Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(OP(Cl)(Cl)=O)=O.[N+:10]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2)([O-:12])=[O:11].N1([C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])CCCCC1>>[N+:10]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15]([C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16][NH:17]2)([O-:12])=[O:11]
Reactant: CCOC(=O)C(=O)N1CCCCC1
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Agent: O=P(Cl)(Cl)OP(=O)(Cl)Cl
Product: CCOC(=O)C(=O)c1c[nH]c2cccc([N+](=O)[O-])c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diphosphoryl chloride (23.5 mL, 170 mmol) was added dropwise to a stirred mixture of 4-nitroindole (25.0 g, 154 mmol) and ethyl 1-piperidineglyoxylate (29.0 g, 170 mmol) at 0° C. The mixture was allowed to warm slowly to ambient temperature and stirring was continued for 18 h. The reaction mixture was cooled to 0° C. and quenched carefully by addition of EtOH (50 mL), followed by saturated aqueous NaHCO3 until no further effervescence was observed. The precipitated yellow solid was isolated by filtration, washed with H2O, and dried in vacuo to give the title compound. MS: m/z=263 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[C:6]([OH:9])=[C:5]([CH:10](O)[C:11]([F:14])([F:13])[F:12])[N:4]([CH3:16])[C:3]=1[CH3:17].S(Cl)(Cl)=O.[BH4-].[Na+]>C(#N)C.CO>[Cl:1][C:2]1[C:7](=[O:8])[C:6]([OH:9])=[C:5]([CH2:10][C:11]([F:12])([F:13])[F:14])[N:4]([CH3:16])[C:3]=1[CH3:17]
Reactant: Cc1c(Cl)c(=O)c(O)c(C(O)C(F)(F)F)n1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: Cc1c(Cl)c(=O)c(O)c(CC(F)(F)F)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
3-Chloro-5-hydroxy-1,2-dimethyl-6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (300 mg, 1.10 mmol) was suspended in 10 mL of acetonitrile and thionyl chloride (398 μL, 5.50 mmol) was added dropwise. The reaction was stirred at room temperature. After 2 hours, the reaction was concentrated. The crude was diluted with 10 mL of methanol and sodium borohydride (329 mg, 8.80 mmol) was added in small portions. After 15 hours, the reaction was filtered and the filtrate was concentrated in vacuo. The resulting solid was dissolved in methanol and ethyl acetate added, filtered and concentrated. The crude product was purified by column chromatography on silica gel using a mixture of 30% EtOAc in MeOH as eluant. Fractions rich in product were combined and evaporated to dryness. The residue product was recrystallised from methanol/ethyl acetate to give 3-chloro-5-hydroxy-1,2-dimethyl-6-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (172 mg) as a white solid. Yield=61%; 1H NMR (MeOD-D4, 90 MHz) δ (ppm): 4.1 (q, J=9.0 Hz, 2H), 3.99 (s, 3H) and 2.77 (s, 3H); MS m/z 256 [M+1]+.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:67][N:68]1[CH2:73][CH2:72][N:71]([C:74]2[CH:81]=[CH:80][C:77]([CH:78]=O)=[CH:76][CH:75]=2)[CH2:70][CH2:69]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:78]([C:77]3[CH:76]=[CH:75][C:74]([N:71]4[CH2:70][CH2:69][N:68]([CH3:67])[CH2:73][CH2:72]4)=[CH:81][CH:80]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: CN1CCN(c2ccc(C=O)cc2)CC1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(-c3nc4c(N5CCN(Cc6cccnc6)CC5)c(Br)cnc4[nH]3)cc2)CC1
Reaction time: 6 h
Yield: 39.4 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenyl piperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (20 mg, 0.051 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.15 mmol, 0.15 mL) and 4-(4-methylpiperazino)benzaldehyde (1.1 eq, 0.056 mmol, 11 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (11 mg, 39%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.26 (s, 3H, CH3), 2.49 (s, br, 4H, piperazine N(CH2)2), 2.63 (s, br, 4H, piperazine N(CH2)2), 3.30 (hidden by DMSO peak, 4H, piperazine N(CH2)2), 3.62 (s, 2H, NCH2), 3.65 (t, J=4.2 Hz, 4H, piperazine N(CH2)2), 7.06 (d, J=8.7 Hz, 2H, phenyl H-3 & H-5), 7.40 (dd, J=7.7, 4.8 Hz, 1H, pyridine H-5), 7.79 (d, br, J=7.7 Hz, 1H, pyridine H-4), 8.03 (d, J=8.7 Hz, 2H, phenyl H-2 & H-6), 8.18 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.50 (d, J=4.5 Hz, 1H, pyridine H-6), 8.57 (s, br, 1H, pyridine H-2), 13.22 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.C([Mg]Br)(C)C.O.[CH2:14]1[CH2:18]O[CH2:16][CH2:15]1>>[N:2]1[C:3]2[C:4](=[CH:18][CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][CH:1]=1
Reactant: CN1CCCC1=O
Reactant: C1CCOC1
Agent: CC(C)[Mg]Br
Solvent: O
Product: c1ccc2ncccc2c1
Reaction time: 0.5 h

Procedure:
0.2 g (6.38×10−4 mol) of 1,1-dibromo-2-(2-quinolyl)ethene obtained from 2-formylquinoline, carbon tetrabromide (CBr4) and triphenylphosphine (PPh3) (Ramirez et al., J. Am. Chem. Soc., 1962, 84: 1745) and 11.28 mg (3.19×10−5 mol, 5 mol %) of iron triacetylacetonate (Fe(acac)3) are dissolved in 3 ml of anhydrous THF and 3 ml of anhydrous N-methylpyrrolidone (NMP) at −10° C., in a dry round-bottomed flask equipped with a magnetic stirrer and a nitrogen inlet. 0.39 ml (7.02×10−4 mol) of a 1.8M solution of isopropyl magnesium bromide in THF is added dropwise to the solution. After stirring for 30 minutes, the reaction is hydrolyzed with 10 ml of water and the solution is brought back to ambient temperature. Next, the two phases are separated and the aqueous phase is extracted with diethyl ether (3×30 ml).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][CH:25]=[CH:24][N:19]3[C:20](=[O:23])[C:21]=2I)[CH2:3][CH2:2]1.[CH:27](=O)C1C=CC=CC=1.[H-].[Na+]>CS(C)=O>[CH3:2][C:1]([CH3:3])([CH3:27])[CH2:4][O:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1/[CH:14]=[CH:15]/[C:16]1[N:17]=[C:18]2[S:26][CH:25]=[CH:24][N:19]2[C:20](=[O:23])[CH:21]=1
Reactant: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Reactant: O=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc(/C=C/c2cc(=O)n3ccsc3n2)c1OCC(C)(C)C
Yield: 177 %

Procedure:
This compound was prepared using Step 2 intermediate from Intermediate 2 (1.00 g, 2.160 mmol), [2-(2,2-dimethylpropoxy)-3-methoxy)]benzaldehyde (527 mg, 2.316 mmol) and NaH (92 mg, 2.685 mmol) in dry DMSO (10 ml) according to the procedure outlined in Intermediate 2, Step 3 to yield a crude residue which was purified by column chromatography using 2% ethyl acetate in chloroform to afford the 1.416 g of the desired compound as a white solid: 1H NMR (300 MHz, DMSO-d6) 1.08 (s, 9H), 3.56 (s, 2H), 3.79 (s, 3H), 6.26 (s, 1H), 7.01-7.17 (m, 2H), 7.33-7.35 (m, 1H), 7.46 (d, J=4.8 Hz, 1H), 7.97 (d, J=4.8 Hz, 1H), 8.11-8.16 (m, 1H); ESI-MS (m/z) 371.52 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H].I[CH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23](=[O:32])[N:24]2[CH3:31].Cl>ClCCl.O1CCCC1>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:19]([CH2:18][CH2:17][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[C:20]2[C:25]=1[N:24]([CH3:31])[C:23](=[O:32])[CH:22]=[CH:21]2
Reactant: [H][H]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc(CCI)c2ccc(=O)n(C)c12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C(CCc1ccc(OC)c2c1ccc(=O)n2C)C(=O)OCC

Procedure:
Sodium hydride (60% in oil) (0.5 g) was added under ice cooling to a tetrahydrofuran (THF) solution (30 ml) of diethyl malonate (2.2 ml), and stirring was carried out until the generation of hydrogen stopped. 5-(2-iodoethyl)-8-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline (1.54 g) was added, followed by stirring at room temperature overnight. The reaction mixture was added to cold hydrochloric acid, and extraction with dichloromethane was performed. After drying over anhydrous sodium sulfate, the dry product was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=50:1→40:1). The purified product was under reduced pressure to thereby obtain 1.73 g (yield: quantitative) of diethyl 2-[2-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]malonate as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([S:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13](O)=[O:14])[CH:4]=1)#[N:2].[BH4-].[Na+].O>S(Cl)(Cl)=O.O1CCOCC1>[OH:14][CH2:13][C:12]1[CH:11]=[C:10]([S:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][N:6]=2)[C:1]#[N:2])[CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1ccnc(Sc2cccc(C(=O)O)c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: N#Cc1ccnc(Sc2cccc(CO)c2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
Dissolve 3-(4-cyano-pyridin-2-ylsulfanyl)-benzoic acid (920 mg, 3.59 mmol) in thionyl chloride (50 mL) and stir. Heat to reflux. After 2 hours, concentrate under reduced pressure to give a residue. Dissolve residue in dioxane (100 mL) and add sodium borohydride (1.36 g, 35.9 mmol). Heat to 50° C. After 2 hours, cool to ambient temperature and add water. Extract with ethyl acetate, combine organic layers, dry with sodium sulfate, filter and concentrate to give the title compound as a yellow oil (378 mg, 44%): 1H NMR (DMSO-d6) δ 4.56 (d, 2H), 5.31 (t, 1H), 7.38 (m, 1H), 7.48 (m, 3H), 7.55 (m, 1H), 7.59 (dd, 1H), 8.62 (dd, 1H).
Reaction SMILES: [H-].[Na+].[C:3](=[N:6][OH:7])([NH2:5])[CH3:4].[C:8]1([CH2:18][C:19]([NH:21][C:22]2[CH:26]=[CH:25][S:24][C:23]=2[C:27](OC)=O)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1>C1COCC1.C(OCC)(=O)C>[CH3:4][C:3]1[N:5]=[C:27]([C:23]2[S:24][CH:25]=[CH:26][C:22]=2[NH:21][C:19](=[O:20])[CH2:18][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[O:7][N:6]=1
Reactant: COC(=O)c1sccc1NC(=O)Cc1cccc2ccccc12
Reactant: CC(N)=NO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1noc(-c2sccc2NC(=O)Cc2cccc3ccccc23)n1
Reaction time: 1 h

Procedure:
Sodium hydride (60% dispersion, 15 mg, 0.39 mmol) was added to a solution of acetamide oxime (29 mg, 0.39 mmol) in THF (1 mL). The resulting mixture was stirred at room temperature for 10 minutes after which a solution of methyl 3-(2-(naphthalen-1-yl)acetamido)thiophene-2-carboxylate (107 mg, 0.33 mmol) in THF (1 mL) was added. The reaction mixture was stirred for 1 h and was subsequently diluted with ethyl acetate (10 mL). The resulting solution was washed with brine (5 mL) and the organic phase was then dried (Na2SO4), filtered and concentrated under vacuum. The residue was dissolved in THF (1 mL) and HCl (1 mL of a 10% aqueous solution) was added. The mixture was stirred for 20 minutes after which ethyl acetate (10 mL) was added. The resulting solution was washed with brine (5 mL) and the organic phase was then dried (Na2SO4), filtered, concentrated under vacuum and the residue was purified by preparative HPLC to give N-(2-(3-methyl-1,2,4-oxadiazol-5-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide. Retention time (min)=9.533, method [7], MS(ESI) 350.1 (M+H). 1H NMR (300 MHz, CDCl3) δ 10.10 (s, 1H), 8.26 (d, J=5.4 Hz, 1H), 8.03 (d, J=9.3 Hz, 2H), 7.59-7.49 (m, 5H), 4.27 (s, 2H), 2.14 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:8][CH:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)=[N:4][CH:5]=[N:6][CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[C:29]1[S:30][CH:31]=[C:32]([C:34](O)=[O:35])[N:33]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[C:29]1[S:30][CH:31]=[C:32]([C:34]([NH:1][C:2]2[C:3]([O:8][CH:9]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]3)=[N:4][CH:5]=[N:6][CH:7]=2)=[O:35])[N:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncncc2N)C1
Reactant: O=C(O)c1csc(-c2c(F)cccc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncncc2NC(=O)c2csc(-c3c(F)cccc3F)n2)C1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Compound (1D3) (47 mg, 0.169 mmol), 2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (1E) (40 mg, 0.169 mmol, HATU (77 mg, 0.203 mmol) and DIEA (93 μL, 0.507 mmol) are mixed in DMF (5 mL) and stirred at 50° C. for 1 hour. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (50 mL), washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified with flash column (eluent: 10-30% ethyl acetate/petroleum ether) to obtain the product 1A (30 mg, 0.0596 mmol)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]2[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=2[CH:25]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]2[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:23])([CH3:24])[C:17]=2[CH:25]=1)=[O:34]
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccccn3)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccccn3)cc21
Reaction time: 8 h

Procedure:
A quantity of 3.58 gm (0.01 mol) 6-[4-(2-pyridylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one is dissolved in 100 ml of chloroform and mixed with 4.3 gm (0.025 mol) of m-chloroperbenzoic acid, under stirring. After stirring for two hours, a further 2 gm of m-chloroperbenzoic acid are added, and the mixture is left to stand overnight. The chloroform phase is extracted with water, the organic phase is dried with sodium sulfate, and the chloroform is distilled off. The non-uniform residue is purified by column chromatography [silica gel, particle size of 0.05 to 0.2 mm; chloroform/ethanol (40:1)]. The uniform fractions are combined, and the residue is triturated with ethyl acetate/ether. The crystals thus obtained are subjected to suction filtration and dried at 50° C.
Reaction SMILES: C(O)(=O)C.[C:5]([NH:8][C:9]1[S:10][C:11]([C:14]([NH2:16])=[NH:15])=[CH:12][N:13]=1)(=[O:7])[CH3:6].[Cl:17][C:18]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:19]=1[CH:20]=O.[C:27]([O:33][CH2:34][CH3:35])(=[O:32])[CH2:28][C:29]([CH3:31])=O.C([O-])(=O)C.[Na+]>C(O)C>[C:5]([NH:8][C:9]1[S:10][C:11]([C:14]2[NH:16][C:29]([CH3:31])=[C:28]([C:27]([O:33][CH2:34][CH3:35])=[O:32])[CH:20]([C:19]3[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:18]=3[Cl:17])[N:15]=2)=[CH:12][N:13]=1)(=[O:7])[CH3:6]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(=O)Nc1ncc(C(=N)N)s1
Reactant: O=Cc1ccc(F)cc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(c2cnc(NC(C)=O)s2)=NC1c1ccc(F)cc1Cl
Yield: 36.6 %

Procedure:
2 mmol 2-Acetylaminothiazol-5-formamidine acetate, 2 mmol 2-chloro-4-fluorobenzaldehyde, 2 mmol ethyl acetoacetate and 2.2 mmol sodium acetate were reacted under reflux in 10 ml anhydrous ethanol for 20 hr, concentrated, and then ethyl acetate and water were added to separate the layers. The ethyl acetate layer was dried over anhydrous sodium sulfate, and separated by a column chromatography to obtain 0.32 g of a yellowish solid with mp>250° C.; 1H-NMR (400 MHz, DMSO-d6) δ 1.0-1.05 (3H, m); 2.14 (3H, s); 2.43 (3H, s); 2.59 (3H, s); 3.89-3.94 (2H, m); 5.89 (1H, s); 7.14-7.39 (3H, m); 8.11 (1H, s); 9.43 (1H, s); 12.22 (1H, br); MS (EI) 436.0 (M+).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9](OC1C=CC=CC=1)(=[O:25])[C:10]1[CH:24]=[CH:23][CH:22]=[C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[CH:11]=1>>[C:9]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)(=[O:25])[C:10]1[CH:24]=[CH:23][CH:22]=[C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[CH:11]=1
Reactant: Oc1ccc(O)cc1
Reactant: O=C(Oc1ccccc1)c1cccc(C(=O)Oc2ccccc2)c1
Product: O=C(Oc1ccccc1)c1cccc(C(=O)Oc2ccc(O)cc2)c1
Temperature: 250 °C

Procedure:
330 g. (3 moles) of hydroquinone and 974 g. (3 moles) of diphenyl isophthalate are placed in a four-necked resin kettle equipped as in Example 3. The reaction mixture is stirred constantly under a nitrogen atmosphere throughout the run. The mixture is heated to 250°C, forming a melt, and the temperature is maintained at 250°C for 16 hours. During this period the hydroquinone and diphenyl isophthalate react to produce, as the principal product, p-hydroxyphenyl phenyl isophthalate, i.e., an ester of the formula ##SPC18##
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][NH2:11].[OH-].[Na+]>CC#N.O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:11][CH3:10])[N:7]=1
Reactant: CN
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CNc1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of cyanuric chloride (184 mg, 1.00 mmol, 1.00 equiv) in CH3CN/H2O (1/1, 33 ml) was cooled to 0° C. Methylamine (40 w % in H2O) (0.252 ml, 3.25 mmol, 1.00 equiv) was added. The reaction mixture was adjusted to a pH of about 9-10 using 1 N NaOH. After being stirred at 0° for 10 min, the reaction was complete. The resulting suspension was used in the next step without workup or purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21]([OH:23])=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].CCN(C(C)C)C(C)C.[F:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[NH:50][CH2:51][CH2:52][CH2:53][N:54]1[N:58]=[N:57][CH:56]=[N:55]1>ClCCl.CN(C=O)C.CN(C1C=CN=CC=1)C>[C:7]([O:11][C:12](=[O:13])[N:14]([CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:21](=[O:23])[N:50]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[F:43])[CH2:51][CH2:52][CH2:53][N:54]2[N:58]=[N:57][CH:56]=[N:55]2)[CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)([CH3:9])([CH3:8])[CH3:10]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: Fc1ccccc1NCCCn1ncnn1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCn2ncnn2)c2ccccc2F)c1)c1ccncc1
Yield: 64.8 %

Procedure:
2M Oxalyl chloride solution in dichloromethane (0.110 ml) and dry DMF (0.002 ml) were added to a stirred suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.060 g) in dry dichloromethane (1 ml) under nitrogen. After 5 min DIPEA (0.090 ml) was added followed after a further 40 min by 2-fluorophenyl-(3-tetrazol-2-yl-propyl)-amine (0.066 g) and DMAP (0.002 g). After 40 h the solvent was evaporated and the residue was purified by flash chromatography, eluting with dichloromethane:methanol (98:2 v/v) to give the title compound as a viscous yellow oil (0.059 g).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:12]3[O:13][C:14]4[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][C:15]=4[C:16](=[O:19])[C:17]=3[OH:18])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>C(Cl)(Cl)Cl.CO>[N:1]1([C:6]2[CH:7]=[C:8]([C:12]3[O:13][C:14]4[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][C:15]=4[C:16](=[O:19])[C:17]=3[O:18][CH2:12][C:8]3[CH:9]=[CH:10][CH:11]=[CH:6][CH:7]=3)[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)Nc1ccc2oc(-c3cccc(-n4ccnc4)c3)c(O)c(=O)c2c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)Nc1ccc2oc(-c3cccc(-n4ccnc4)c3)c(OCc3ccccc3)c(=O)c2c1
Yield: 55 %

Procedure:
Prepared analogously to Example 5.d, starting from 2-[(3-(imidazol-1-yl)-phenyl]-3-hydroxy-6-acetamido-4H-1-benzopyran-4-one. Yield: 55%; TLC (85/15 Chloroform/Methanol) Rf: 0.64; 1H-NMR (d6-DMSO): 10.28 (s broad, 1H), 8.44 (d, 1H), 8.23-8.16 (m, 2H), 8.04-7.9 (m, 2H), 7.85-7.65 (m, 4H), 7.27 (m, 4H), 7.14 (m, 1H), 5.17 (s, 2H), 2.12 (s, 3H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:18]([NH2:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=[N:26][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccccc1OCCN1CCOCC1
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Product: C(=NCCc1ccccc1)c1ccccc1OCCN1CCOCC1
Yield: 85.6 %

Procedure:
2-[2-(4-Morpholinyl)ethoxy]benzaldehyde (55.9 g) is reacted with 29 g of phenethylamine in 240 ml of toluene following the procedure described in Example 1A to yield 68.8 g of product as an oil, boiling point 204°-210° C at 0.1-0.2 mm of Hg.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23](OC)=[C:22]([C:28]3[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=3)[CH:21]=[N:20]2)=[CH:15][CH:14]=1.[NH2-].[Li+]>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:22]([C:28]3[CH:29]=[CH:30][C:31]([S:34][CH3:35])=[CH:32][CH:33]=3)[CH:21]=[N:20]2)=[CH:15][CH:14]=1
Reactant: COc1c(-c2ccc(SC)cc2)cnn(-c2ccc(F)cc2)c1=O
Reactant: C1CCNCC1
Agent: [Li+]
Agent: [Li]CCCC
Agent: [NH2-]
Solvent: Cc1ccccc1
Product: CSc1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2N2CCCCC2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 95.1 %

Procedure:
To a slightly heterogeneous solution of piperidine (99.7 mg, 1.17 mmol) and toluene (8 mL) cooled to −78° C. was slowly added dropwise an n-BuLi solution (0.235 mL, 0.59 mmol, 2.5 M in hexanes). After stirring at −78° C. for 10 minutes, the cooling bath was removed and the mixture stirred an additional 1 hour at 23° C. The 2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (400 mg, 1.17 mmol) was dissolved in portions in toluene (3×6–7 mL aliquots) with a heat gun and cooled to 0° C. prior to transfer via syringe to the lithium amide solution (cooled to −78° C.). The addition was made slowly along the interior wall of the reaction vessel. This reaction mixture was stirred overnight, slowly warming to 23° C. as the cooling bath evaporated. The reaction was quenched with water and diluted with a large excess of ethyl acetate. The layers were separated, and the ethyl acetate layer washed with additional water and brine and dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes 1:2) to provide 440 mg (95%) of 2-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-4-piperidino-3(2H)-pyridazinone.