Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([CH3:13])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[CH3:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(N(CC)CC)C>[C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:29](=[O:30])[NH:28][C:25]3[CH:26]=[CH:27][C:22]([S:21][CH3:20])=[CH:23][CH:24]=3)[C:9]([CH3:13])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=NN(c2ccccc2)C(=O)C1
Reactant: CSc1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CSc1ccc(NC(=O)C2C(=O)N(c3ccccc3)N=C2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of 2.6 g of 1-phenyl-3-methyl-2-pyrazolin-5-one, 75 ml of benzene, 1.8 g of triethylamine and 2.5 g of p-methylthiophenylisocyanate is stirred at ambient temperature and allowed to stand overnight. It is evaporated; the residue taken up in methanol, the solution is filtered and combined with the mixture of 10 ml of 5 N hydrochloric acid and 250 ml of water. The precipitate formed is collected, washed with water, dried, triturated with diethyl ether and dissolved in 2 N aqueous sodium hydroxide. The solution is filtered, acidified with 5 N hydrochloric acid, the precipitate washed with water, dried, triturated with methanol and recrystallized from ethyl acetate, to yield the 1-phenyl-3-methyl-4-(p-methylthiophenylcarbamoyl)-2-pyrazolin-5-one melting at 196°-199°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:13]2)=[CH:8][CH:9]=1
Reactant: COC(=O)C1CC(c2ccc([N+](=O)[O-])cc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(c2ccc(N)cc2)C1

Procedure:
A solution of this nitro compound (750mg.) in ethyl acetate (20ml.) was stirred for 16 hours with a 5% palladium on carbon catalyst (250mg.) in an atmosphere of hydrogen. The solution was filtered through a pad of "Hyflo" and evaporated to give methyl 3-(4-aminophenyl)cyclobutanecarboxylate. A solution of this amine (800mg.) in dry benzene (20ml.) was stirred under argon at room temperature during the dropwise addition of amyl nitrite (0.755ml.). The temperature of the reaction mixture was slowly (over 21/2 hours) raised to its boiling point and the mixture was then refluxed for 1 hour. The solvent was evaporated under reduced pressure and the residue was chromatographed on a dry column of silica gel `MFC` (supplied commercially by Hopkin and Williams) (25g.), eluting with toluene to give a mixture of cis and trans isomers of methyl 3-(4-biphenylyl)cyclobutanecarboxylate, RF = 0.70 (9:1 v/v toluene/ethyl acetate). The n.m.r. spectrum in deuteriochloroform showed the following characteristic features (δ values):
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][C:17]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][C:17]=1[O:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(Cl)c(OCc2ccc(F)cc2)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)c(OCc3ccc(F)cc3)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-3-[(4-fluorophenyl)methoxy]phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.10 (2H, s), 5.18 (2H, s), 5.68 (1H, d, J=1.6 Hz), 6.97 (1H, dd, J=1.2 Hz, 8.0 Hz), 7.03-7.07 (3H, m), 7.39-7.43 (4H, m), 7.55 (1H, d, J=1.6 Hz), 8.04 (1H, s), 8.67 (1H, d, J=5.2 Hz). [M+H] Calc'd for C23H16ClFN4O2, 435. Found, 435.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:21][CH2:20]1>>[CH:19]1([NH:22][C:23]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([C:2]3[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=4)=[O:7])=[CH:4][N:3]=3)[CH:25]=2)=[O:40])[CH2:20][CH2:21]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Product: COc1ccc(NC(=O)c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)nc2)cc1

Procedure:
6-[5-Cyclopropylcarbamoyl-2-methyl-phenyl]-N-(4-methoxyphenyl)-nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (Intermediate 2) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 8) using General Method B. LCMS: retention time 2.96 min, MH+ 402.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=2)[C:23]([N:25]([CH2:27][CH2:28][OH:29])[CH3:26])=[O:24])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([F:33])[CH:3]=1.Cl.[NH2:35][OH:36].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=2)[C:23]([N:25]([CH2:27][CH2:28][OH:29])[CH3:26])=[O:24])[CH2:9]/[C:10](=[N:35]\[OH:36])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([F:33])[CH:3]=1
Reactant: NO
Reactant: CN(CCO)C(=O)c1cccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccc(Cl)cc2F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(CCO)C(=O)c1cccc(C(C/C(=N\O)c2ccc(=O)n(C)c2)c2ccc(Cl)cc2F)c1

Procedure:
In analogy to example 151, step 3, 3-(1-(4-chloro-2-fluorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-N-(2-hydroxyethyl)-N-methylbenzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid containing 7% of the corresponding Z isomer, MS (ESI+): m/z=486.4 [M+H]+.
Reaction SMILES: CS[C:3]([N:7]1[N:11]=[CH:10][C:9]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8]1)=[N:4][CH2:5][CH3:6].[C:16]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)(=[O:18])[CH3:17]>C(#N)C>[CH2:8]1[C:9]2([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH:10]=[N:11][N:7]1[C:3](=[N:29][S:26]([C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:16](=[O:18])[CH3:17])=[CH:25][CH:24]=1)(=[O:27])=[O:28])[NH:4][CH2:5][CH3:6]
Reactant: CCN=C(SC)N1CC2(C=N1)CCCC2
Reactant: CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Solvent: CC#N
Product: CCNC(=NS(=O)(=O)c1ccc(NC(C)=O)cc1)N1CC2(C=N1)CCCC2
Yield: 0.1 %

Procedure:
157 mg (1 mol equiv.) N-Ethyl-2,3-diaza-spiro[4.4]non-3-ene-2-carboximidothioic acid methyl ester and 157 mg (1.05 mol equiv.) 4-acetamidobenzenesulfonamide were taken up in 5 mL acetonitrile. The reaction mixture was refluxed overnight under magnetic stirring and volatiles were removed in vacuo. The residue was taken up in ethyl acetate and extracted with 2N NaOH. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Purification by flash chromatography on silica gel (ethyl acetate) afforded 236 mg (87%) of N-(4-{[(2,3-diaza-spiro[4.4]non-3-en-2-yl)-ethylamino-methylene]-sulfamoyl}-phenyl)-acetamide. 1H NMR (400 MHz, CDCl3) δ 1.14 (t, J=7.2 Hz, 3H), 1.62-1.83 (m, 8H), 2.20 (s, 3H), 3.43-3.51 (m, 2H), 3.80 (s, 2H), 6.80 (s, 1H), 6.87 (br.s., 1H), 7.56 (d, J=8.8 Hz, 2H), 7.77 (br.s., 1H), 7.83 (d, J=8.8 Hz, 2H).
Reaction SMILES: [SH2:1].[Na].CS(O[CH:8]([CH2:10][CH:11]([S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH:12]=[O:13])[CH3:9])(=O)=O.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:9][CH:8]1[S:1][CH:12]([OH:13])[CH:11]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10]1
Reactant: CC(CC(C=O)Sc1ccccn1)OS(C)(=O)=O
Reactant: S
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1CC(Sc2ccccn2)C(O)S1
Yield: 25456.4 %

Procedure:
0.74 g of sodium hydrogen sulfide (Wako Pure Chemical Industries, Ltd.) was added to a solution of 0.60 mg of 5-oxo-4-(pyridin-2-ylsulfanyl)pentan-2-yl methanesulfonate in 10 mL of N,N-dimethylformamide at a temperature of 0° C. to 10° C., and the obtained mixture was then stirred at the same temperature as described above for 1.5 hours. Thereafter, 30 mL of ethyl acetate and 30 mL of a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture, and the water layer was then removed. The organic layer was successively washed with 30 mL of water and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=5/1), so as to obtain 120 mg of 5-methyl-3-(pyridin-2-ylsulfanyl)thiolan-2-ol in the form of a light yellow oily product.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=O)[CH2:11][C:12](=O)[CH:13]([F:15])[F:14].Cl.[S:19]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1)(=[O:22])(=[O:21])[NH2:20]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:29]([C:26]2[CH:25]=[CH:24][C:23]([S:19]([NH2:20])(=[O:22])=[O:21])=[CH:28][CH:27]=2)[N:30]=[C:12]([CH:13]([F:15])[F:14])[CH:11]=1
Reactant: O=C(CC(=O)C(F)F)c1nc2ccccc2s1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2-c2nc3ccccc3s2)cc1
Yield: 37 %

Procedure:
The procedure of Example 9 was repeated using 1-(benzothiazol-2-yl)-4,4-difluorobutane-1,3-dione and 4-sulfamoylphenylhydrazine hydrochloride as the starting materials to obtain 4-[5-(benzothiazol-2-yl)-3-difluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide (yield, 37%). NMR(CDCl3 -DMSO-d6) δ: 6.86 (1H, t, J=54.5 Hz), 7.12 (2H, s), 7.25 (1H, s), 7.43-7.66 (4H, m), 7.92-8.06 (4H, m); mp 247-249° C. (DMF-ethanol)
Reaction SMILES: [OH:1][CH:2]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[CH2:3][NH:4][C:5]1[N:10]([CH3:11])[C:9](=[O:12])[C:8]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[C:7]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[N:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][C:2](=[O:1])[CH2:3][NH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[C:8]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)=[C:7]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[N:6]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc(CC(O)CNc2nc(-c3ccncc3)c(-c3ccc4ccccc4c3)c(=O)n2C)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc(CC(=O)CNc2nc(-c3ccncc3)c(-c3ccc4ccccc4c3)c(=O)n2C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of 2-[2-hydroxy-3-(4-methoxy-phenyl)-propylamino]-3-methyl-5-naphthalen-2-yl-6-pyridin-4-yl-3H-pyrimidin-4-one (765 mg, 1.55 mmol) in 20 mL dichloromethane was added Dess-Martin Periodinane (660 mg, 1.55 mmol). The dark red solution was stirred for 18 h at room temperature. The reaction mixture was diluted with 80 mL dichloromethane and washed twice with 15 mL 5% sodium bicarbonate, and dried over magnesium sulfate. The product was purified on 40 g silica eluting with 0 to 4% methanol/dichloromethane to provide the product as a yellow foam. The product was further purified on reverse phase high performance chromatography using an water/acetonitrile (0.1% TFA) gradient. The final sample was lyophilized from 50% acetonitrile/water to give a yellow powder. M+1=491.2.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1.[CH3:16]I>CN(C=O)C.O>[CH3:16][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(C)c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.3 %

Procedure:
NaH (60% dispersion in mineral oil, 8.56 g, 214.0 mmole) was added portionwise, allowing for gas evolution, to a solution of methyl 1H-indole-3-carboxylate (25.00 g, 142.7 mmole) in DMF (350 mL) at 0° C. When the NaH addition was complete, methyl iodide (44.4 mL, 713.5 mmole) was added at 0° C. The reaction was stirred at 0° C. for 15 minutes then at RT overnight. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were dried over K2CO3 and concentrated to afford the title compound (26.00 g, 96%) as an orange solid: MS (ES) m/e 190 (M+H)+.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[C:34]([F:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[C:34]([F:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1
Reactant: CC(C)c1nc2ncnc(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)c2cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc2ncnc(Nc3cc(C(=O)O)ccc3Sc3ccc(N)cc3)c2cc1F
Reaction time: 1 h
Yield: 69.1 %

Procedure:
The product of Example 451C (0.23 g, 0.4 mmo) in CH2Cl2 (4.6 mL) was treated with trifluoroacetic acid [TFA] (1.15 mL) dropwise at room temperature then stirred for 1 hour. The reaction mixture was concentrated. The residue was diluted with water, made basic with K2CO3, stirred at room temperature overnight. The pH was adjusted to pH 5-6 with 1N HCl stirred at room temperature for 1 hour, the resulting precipitate was collected by filtration, washed with water and i-Pr2O, and dried at 40° C. in vacuum overnight to give the title compound as yellow crystal (0.13 g, 71%). 1H-NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=7.0 Hz, 6H), 3.42-3.60 (m, 1H), 5.64 (br-s, 2H), 6.64 (d, J=8.4 Hz, 2H), 6.84 (d, J=7.7 Hz, 1H), 7.14 (d, J=8.4 Hz, 2H), 7.73 (br-d, J=7.7 Hz, 1H), 7.83 (br-s, 1H), 8.58 (s, 1H), 8.65-8.80 (m, 1H), 10.10 (s, 1H), 12.91 (br-s, 1H). MS ESI+m/z: 450 (M+H), ESI− m/z: 448 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[S:21]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(C2CCCN2)cc1Cl
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=S(=O)(c1ccc(F)cc1)N1CCCC1c1ccc(F)c(Cl)c1

Procedure:
The title compound, white solid, m.p. 116° C. and MS: m/e=358.1 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(3-chloro-4-fluoro-phenyl)-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[O:15])=[CH:9][CH:8]=1)[CH3:5].[CH2:17]([OH:20])[CH2:18][OH:19]>O>[CH3:1][O:2][C:3](=[O:16])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:19][CH2:18][CH2:17][OH:20])=[O:15])=[CH:9][CH:8]=1)[CH3:5]
Reactant: COC(=O)C(C)Oc1ccc(N=C=O)cc1
Reactant: OCCO
Solvent: O
Product: COC(=O)C(C)Oc1ccc(NC(=O)OCCO)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(4-Isocyanatophenoxy)-propionic acid methyl ester 11 (20 g, 90.49 mmol) was added to ethylene glycol (40 ml) at room temperature. The reaction was exothermic and the temperature rose to 58° C. This was followed by stirring at room temperature for 16 hours. Water (150 ml) was added and crude 12 was extracted in to chloroform, washed with water (2×50 ml), dried over sodium sulphate and distilled. Crude 12 was purified by column chromatography on silica gel using chloroform as eluant to get pure 12 (13 g; 50.76%) as a syrup which crystallized in 48 hours as a white powder with an m.p between 90.5-92.8° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:11][CH2:12][C:13]1[NH:14][C:15](=[O:23])[C:16]2[CH2:22][O:21][CH2:20][CH2:19][C:17]=2[N:18]=1)[CH3:10].[F:24][C:25]1[CH:42]=[CH:41][C:28]([C:29]([CH:31]2[CH2:36][CH2:35][N:34]([CH2:37][C:38](O)=[O:39])[CH2:33][CH2:32]2)=[O:30])=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([N:11]([CH2:12][C:13]1[NH:14][C:15](=[O:23])[C:16]2[CH2:22][O:21][CH2:20][CH2:19][C:17]=2[N:18]=1)[C:38](=[O:39])[CH2:37][N:34]1[CH2:35][CH2:36][CH:31]([C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([F:24])=[CH:42][CH:41]=2)[CH2:32][CH2:33]1)[CH3:10]
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: CC(NCc1nc2c(c(=O)[nH]1)COCC2)c1ccc(F)cc1F
Product: CC(c1ccc(F)cc1F)N(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following general procedure of Example 4, the title compound was prepared (43.3 mg) from 2-((1-(2,4-difluorophenyl)ethylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C30H31F2N4O4 568.6. found 569.4 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.80-8.00 (m, 2H) 7.23-7.41 (m, 1H) 7.11 (t, J=8.59 Hz, 3H) 6.81-6.95 (m, 2H) 6.67-6.81 (m, 2H) 6.41-6.61 (m, 1H) 4.32-4.58 (m, 4H) 4.17-4.32 (m, 1H) 3.70-3.96 (m, 4H) 3.47 (d, J=11.12 Hz, 1H) 3.15-3.37 (m, 1H) 3.09 (br. s., 1H) 2.62 (br. s., 1H) 2.50 (br. s., 1H) 2.36 (br. s., 1H) 2.14 (br. s., 2H) 2.04 (s, 1H) 1.60 (d, J=6.57 Hz, 1H) 1.39 (d, J=6.57 Hz, 2H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([N+:13]([O-])=O)=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=2)[O:2]1.[CH3:16]N>C(O)C>[CH3:16][NH:13][C:5]1[CH:4]=[C:3]2[O:2][CH2:1][O:9][C:8]2=[CH:7][C:6]=1[N+:10]([O-:12])=[O:11]
Reactant: CN
Reactant: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OCO2
Solvent: CCO
Product: CNc1cc2c(cc1[N+](=O)[O-])OCO2

Procedure:
0.05 mol (10.6 g) of 4,5-methylenedioxy-1,2-dinitrobenzene is added to 40 ml of a 33% strength solution of methylamine in absolute ethanol to which 20 ml of 96° strength ethanol have been added. The reaction edium is heated under reflux for 30 minutes. After dilution with 150 ml of ice-cold water, the expected product precipitates. After being drained and washed with water, it is recrystallized from a mixture of ethanol and acetone. It melts at 170° C. (literature 171° C.).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)[CH3:2].C[N:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=C([N+]([O-])=O)C1=O.N>>[CH2:1]([N:3]1[CH2:8][CH2:7][C:6]2[N:11]=[CH:16][C:15]([N+:17]([O-:19])=[O:18])=[CH:14][C:5]=2[CH2:4]1)[CH3:2]
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Reactant: CCN1CCC(=O)CC1
Agent: N
Product: CCN1CCc2ncc([N+](=O)[O-])cc2C1
Yield: 92.8 %

Procedure:
1-Ethyl-4-piperidone (500 mg, 3.93 mmol) was mixed with 1-methyl-3,5-dinitro-2-pyridone (392 mg, 1.97 mmol) in 1M methanolic ammonia (40 mL, 40 mmol) and heated at reflux for 3 h. The solvent was evaporated off and the residue was suspended in CHCl3 and flash chromatographed over silica gel (32 g) eluting with EtOAc to afford an orange solid (379 mg, 93% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:29])=[C:6]([C:8]2[C:9]3[CH:19]=[CH:18][C:17](=[O:20])[N:16]([C:21]4[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=4[F:28])[C:10]=3[N:11]=[C:12]([S:14][CH3:15])[N:13]=2)[CH:7]=1.[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][C:32]=1[CH3:40]>>[F:27][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([F:28])[C:21]=1[N:16]1[C:10]2[N:11]=[C:12]([S:14][CH3:15])[N:13]=[C:8]([C:6]3[CH:7]=[C:2]([NH:1][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][C:31]([F:30])=[C:32]([CH3:40])[CH:33]=4)[CH:3]=[CH:4][C:5]=3[CH3:29])[C:9]=2[CH:19]=[CH:18][C:17]1=[O:20]
Reactant: CSc1nc(-c2cc(N)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: Cc1cc(C(=O)Cl)ccc1F
Product: CSc1nc(-c2cc(NC(=O)c3ccc(F)c(C)c3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1

Procedure:
The title compound was prepared as described in Example 7b from 4-(5-amino-2-methylphenyl)-8-(2,6-difluorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one and 4-fluoro-3-methylbenzoyl chloride: LC-MS m/z 547(M+H)+, 2.70 min (ret time).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]3)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[F:21][N+]1C=C(OC(F)(F)F)C=CC=1S([O-])(=O)=O>ClCCl>[F:21][C:16]1[C:17]2[C:12](=[CH:11][C:10]([C:7]3[CH:6]=[CH:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:9][CH:8]=3)=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:15]=1[OH:20]
Reactant: O=S(=O)([O-])c1ccc(OC(F)(F)F)c[n+]1F
Reactant: CCCc1ccc(-c2ccc3cc(O)ccc3c2)cc1
Solvent: ClCCl
Product: CCCc1ccc(-c2ccc3c(F)c(O)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.7 %

Procedure:
3.4 g of 4-propylphenylboric acid (obtained by reacting a Grignard reagent prepared from 1-bromo-4-propylbenzone with trimethyl borate, and then subjecting the product to hydrolysis with hydrochloric acid) and 25.5 g of 6-bromo-2-naphthol ware dissolved in a mixture of 92 ml of toluene, 46 ml of ethanol and 92 ml of water. To the solution were then added 25.5 g of potassium carbonate and 1.3 g of tetrakia (triphenyl phosphine) palladium (0). The reaction mixture was then stirred at a temperature of 75° C. for 7 hours. To the reaction solution were then added water and toluene. To the reaction solution was then added diluted hydrochloric acid until the aqueous phase became weakly acidic. The reaction solution was then extracted with toluene. The material thus extracted and the organic phase were together washed with water and then with saturated brine, and then dried over anhydrous sodium sulfate The solvent was then distilled off under reduced pressure to obtain 41.4 g of 6-(4-propylphenyl)naphthalone-2-ol. 12.7 g of 6-(4-propylphenyl)naphthalene-2-ol was then dissolved in 50 ml of dichloromethane. To the solution was then added 13.1 g of N-fluoro-5-trifluoromethoxypyridinium-2-sulfonate. The reaction mixture was then stirred at room temperature for 18 hours. The reaction mixture was post-treated in the same manner as mentioned above to obtain an oily matter which was then purified through silica gel column chromatography (hexane/ethyl acetate=9/1) to obtain 10 g of 1-fluoro-6-(4-propylphenyl)naphthalene-2-ol. The product was converted to S-ethyl dithiocarbonate which was then trifluoromethoxylated in the same manner as in Example 1 to obtain 2.3 g of the titled 1-fluoro-2-trifluoromethoxy-6-(4-propylphanyl)naphthalene.
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)=[CH:9][CH:10]=[C:5]2[O:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1B(O)O>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[C:2]1[C:6]2=[N:7][C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)=[CH:9][CH:10]=[C:5]2[O:4][CH:3]=1
Reactant: Cc1nnc(-c2ccc3occ(Br)c3n2)o1
Reactant: OB(O)c1cc(F)ccc1F
Product: Cc1nnc(-c2ccc3occ(-c4cc(F)ccc4F)c3n2)o1
Yield: 43 %

Procedure:
In the same manner as in Example 132 and using 3-bromo-5-(5-methyl-1,3,4-oxadiazol-2-yl)furo[3,2-b]pyridine instead of 2-(3-bromo-1-benzofuran-5-yl)-5-methyl-1,3,4-oxadiazole, using (2,5-difluorophenyl)boronic acid instead of (4-fluorophenyl)boronic acid, and using [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex instead of tetrakis(triphenylphosphine)palladium(0), the title compound (yield 43%) was obtained as colorless crystals.