Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[NH2:14][C:15]1[C:16](=[O:23])[C:17](=[O:22])[C:18]=1OCC.O>N1C=CC=CC=1>[NH2:14][C:15]1[C:16](=[O:23])[C:17](=[O:22])[C:18]=1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2cccnc2)cc1
Reactant: CCOc1c(N)c(=O)c1=O
Solvent: c1ccncc1
Solvent: O
Product: Nc1c(Nc2ccc(-c3cccnc3)cc2)c(=O)c1=O
Yield: 41.8 %

Procedure:
A solution of 3-(4-aminophenyl)pyridine (0.51 g) and 3-amino-4-ethoxy-3-cyclobutene 1,2-dione (0.42 g) in pyridine (2 ml) is stirred at 80° for 20 hours. The cool mixture is treated with water (15 ml), and the solid filtered off and washed with water and hot methanol. Recrystallation from dimethylformamide gives 0.33 g of the title compound, mp 3224° C. dec.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][CH2:27][CH2:28][OH:29])=[N:24][CH:25]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C=O)C>[OH:29][CH2:28][CH2:27][NH:26][C:23]1[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][CH:22]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: Nc1ccc(NCCO)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1ccc(NCCO)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (311 mg, 1.21 mmol), 2-(5-amino-pyridin-2-ylamino)-ethanol (84 mg, 0.55 mmol), N-hydroxybenzotriazole (185 mg, 1.38 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (264 mg, 1.38 mmol) in a mixture of methylene chloride (5 mL) and DMF (1 mL) was stirred at room temperature for 5 hr. The solvents were removed, and lithium hydroxide hydrate (excess) in a mixed solvent of methanol, tetrahydrofuran, and water (3:1:1, 5 mL) was added. The reaction mixture was stirred at room temperature for overnight. Solvents were removed, and water was added. The resulted mixture was extracted twice with ethyl acetate. The organic layers were collected, and washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck silica gel 60, 230-400 mesh, 0-15% methanol in methylene chloride for 30 min), and then preparative HPLC (0-90% acetonitrile in water for 20 min), followed by lyophilization gave 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-hydroxy-ethylamino)-pyridin-3-yl]-amide as a light yellow solid. LCMS calcd for C18H15F3N4O3 (m/e) 392, obsd 393 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[C:17]3[CH:16]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[C:22]([CH2:24][CH3:25])[CH:23]=4)[N:14]=[CH:13][C:12]=3[CH:11]=[N:10]2)=[N:6][C:7]=1F.[NH:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:27]1.CN1CCOCC1.O>CN1CCCC1=O>[Cl:1][C:2]1[C:7]([N:26]2[CH2:31][CH2:30][CH2:29][C@H:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH2:27]2)=[N:6][C:5]([N:9]2[C:17]3[CH:16]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[C:22]([CH2:24][CH3:25])[CH:23]=4)[N:14]=[CH:13][C:12]=3[CH:11]=[N:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: CCc1cncc(-c2cc3c(cn2)cnn3-c2ccc(Cl)c(F)n2)c1
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1cncc(-c2cc3c(cn2)cnn3-c2ccc(Cl)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)c1
Temperature: 100 °C
Yield: 80.5 %

Procedure:
A mixture of 1-(5-chloro-6-fluoro-2-pyridyl)-6-(5-ethyl-3-pyridyl)pyrazolo[4,3-c]pyridine (0.155 mmol; 54.9 mg), tert-butyl N-[(3S)-3-piperidyl]carbamate (0.466 mmol; 93.2 mg), and N-Methylmorpholine (1.55 mmol; 159 mg; 0.172 mL) in 1-Methyl-2-pyrrolidinone (3 mL) in a sealed pressure vial was heated at 100° C. overnight. The mixture was poured into water. The precipitate was collect by filtration and dried on high vacuum to afford tert-butyl N-[(3S)-1-[3-chloro-6-[6-(5-ethyl-3-pyridyl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate (66.6 mg, 80%), which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[C:22](O)(=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1>>[CH3:30][O:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[C:22]([N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:2]2([CH3:1])[CH2:6][C:5]3[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=3[O:3]2)[CH2:17][CH2:18]1)=[O:31]
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCNCC1)O2
Reactant: COc1cccc(C(=O)O)c1
Product: COc1cccc(C(=O)N2CCN(CC3(C)Cc4c(C)c(N)c(C)c(C)c4O3)CC2)c1
Yield: 73 %

Procedure:
Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl)methyl]-5-benzofuranamine and m-anisic acid, the procedure of Example 10, presented hereinafter, was otherwise followed to provide the title compound. Yield 73%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[S:17])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Br:16])[CH:10]=2)=[N:4][S:5][N:6]=1.F[C:19](F)(F)S(OC)(=O)=O.C(N(CC)C(C)C)(C)C>ClCCl>[NH2:1][C:2]1[C:3]([C:7]([S:17][CH3:19])=[N:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Br:16])[CH:10]=2)=[N:4][S:5][N:6]=1
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: Nc1nsnc1C(=S)Nc1ccc(F)c(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSC(=Nc1ccc(F)c(Br)c1)c1nsnc1N
Reaction time: 1 h
Yield: 95.8 %

Procedure:
A solution of 4-amino-N-(3-bromo-4-fluorophenyl)-1,2,5-thiadiazole-3-carbothioamide (130 mg, 0.4 mmol) in dichloromethane (5.2 mL) was treated with methyl trifluoromethanesulfonate (64 μL, 0.6 mmol) followed by N,N-diisopropylethylamine (102 μL, 0.6 mmol) and stirred for 1 h. The reaction mixture was diluted with dichloromethane (100 mL), washed with water (50 mL) and brine (50 mL), dried with sodium sulfate, filtered, and concentrated to give the desired product (133 mg, 98%). LCMS for C10H9BrFN4S2 (M+H)+: m/z=346.8, 348.8.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:28]([OH:30])=O)[CH2:20][CH2:19][N:18]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:31][N:32]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.NO>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:28]([NH:32][OH:31])=[O:30])[CH2:20][CH2:19][N:18]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(S(=O)(=O)C(F)(F)F)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)NO)CCN(S(=O)(=O)C(F)(F)F)CC2)cc1

Procedure:
4-(4-but-2-ynyloxy benzenesulfonyl)-N-hydroxy-1-[(trifluoromethyl)sulfonyl]-4-piperidinecarboxamide was prepared following the procedure Example 64 (step 6). Starting from 4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(trifluoromethyl)sulfonyl]-4-piperidinecarboxylic acid (145 mg, 0.31 mmol) in dimethylformamide (3 ml), 1-hydroxybenzotriazole (50 mg, 0.37 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (83 mg, 0.47 mmol), N-methylmorpholine (0.051 ml, 0.47 mmol), and hydroxylamine (0.095 ml, 1.55 mmol), 90 mg (60%) of the product was isolated as a solid. HR—MS: m/z Calculated for C17H19F3N2O7S2 485.0659; Found 485.0666.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=2)[N:7]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:20]=2)[N:7]=1
Reactant: COC(=O)CCc1nc(C#Cc2ccc(CC(=O)OC)cc2)ccc1O
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1nc(CCc2ccc(CC(=O)OC)cc2)ccc1O
Yield: 52.6 %

Procedure:
Under the conditions of example 14 A, a solution of 500 mg of 3-{3-hydroxy-6-[2-(4-methoxycarbonylmethylphenyl)-ethinyl]-2-pyridyl}-propionic acid-methyl ester in 5 ml of methanol is hydrogenated in the presence of 50 mg of 10% palladium catalyston activated carbon and worked up. The crude product is chromatographed on silica gel with hexane/0-30% ethyl acetate. 266 mg of 3-{3-hydroxy-6-[2-(4-methoxycarbonylmethylphenyl)-ethyl]-2-pyridyl}-propionic acid-methyl ester of melting point 90°-91° is obtained.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:25]I.[Br:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH2:35][CH2:36]O>C(Cl)Cl>[Br:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH2:35][CH2:36][I:25]
Reactant: II
Reactant: OCCc1ccc(F)cc1Br
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(CCI)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
A solution of Ph3P (2.57 g, 9.81 mmol) and imidazole (0.668 g, 9.81 mmol) in DCM (50 mL) was cooled to 0° C. Added to this was iodine (2.489 g, 9.81 mmol) and the resulting mixture was stirred at 0° C. for 30 min. 2-(2-Bromo-4-fluorophenyl)ethanol (1.79 g, 8.17 mmol) was added portionwise over several minutes and the resulting mixture was stirred at room temp. After 16 h, the mixture was filtered washing the solids with DCM. The filtrate was washed with aq Na2S2O3 and the organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-100% EtOAc/hexane; 20 CV) to give 2-bromo-4-fluoro-1-(2-iodoethyl)benzene (2.4 g, 7.30 mmol, 89% yield) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.33 (dd, J=8.2, 2.7 Hz, 1H), 7.25 (dd, J=8.5, 5.8 Hz, 1H), 7.02 (td, J=8.2, 2.6 Hz, 1H), 3.41-3.35 (m, 2H), 3.32-3.26 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)#[CH:18]>>[C:19]1([C:17]#[C:18][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: C#Cc1cccc2ccccc12
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: O=c1[nH]c2nccc(C#Cc3cccc4ccccc34)c2c2ccccc12
Yield: 66.5 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using 83 (100 mg, 0.43 mmol) and 1-ethynylnaphthalene (0.09 mL, 0.65 mmol) to provide 253 (99 mg, 66% yield) as a tan solid. LC-MS (M+H=347 obsd.=347). 1H NMR (400 MHz, d6-DMSO): δ 12.25 (s, 1H), 9.89 (d, 1H), 8.55 (d, 1H), 8.46 (d, 2H), 8.16 (d, 1H), 8.10 (m, 2H), 8.01 (m, 1H), 7.75 (m, 5H).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[F:9][C:10]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:11]=1[NH2:12].C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[ClH:2].[F:9][C:10]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:11]=1[N:12]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: Nc1cc(F)ccc1F
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: Fc1ccc(F)c(N2CCNCC2)c1

Procedure:
7.0 g of bis(2-chloroethyl)amine hydrochloride was suspended in 60 ml of butanol and 5 g of 2,5-difluoroaniline was added thereto at room temperature. After heating under reflux for 72 hours, the reaction mixture was cooled and 4.1 g of sodium carbonate was added. After heating under reflux for additional 24 hours, the precipitate was taken up by filtration, dissolved in water and extracted with chloroform. Then the extract was washed successively with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was dissolved in a small amount of chloroform, converted into hydrochloride by adding a 4N hydrochloric acid/dioxane solution and filtered to thereby give 2.39 g mg of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]([C@H:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[OH:17])=[CH:10][CH:9]=[N:8]1.[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[CH2:20]([O:17][C@H:13]1[CH2:14][CH2:15][CH2:16][C@@H:12]1[C:11]1[N:7]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[N:8]=[CH:9][CH:10]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O[C@H]1CCC[C@@H]1c1ccnn1C1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(CO[C@H]2CCC[C@@H]2c2ccnn2C2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 85.3 %

Procedure:
To a solution of the (1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclopentanol (975 mg, 4.13 mmol) prepared in Example 138a in DMF (20 mL), sodium hydride (63%; 236 mg, 6.19 mmol) and benzyl bromide (0.735 mL, 6.19 mmol) were added, and the reaction solution was stirred at room temperature for 7 hours. To the reaction solution, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was washed twice with water (50 mL) and dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=7:3) to yield the title compound (1.15 g, 57%) in the form of a diastereomeric mixture as a colorless oil.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:8][N:7]=[C:6]([C:9](=[O:16])[CH:10](SC)[S:11]([CH3:13])=O)[N:5]=1)=[O:2].I([O-])(=O)(=O)=[O:18].[Na+]>C(O)(=O)C>[CH:1]([NH:3][C:4]1[S:8][N:7]=[C:6]([C:9](=[O:16])[C:10]([S:11][CH3:13])=[O:18])[N:5]=1)=[O:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSC(C(=O)c1nsc(NC=O)n1)S(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CSC(=O)C(=O)c1nsc(NC=O)n1
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 129.5 %

Procedure:
A mixture of 5-formamido-3-(2-methylthio-2-methylsulfinylacetyl)-1,2,4-thiadiazole (0.85 g) and sodium periodate (0.2 g) in glacial acetic acid (10 ml) was stirred for 45 minutes at 70° C. The reaction mixture was evaporated and the residue was dissolved in a mixture of ethyl acetate and water. The mixture was adjusted to pH 7 with an aqueous solution of sodium bicarbonate and treated with an aqueous solution of sodium thiosulfate. The organic layer was separated, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with a mixture of diethyl ether and petroleum ether to give the title compound (280 mg), mp. 186° to 187° C.
Reaction SMILES: [Cl:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[Na].[CH3:10][SH:11].O>C(O)C>[CH3:10][S:11][C:2]1([Cl:1])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8]
Reactant: CS
Reactant: O=C1CCCCC1Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CSC1(Cl)CCCCC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
In a 300-ml egg-plant type flask 7.07 g (0.053 mol) of 2-chlorocyclohexanone was dissolved in 50 ml of ethanol, and 25 ml of 15 % aqueous solution of sodium salt of methylmercaptan was added dropwise with a dropping funnel, and the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into 300 ml of water, and an organic layer was extracted with methylene chloride, dried with magnesium sulfate and distilled to remove methylene chloride. After that reduced pressure distillation was performed to obtain 6.0 g of methylmercapto-2-chlorocyclohexanone (78 % yield; b.p. 46.5° -47.5° C./0.3 mmHg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:17][CH2:18]OS(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([O:8][CH2:18][F:17])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCF)cc1
Reactant: N#Cc1ncc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ncc(OCF)cc1Cl
Temperature: 80 °C

Procedure:
To a solution of 3-chloro-5-hydroxy-pyridine-2-carbonitrile (315 mg, 2.03 mmol) in DMF (16 ml) was added Cs2CO3 (1.652 g, 5.07 mmol) and toluene-4-sulfonic acid fluoromethyl ester (CAS registry 114435-86-8) (621 mg, 3.04 mmol) and the reaction mixture was heated at 80° C. for 24 h. The solvent was removed under reduced pressure and the residue taken up in TBME, washed with water and brine, dried over MgSO4, filtered and concentrated. The title compound was obtained as a yellow oil after chromatography on silica gel (hexane-EtOAc 10:1 to 2:1) to provide the title compound as a light yellow oil: TLC (hexane-EtOAc 1:1): Rf=0.62;
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20]([NH:22][C:23]3[C:32]4[O:31][C:30]([C:33]([O:35]CC)=[O:34])=[CH:29][C:28](=[O:38])[C:27]=4[CH:26]=[CH:25][CH:24]=3)=[O:21])[CH:16]=2)[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20]([NH:22][C:23]3[C:32]4[O:31][C:30]([C:33]([OH:35])=[O:34])=[CH:29][C:28](=[O:38])[C:27]=4[CH:26]=[CH:25][CH:24]=3)=[O:21])[CH:16]=2)[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(=O)c2cccc(NC(=O)c3ccc4c(c3)CCC(COCc3ccccc3)O4)c2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1cccc2c(=O)cc(C(=O)O)oc12)c1ccc2c(c1)CCC(COCc1ccccc1)O2
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 96.9 %

Procedure:
A suspension of ethyl 8-[2-(benzyloxymethyl)chromane-6-carboxamido]-4-oxo-4H-1-benzopyran-2-carboxylate (0.240 g, 0.47 mmol) in a mixture of methanol (15 ml) and tetrahydrofuran (15 ml) was added with 0.510 ml of a 1M NaOH solution, stirring at room temperature for 1.30 h. After that the mixture was evaporated to dryness and the resulting residue was suspended in water adding 0.2M hydrochloric acid to slightly acid pH (pH=4-5). The solid was recovered by filtration, washed with methanol and dried on phosphorous pentoxyde under vacuum, thereby obtaining 0.221 g of the title compound as a white solid which decomposes above 283° C. (97% yield).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:27])[CH2:14][C:15]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=2)=O)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+].Cl.[NH2:31]O.Cl>C(O)C.O>[CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:27][N:31]=[C:15]([C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc(C(=O)CC(=O)c2ccc(C(=O)OC)cc2)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)O)cc3)no2)cc1
Temperature: 25 °C
Yield: 23.1 %

Procedure:
To 92 mg (0.26 mmol) methyl 4-[3-(4-pentyloxyphenyl)-3-oxopropanoyl]benzoate in 10 mL ethanol was added 146 mg (3.63 mmol) sodium hydroxide and 500 mg (7.25 mmol) hydroxylamine hydrochloride in 2 mL water. The solution was refluxed for 7 h. After cooling to room temperature, 1 M hydrochloric acid was added and the precipitate formed was filtered off and washed with water. Upon drying, the product was obtained as a white solid (22 mg, 0.06 mmol, 23%). 1H NMR (D6-acetone, 500 MHz): δ=8.18 (d, 2H, J=8.6 Hz), 8.06 (d, 2H, J=8.5 Hz), 7.89 (d, 2H, J=8.6 Hz), 7.30 (s, 1H), 7.11 (d, 2H, J=8.6 Hz), 4.08 (t, 2H, J=7.3 Hz), 1.82 (m, 2H), 1.47 (m, 4H), 0.93 (t, 3H, J=7.3 Hz). HPLC: 4.641 min.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na].[C:10](Cl)(=[O:14])[C:11]([CH3:13])=[CH2:12]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[C:10]([N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8])(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C1CCCCCN1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: C=C(C)C(=O)N1CCCCCC1=O

Procedure:
74 g of ε-caprolactam in 700 ml dry toluene is heated with 9.5 g of sodium at 90°-95° C. When all of the sodium metal has reacted, 43 ml of methacryloyl chloride in 50 ml dry benzene is added dropwise into the voluminous caprolactam salts at 4°-6° C. The mixture is then poured into a separatory funnel, washed with 200 ml water, 200 ml of sodium dicarbonate solution, and again with 20 ml water. The organic compounds are extracted with ether from the water phase, and the ether solution and benzene solution are dried over CaCl2 and the solvent evaporated under reduced pressure. The product, N-methacryloylcaprolactam, comes off at 90° C./2 mm hg. The yield is 32.3 g (42.8% based on sodium).
Reaction SMILES: C1(/C=[CH:8]/[C:9]2[N:10]=[CH:11][C:12]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:13]=3[N:14]=2)C=CC=CC=1.CSC.CN(C=[O:27])C>CO>[O:19]=[C:16]1[NH:15][C:13]2[N:14]=[C:9]([CH:8]=[O:27])[N:10]=[CH:11][C:12]=2[CH2:18][CH2:17]1
Reactant: CN(C)C=O
Reactant: O=C1CCc2cnc(/C=C/c3ccccc3)nc2N1
Solvent: CSC
Solvent: CO
Product: O=Cc1ncc2c(n1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
To a round bottom flask was added 2-[(E)-2-phenylethenyl]-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (600 mg, 2.39 mmol) in DMF (10 mL) and methanol (10 mL). Ozone was bubbled through the solution at room temperature for 20 minutes and the excess ozone was purged with a stream of nitrogen. Dimethyl sulfide (1.77 mL, 23.9 mmol) was added and the reaction was stirred at room temperature for 24 h. The solvent was evaporated and the resulting solid was dissolved in 20% MeOH-DCM. The crude product was added to a silica gel column and was eluted with 0-20% MeOH-DCM. The collected fractions gave the title compound (400 mg, 95% yield).
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:19]1([C:25]2[N:29]=[C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([N:33]2[CH2:34][CH2:35][N:30]([C:28]3[S:27][N:26]=[C:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:29]=3)[CH2:31][CH2:32]2)=[O:11])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 18 %

Procedure:
Prepared in analogy to example 1 (b) from 2-morpholin-4-yl-5-nitro-benzoic acid (Example A27) and 3-phenyl-5-piperazino-1,2,4-thiadiazole. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a yellow solid (yield 18%). MS (m/e): 481.0 (M+H+, 100%).
Reaction SMILES: C(=O)(O)[O-].[Na+].N[C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:20])[C:9]=2[CH:8]=1.ClCC(Cl)=O>C(OCC)(=O)C>[CH:12]1[C:11]2[C:10](=[O:20])[C:9]3[C:17](=[CH:18][CH:19]=[CH:7][CH:8]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc2c(c1)C(=O)c1ccccc1-2
Agent: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.8 %

Procedure:
A saturated solution of sodium bicarbonate (5 mL) was added to a solution of 2-amino-9-fluorenone (190 mg. 0.97 mmol) in ethyl acetate (5 mL). Next, chloroacetyl chloride (0.4 mL, 4.8 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The ethyl acetate layer was separated, and washed thoroughly with cold water. It was then dried under vacuum to give 2-N-chloroacetyl)-9-fluorenone (185 mg, 70%).