature and then the flask was immersed in a 60° C. oil bath for 1 hour. The layers were separated and the aqueous fraction was extracted with ethyl acetate (2×20 mL). The combined organic fractions were dried over sodium sulfate and the solvent was removed in vacuo, giving the desired product as a yellow solid (58.6 mg, 18%). ESI-MS m/z 243 (MH+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][N:4]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:22])[C:20]=1F)[CH:16]=[O:17]>>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([F:22])[C:20]=1[O:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:8]=1)[CH:16]=[O:17]
Reactant: Oc1ccnc(C(F)(F)F)c1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Product: O=Cc1cc(F)c(Oc2ccnc(C(F)(F)F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D30 starting from 2-(trifluoromethyl)pyridin-4-ol and 3,4,5-trifluorobenzaldehyde.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[N+:13]([CH3:16])([O-:15])=[O:14].C1CCN2C(=NCCC2)CC1.Cl>CCOCC>[CH3:1][C:2]([CH3:12])([CH2:16][N+:13]([O-:15])=[O:14])[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)=CC(=O)c1cccnc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: CC(C)(CC(=O)c1cccnc1)C[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a mixture of 3-methyl-1-pyridin-3-yl-but-2-en-1-one (440 mg, 2.73 mmol) and nitromethane (0.74 mL, 13.65 mmol) that is cooled with a water bath, add DBU (0.41 mL, 2.73 mmol) dropwise. After 30 min, add ether (15 mL) and 1N hydrochloric acid (15 mL). Neutralize with 1M NaOH and extract with ether. Dry over magnesium sulfate and evaporate to obtain 340 mg (61%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[N:7]=1)=[O:5])[CH3:2].[CH:13]([Si:16]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[SH:17])([CH3:15])[CH3:14]>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:17][Si:16]([CH:18]([CH3:20])[CH3:19])([CH:21]([CH3:23])[CH3:22])[CH:13]([CH3:14])[CH3:15])[N:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Reactant: CCOC(=O)c1cccc(Br)n1
Product: CCOC(=O)c1cccc(S[Si](C(C)C)(C(C)C)C(C)C)n1

Procedure:
Prepared according to the procedure described in Example 6, Step 1, using the following starting materials: 6-bromo-pyridine-2-carboxylic acid ethyl ester and triisopropylsilane-thiol.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].FC(F)(F)S(O[C:15]1[CH2:20][CH2:19][CH:18]([O:21][Si](C(C)(C)C)(C)C)[CH2:17][CH:16]=1)(=O)=O.[F:31][C:32]1[C:37](B(O)O)=[CH:36][CH:35]=[CH:34][N:33]=1>>[F:31][C:32]1[C:37]([C:15]2[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH:16]=2)=[CH:36][CH:35]=[CH:34][N:33]=1
Reactant: OB(O)c1cccnc1F
Reactant: CC(C)(C)[Si](C)(C)OC1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: OC1CC=C(c2cccnc2F)CC1

Procedure:
To a 25 mL microwave vial was added potassium phosphate tribasic (0.354 mL, 4.27 mmol), PdCl2(AmPhos) (0.121 g, 0.171 mmol), 4-(tert-butyldimethylsilyloxy)cyclohex-1-enyl trifluoromethanesulfonate (0.616 g, 1.710 mmol), and 2-fluoropyridin-3-ylboronic acid (0.265 g, 1.881 mmol) before evacuating and backfilling with nitrogen (3×). A mixed solvent of Dioxane (7.12 mL):water (1.425 mL) was added, and the contents were irradiated at 150° C. for 30 minutes in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden). The biphasic solution was diluted with water and extracted with DCM (3×25 mL) before drying over sodium sulfate, filtering, and concentrating under reduced pressure to a dark brown residue. The residue was taken up in 5 mL DCM and applied directly to silica (0 to 70% ethyl acetate/hexanes for followed by 5 to 10% MeOH/DCM). The resulting yellow oil was taken forward without further manipulation.
Reaction SMILES: [NH2:1][C:2]([NH2:25])=[N:3][C:4](=[O:24])[C:5]1[C:10](C)=[CH:9][C:8]([O:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=2)=[C:7]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:6]=1.CS(C1C=C(C=CC=1OC1(Br)C=CC=CN1)C(OC)=O)(=O)=[O:28]>>[NH2:1][C:2]([NH2:25])=[N:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([O:12][C:13]2[C:14]([OH:28])=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=2)=[C:7]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:6]=1
Reactant: Cc1cc(Oc2cncc(Cl)c2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Reactant: COC(=O)c1ccc(OC2(Br)C=CC=CN2)c(S(C)(=O)=O)c1
Product: CS(=O)(=O)c1cc(C(=O)N=C(N)N)ccc1Oc1cc(Cl)cnc1O

Procedure:
N-diaminomethylene-3-methylsulfonyl-4-(5-chloro-3-pyridyloxy)-6-methylbenzamide, m.p. 208-210°; with methyl 3-methylsulfonyl-4-(2-bromo-2-pyridyloxy)benzoate,
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:10][CH:11]=[C:12]([C:18](OCC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])C.C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1>>[OH:10][C:11]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:1]=[CH:18][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccccc2c1O

Procedure:
In step 1 of sequence A, an aniline, substituted by the appropriate R2 group or groups, is condensed with a dialkyl alkoxymethylenemalonate such as diethyl ethoxymethylenemalonate by heating at 120° to 150°C. The intermediate formed is condensed by heating at a temperature of 150° to 300°C. in a high boiling inert solvent such as diphenyl ether or mixtures of diphenyl ether and biphenyl (e.g. Dowtherm A) to give the ethyl 4-hydroxyquinoline-3-carboxylate product of step 1.
Reaction SMILES: [NH2:1][OH:2].[CH3:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([CH2:9][CH2:10][N:11]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:12][CH2:13][C:14]([O:16]C)=O)=[CH:7][CH:6]=1>>[OH:2][NH:1][C:14](=[O:16])[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:33][CH:32]=1)[S:18]([C:21]1[CH:22]=[CH:23][C:24]([C:27]2[NH:31][N:30]=[N:29][N:28]=2)=[CH:25][CH:26]=1)(=[O:20])=[O:19]
Reactant: COC(=O)CCN(CCc1ccc(OC)cc1)S(=O)(=O)c1ccc(-c2nnn[nH]2)cc1
Reactant: NO
Product: COc1ccc(CCN(CCC(=O)NO)S(=O)(=O)c2ccc(-c3nnn[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Freshly prepared NH2OH solution (1 M in MeOH) (1.5 mL) was added to methyl 3-[(4-methoxyphenethyl)-(4-(tetrazol-5yl)-benzenesulfonyl)-amino]-propionate (112 mg, 0.25 mmol). After stirring at room temperature for 18 h, the reaction mixture was partitioned between 1 N HCl solution (20 mL) and ethyl acetate (30 mL). Two phases were separated and the aqueous layer was extracted with another 30 mL of ethyl acetate. Combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give N-hydroxy-3-[(4-methoxyphenethyl)-(4-(tetrazol-5yl)benzene-sulfonyl)amino]-propionamide (52 mg, 0.12 mmol). NMR (360 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.74 (br s, 1H), 8.22 (d, J=8.4 Hz, 2H), 7.99 (d, J=8.7 Hz, 2H), 7.10 (d, J=8.2 Hz, 2H), 6.81 (d, J=8.2 Hz, 2H), 3.69 (s, 3H), 3.42 (t, J=7.5 Hz, 2H), 3.31 (t, J=7.9 Hz, 2H), 2.70 (t, J=7.6 Hz, 2H), 2.25 (t, J=7.5 Hz, 2H).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][N:16]=1)C.[OH-].[Na+]>C(O)C.O>[Cl:21][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([C:7]2[N:6]([CH2:5][C:4]([OH:22])=[O:3])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)[CH:20]=1
Reactant: CCOC(=O)Cn1c(-c2cc(Cl)ccn2)nc2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cn1c(-c2cc(Cl)ccn2)nc2cccnc21
Yield: 58.2 %

Procedure:
A mixture of 2-(4-chloro-2-pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester (1.6 g, 0.005 mole), and crushed sodium hydroxide (0.2 g, 0.005 mole) in aqueous ethanol (5 ml water and 4 ml ethanol) was heated at reflux for 1/2 hr. The reaction mixture was diluted with water (10 ml) and extracted with ether (2×). The aqueous layer was acidified with 3N hydrochloric acid. The precipitate was collected, washed with water, and dried under high vacuum at 50° C. overnight to give 0.84 g of crystals, mp 218°-20° C. with decomposition.
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][C:32](Cl)=[O:33]>>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][C:32]([NH:15][C:14]1[N:9]2[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:22]=[C:10]2[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:13]=1)=[O:33]
Reactant: O=C(Cl)Cc1ccc(Cl)cc1Cl
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Product: O=C(Cc1ccc(Cl)cc1Cl)Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12

Procedure:
The title compound, MS m/e (%): 474 (M+H+, 100), was prepared in accordance with the general method of example 31 from 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and 2,4-dichlorophenylacetyl chloride.