Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[CH3:13][Si](C=[N+]=[N-])(C)C>C(OCC)C.CO>[CH3:13][O:9][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:4]([CH:2]([Br:1])[CH3:3])=[CH:5][CH:6]=1
Reactant: CC(Br)c1ccc(C(=O)O)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1ccc(C(C)Br)cc1

Procedure:
A solution of 4-(1-bromo-ethyl)-benzoic acid (2.70 g, 11.8 mmol) in diethyl ether (20 mL) and methanol (5 mL) was cooled to 0° C. and treated with trimethylsilyldiazomethane (2 M in diethylether, 11.8 mL). After 1 h at 0° C. the solvents were removed under reduced pressure, the residue was re-dissolved in ethyl acetate (20 mL) and washed with aqueous NaHCO3 solution. The organic layer was collected, dried over MgSO4 and evaporated under reduced pressure.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][C:14]=3[F:25])[C:9](=[O:26])[C:8]=2[C:7]([O:27][CH2:28][CH3:29])=[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=12)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[C:12]2[CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][C:14]=3[F:25])[C:9](=[O:26])[C:8]=2[C:7]([O:27][CH2:28][CH3:29])=[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=12)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC)c4ccccc4c3OCC)C2=O)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1c2c(c(OCC)c3ccccc13)C(=O)N(c1ccc(CC(=O)O)cc1F)C2
Temperature: 100 °C
Yield: 56.3 %

Procedure:
Ethyl {4-[4,9-bis(ethyloxy)-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-3-fluorophenyl}acetate (0.072 g, 0.16 mmol) was suspended in ethanol (2 ml) and treated with 2N sodium hydroxide (6 ml). Heated to reflux at 100° C. under argon for 1 hour. The reaction was shown to be complete by LC/MS. The reaction mixture was cooled and the solvent evaporated to dryness. Water and 2N HCl was added to acidify. This was extracted with ethyl acetate (×2), dried over magnesium sulphate and evaporated to a solid which was dried overnight in a vacuum oven to give the title compound (0.038 g, 0.09 mmol).
Reaction SMILES: ClC(Cl)(Cl)C[CH:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.S(=O)(=O)(O)O.Cl.[C:20]([OH:23])(=[O:22])[CH3:21]>S(=O)(=O)(O)O.O>[C:20]([OH:23])(=[O:22])[CH:21]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)O
Reactant: ClC(CC(Cl)(Cl)Cl)c1ccccc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)C=Cc1ccccc1

Procedure:
A mixture of 77.4 g of 1,1,1,3-tetrachloro-3-phenylpropane, 7.7 g of 98% acetic acid and 1.8 g of 98% sulphuric acid is stirred and refluxed at 130° to 138° C. while a mixture of 15.5 g of water, 4 ml of acetic acid and 0.5 ml of sulphuric acid is gradually added over the period of 2.5 h, after which time the hydrogen chloride evolution ceases. The work-up of the reaction mixture as described in Example 1 gives 33.6 g of cinnamic acid in 75.6% total yield (melting point 132° to 133° C., min. 99% purity).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:16])[O:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([OH:15])[CH:9]=2)=[O:4].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:16])[O:7][C:8]2[CH:9]=[C:10]([O:15][CH2:14][C:13]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:11]=[CH:12][C:13]=2[CH:14]=1)=[O:4]
Reactant: COC(=O)c1cc2ccc(O)cc2oc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc2ccc(OCc3ccccc3)cc2oc1=O
Temperature: 70 °C
Reaction time: 12 h
Yield: 135.4 %

Procedure:
7-hydroxyl-3-coumarin carboxylic acid methyl ester (0.2g, 1 mmol) is dissolved in N,N′-dimethyl formamide (2 mL), and bromobenzyl (0.36 ml, 3 mmol) and levigated potassium carbonate (0.5 g) are added into. The resulting mixture is stirred for 12 hours at 70° C. After adding 10 mL of water, extraction is conducted with ethyl acetate, and all of ethyl acetate are combined, followed by washing with water, drying on anhydrous sodium sulfate. Then the solution is concentrated under reduced pressure to approximately 5 mL and is placed to separate out a solid, followed by filtering under reduced pressure to obtain 0.21 g of the captioned compound, yield: 67.7%. m.p.129-130° C. 1H NMR(CDCl3): δ=3.92(s, 3H), 5.19(s, 2H), 6.85(d, J=2.4 Hz, 1H), 6.95(dd, J=8.8 Hz, 2.4 Hz, 1H), 7.40(m, 5H), 7.52(d, J=8.8 Hz, 1H), 8.55(s, 1H); Elements Analysis, C18H14O5 (310): Calculated C, 69.68; H, 4.52. Found C, 69.63; H, 4.51; IR(KBr) : 3054.7, 2948.7, 1749.1, 1697.1, 1610.3, 1558.2, 1500.4, 1438.7, 1378.9, 1226.5, 1116.6, 1026, 794.5, 725.1, 692.3, 636.4 cm−1; EI-MS(m/z): 310(12, M+), 91(100).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9].[OH-].[Na+].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:12]([O:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1ccccc1
Reactant: Cc1occc(=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1occc(=O)c1OCc1ccccc1
Yield: 91.9 %

Procedure:
3-Hydroxy-2-methyl-4-pyrone (22.2 g) in methanol 225 ml) is added to aqueous sodium hydroxide (25 ml containing 7.5 g NaOH). Benzyl chloride (25.5 g) is added and the mixture is refluxed for 6 hours and is then allowed to cool overnight. The bulk of the methanol is removed under vacuum and the residue is treated with water (50 ml). The mixture is extracted into dichloromethane (3×25 ml). The extracts are combined, washed with 5% w/v NaOH (2×25 ml), then water (2×25 ml) and dried over magnesium sulphate. Evaporation of the solvent gives crude 3-benzyloxy-2-methyl-4-pyrone (35 g, 92%) which is purified by distillation in nitrogen under reduced pressure to yield a colourless oil (28 g) of b.p. 148° C./0.2 mm.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[CH2:23][C:22]2[CH:25]=[CH:26][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Product: N#Cc1ccc(N(Cc2ccc([N+](=O)[O-])cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[(4-Cyanophenyl)amino]pyrimidine and 4-nitrobenzyl bromide
Reaction SMILES: C(OC(=O)C)(=O)C.NCC[N:11]1[C:15](=[O:16])[CH:14](CCCCCCCCC)[S:13][CH:12]1[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[N:28]1[CH:29]=[CH:30][CH:31]=[C:26]([CH:12]2[NH:11][C:15](=[O:16])[CH2:14][S:13]2)[CH:27]=1
Reactant: CCCCCCCCCC1SC(c2cccnc2)N(CCN)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: O=C1CSC(c2cccnc2)N1
Reaction time: 8 h
Yield: 201.8 %

Procedure:
Acetic anhydride (0.2 g) was added dropwise to a solution of 3-(2-aminoethyl)-5-(n-nonyl)-2-(3-pyridyl)thiazolidin-4-one (0.50 g, 1.43 mmol) in pyridine (2 ml) with stirring under cooling with ice. The mixture was left standing overnight at room temperature. To this solution was added saturated aqueous NaHCO3 (30 ml), and the mixture was extracted with benzene. After drying of the extract, the solvent was removed therefrom by evaporation under reduced pressure, giving the intended 3-(2-acetylam:inoethyl)-5-(n-nonyl)- ,2-(3-pyridyl)thiazolidin-4-one (0.52 g, 92% yield) in oily form.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[S:12])=[CH:6][CH:5]=1)([O-])=O.O.NN>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][CH2:14][C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[S:12])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(NC(=S)NCc2ccncc2)cc1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc(NC(=S)NCc2ccncc2)cc1
Reaction time: 8 h

Procedure:
To a mixture of 5.76 gms. (0.02 mole) of 1-(p-nitrophenyl)-3-(4-pyridylmethyl)-2-thiourea, (Example 2, supra.), 200 ml. of ethanol and 65 ml. of hydrazine hydrate is added with stirring 0.5 grams of 5 percent palladium-on-carbon in 50 ml. of ethanol. The resulting mixture is allowed to stand overnight at room temperature and then refluxed for 2 to 3 hours. The hot reaction mixture is then filtered and the filtrate evaporated to remove solvents. The residue is 1-(p-aminophenyl)-3-(4-pyridylmethyl)-2-thiourea.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:8])=[CH:4][CH:3]=1.[CH3:17][C:18]1[C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][C:21]2[N:22]=[CH:23][S:24][C:20]=2[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(=O)OCC.[Cl-].[Na+].O>COCCOC.CCO.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:7]([C:5]1[S:6][C:2]([C:26]2[C:18]([CH3:17])=[CH:19][C:20]3[S:24][CH:23]=[N:22][C:21]=3[CH:25]=2)=[CH:3][CH:4]=1)=[O:8]
Reactant: O=C(Nc1ccccc1F)c1ccc(Br)s1
Reactant: Cc1cc2scnc2cc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc2scnc2cc1-c1ccc(C(=O)Nc2ccccc2F)s1
Temperature: 110 °C
Yield: 90.7 %

Procedure:
A mixture of (5-bromo(2-thienyl))-N-(2-fluorophenyl)carboxamide (9, 21 mg, 0.07 mmol), 6-methyl-5-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))benzothiazole (14) (19 mg, 0.07 mmol), tetrakis(triphenylphosphine)-palladium(0) (Pd(Ph3P)4, 8 mg) and sodium carbonate (22 mg) in 0.5 ml DME, 0.5 ml EtOH and 0.25 ml water was heated under Ar in microwave reactor at 110° C. for 30 min. The reaction mixture was worked up with EA/brine. Org. phase was concentrated and then subjected to prep HPLC chromatography to furnish 23.4 mg of N-(2-fluorophenyl)[5-(6-methylbenzothiazol-5-yl)(2-thienyl)]carboxamide (16) as yellow solid (yield: 90.7%; purity>95%). LC-MS: calcd. for C19H13FN2OS2: 369 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([CH2:21][C:22](O)=[O:23])#[N:20].C(OC(=O)C)(=O)C>O>[C:19]([CH2:21][C:22]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=[O:23])#[N:20]
Reactant: O=C(NCc1ccccc1)NCc1ccccc1
Reactant: N#CCC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: N#CCC(=O)N(Cc1ccccc1)C(=O)NCc1ccccc1

Procedure:
36.0 g (0.15 mol) of dibenzylurea, 15.3 g (0.18 mol) of cyanoacetic acid and 30.6 g (0.3 mol) of acetic anhydride are stirred at 80-85° C. for 2 hours. After cooling, the reaction mixture is stirred into 600 ml of water and the resultant precipitate is filtered off with suction and then dried to constant weight.
Reaction SMILES: Cl.Cl.[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([O:26][CH3:27])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:11]=2)[C:8]2[CH:34]=[CH:35][CH:36]=[CH:37][C:7]=2[N:6]=1)[CH3:4].CCN(C(C)C)C(C)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>C1COCC1>[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([O:26][CH3:27])[CH2:25][CH2:24][CH2:23][N:22]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:11]=2)[C:8]2[CH:34]=[CH:35][CH:36]=[CH:37][C:7]=2[N:6]=1)[CH3:4]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCCNC3)n(C)c2n1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCCN(S(C)(=O)=O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 26 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-8-(3-methoxypiperidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine dihydrochloride (150 mg, 0.27 mmol) and DIPEA (190 μL, 1.09 mmol) in THF (3 mL) was stirred for 5 min before the addition of methanesulfonyl chloride (21 μL, 0.27 mmol). The resulting mixture was stirred at r.t. for 4 h then partitioned between H2O and DCM. The organic phase was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:TBME, 0-100%) affording 766 (39 mg, 26%). LCMS (method I): RT 3.74 min, [M+H]+ 555.2. 1H NMR (DMSO, 400 MHz): δ 8.05-8.04 (1 H, m), 7.64-7.63 (1 H, m), 7.28-7.24 (2 H, m), 4.27 (4 H, brd s), 3.97 (1 H, d, J=13.24 Hz), 3.92 (3 H, s), 3.79 (4 H, t, J=4.61 Hz), 3.50-3.47 (2 H, m), 3.28-3.26 (2 H, m), 3.08 (3 H, s), 3.05-2.95 (4 H, m), 2.35-2.25 (1 H, m), 1.98-1.95 (2 H, m), 1.76-1.72 (1 H, m), 1.35 (3 H, t, J=7.43 Hz)
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH:13]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14][S:15]([CH3:18])(=[O:17])=[O:16].O.NN>C(O)C>[NH2:3][CH2:12][CH:13]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:14][S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: CC(C)(C)OC(=O)NC(CN1C(=O)c2ccccc2C1=O)CS(C)(=O)=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC(CN)CS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl [1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-(methylsulfonyl)propan-2-yl]carbamate (10.0 g, 26.2 mmol) in ethanol (150 mL) was added dropwise hydrazine hydrate (15.7 g, 262 mmol) at 0° C., and the reaction mixture was allowed to warm to ambient temperature. After 30 minutes, the reaction mixture was heated to reflux. After two hours, the reaction mixture was cooled, filtered, and concentrated under reduced pressure. The residue was purified via chromatography on silica gel to afford tert-butyl [1-amino-3-(methylsulfonyl)propan-2-yl]carbamate. MS ESI calc'd. for C9H21N2O4S [M+H]+ 253. found 253. 1H NMR (400 MHz, CD3OD) δ 4.06-4.00 (m, 1H), 3.30-3.27 (m, 2H), 3.00 (s, 3H), 2.82-2.69 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: Cl.Cl[CH:3]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[O:18]([CH2:22][CH3:23])[C:19]([S-:21])=[S:20].[K+]>C(O)C>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[CH:3]([S:21][C:19]([O:18][CH2:22][CH3:23])=[S:20])[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: CCOC(=S)[S-]
Reactant: Clc1ccc(C(Cl)Cn2ccnc2)c(Cl)c1
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CCOC(=S)SC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Twenty grams of 1-(β, 2,4-trichlorophenethyl)imidazole hydrochloride was added to 300 milliliters (ml) of absolute ethanol and 25 grams of anhydrous potassium ethyl xanthate. The mixture was stirred at room temperature for about 3 days until the reaction was complete as indicated by thin layer chromatography. The solvent was removed, water added and the product extracted with ether. The extracts were washed with water, dried over magnesium sulfate and the ether evaporated. The resulting oil was purified by chromatography on silicia gel eluting with 15% acetone in dichloromethane. The resulting oil was then dissolved in ether and an ethereal solution of oxalic acid was added dropwise until precipitation was complete. Recrystallization of the precipitate from acetone provides the oxalate salt of 1-[2,4-dichloro-β-(ethoxythiocarbonylthio)phenethyl]imidazole as a white solid having a melting point of 122.5°-124° C. (foaming).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH:3]=[CH2:4].[CH:7](=[O:16])[C:8]1[C:9]([O:14][CH3:15])=[CH:10][CH:11]=[CH:12][CH:13]=1.O>C1COCC1>[OH:16][CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])[CH2:4][CH2:3][CH:2]=[CH2:1]
Reactant: C=CCC[Mg]Br
Reactant: COc1ccccc1C=O
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(O)c1ccccc1OC

Procedure:
To a solution of 3-butenylmagnesium bromide in THF (0.50 M, 200 mL) at 0° C. was added o-anisaldehyde (13.62 g, 100 mmol) in THF (20 mL) dropwise and the reaction mixture was heated under reflux for 1 hour. Water was added, the aqueous layer was extracted with ether (x4), and the combined organic layers were washed with brine, dried over MgSO4 and evaporated in vacuo to give the title compound. The crude product was used for Preparation 17 without purification. 1H NMR (CDCl3, 400 MHz) δ: 7.3 (2H), 6.9 (2H), 5.8 (2H), 4.8-5.1 (3H), 3.85 (3H, OMe), 2.5 (1 H), 1.8-2.3 (4H).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][C:9]3[C:14]([C:15](=[O:16])[C:4]2=[CH:3][CH:2]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.FC(F)(F)C([O-])=O.[Tl+].[I-:25].[K+]>>[I:25][C:3]1[C:4]2[C:15](=[O:16])[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH:8]=[CH:7][C:5]=2[CH:6]=[CH:1][CH:2]=1
Reactant: [I-]
Reactant: O=c1c2ccccc2ccc2ccccc12
Agent: O=C([O-])C(F)(F)F
Agent: [K+]
Agent: [Tl+]
Product: O=c1c2ccccc2ccc2cccc(I)c12

Procedure:
2.06 g of dibenzosuberenone [CAS No. 2222-33-5] was subjected to the procedure of Example 1-g using 6.5 g of thallium trifluoroacetate and 2.0 g of potassium iodide, to give 1.0 g of a mixture of the title compound with dibenzosuberenone as a colorless powder.
Reaction SMILES: [C:1]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([CH3:16])[CH:10]=[C:9]([CH3:17])[N:8]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].CS(O[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:36]([CH3:37])=[CH:35][CH:34]=[C:33]2[C:38]#[N:39])=[CH:28][CH:27]=1)(=O)=O>CN(C)C=O>[C:1]([N:6]([C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([CH3:16])[CH:10]=[C:9]([CH3:17])[N:8]=1)[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:36]([CH3:37])=[CH:35][CH:34]=[C:33]2[C:38]#[N:39])=[CH:28][CH:27]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(C#N)n1-c1ccc(COS(C)(=O)=O)cc1
Reactant: CCCC(=O)Nc1nc(C)cc(C)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(=O)N(Cc1ccc(-n2c(C)ccc2C#N)cc1)c1nc(C)cc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a solution of 2-butyrylamino-4,6-dimethyl-3-nitropyridine (2.49 g) in dimethylformamide (12.5 ml) was added sodium hydride (441 mg) in an ice-water bath. The mixture was stirred at room temperature for an hour, and a solution of 1-(4-methanesulfonyloxymethylphenyl)-5-methylpyrrole-2-carbonitrile (3.05 g) in dimethylformamide (15 ml) was dropwise therein. The reaction mixture was stirred at room temperature for 5.5 hours and was stood overnight. The separated oil was extracted with ethyl acetate. The extract were washed with brine, dried, and concentrated in vacuo. The residue was purified by flash column chromatography eluted by n-hexane/ethyl acetate (1/1) to give 2-[N-butyryl-N-[4-(2-cyano-5-methyl-1-pyrrolyl)benzyl]amino]-4,6-dimethyl-3-nitropyridine (2.75 g) as oil.
Reaction SMILES: C(#N)C.[CH:4]1([C:7]2[N:11]([C:12]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[N:17]4)[N:10]=[CH:9][C:8]=2[C:22](Cl)=[O:23])[CH2:6][CH2:5]1.C1(C2N(C3C=CC=C4C=3C=CC=N4)N=CC=2C(Cl)=O)CC1.[NH2:46][C:47]([NH2:49])=[NH:48].O1CCCC1>Cl.NC(N)=N.O.[OH-].[Na+]>[CH:4]1([C:7]2[N:11]([C:12]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[N:17]4)[N:10]=[CH:9][C:8]=2[C:22]([NH:48][C:47]([NH2:49])=[NH:46])=[O:23])[CH2:6][CH2:5]1
Reactant: N=C(N)N
Reactant: O=C(Cl)c1cnn(-c2cccc3ncccc23)c1C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: N=C(N)NC(=O)c1cnn(-c2cccc3ncccc23)c1C1CC1
Temperature: 52.5 °C
Reaction time: 2 h

Procedure:
In a reaction flask, guanidine HCl (35.1 g) was dissolved in water (268 ml) and 50% NaOH (114.6 g). The acetonitrile/5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl chloride mixture of Example 4, was added in three equal portions to the flask containing the guanidine solution while maintaining the reaction temperature below 15° C. throughout the addition. The reaction mixture was brought to room temperature and stirred under nitrogen atmosphere for two hours. The reaction was confirmed to be complete by HPLC. A distillation head and condensor were then attached to the reaction vessel. The product mixture was atmospherically distilled at 85° C. resulting in a slurry having a volume of 400-450 ml. Tetrahydrofuran (THF) (720 ml) was added to the reaction flask and the mixture was warmed to 50-55° C. for 45 minutes and until all all contents had entered solution resulting in an orange biphasic mixture. The mixture was transferred to a separatory funnel and the layers were allowed to separate. The layers were separated and the aqueous layer was extracted with an additional 300 ml of THF. The resulting organic THF layers were combined. Darco® KB-B (5 g) (NORIT Americas Inc., Atlanta, Ga.) and Celite® (5 g) (Celite Corp., Lompoc, Calif.) were added to the THF layers and stirred at room temperature for one hour. The black mixture was vacuum filtered through a #2 Whatman paper filter (Whatman Inc., Clifton, N.J.) and the carbon cake was rinsed with THF. The filtrate was then collected, transferred to a clean flask. and atmospherically distilled at 70° C. to a volume of 450 ml. Ethanol (500 mL) was added to the flask and the mixture was atmospherically distilled at 85° C. to 450 ml. The addition of ethanol and subsequent distillation was repeated three more times. The resulting slurry was cooled to room temperature and allowed to granulate while stirring for three hours. The slurry was then filtered onto a #2 Whatman filter paper and rinsed with THF. The resulting white crystalline solid was allowed to dry for about 48 hours in a vacuum oven at 45 to 50° C. resulting in 52.2 g of N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7](=[O:26])[C:8](=[N:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH:24]=[CH:23][CH:22]=[N:21]2)=[CH:16][C:15]=1[F:25])[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:9]([C:8]1[C:7](=[O:26])[C:3]2[O:4][CH:5]=[CH:6][C:2]=2[N:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:16][C:15]=2[F:25])[N:12]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)C(=NNc1ccc(-n2cccn2)cc1F)C(=O)c1occc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1nn(-c2ccc(-n3cccn3)cc2F)c2ccoc2c1=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
A suspension of 1-(3-bromofuran-2-yl)-2-{[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]hydrazono}butane-1,3-dione (5.3 g) and potassium carbonate (3.5 g) in DMF (40 mL) was stirred at 90° C. for 4 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was suspended in diisopropylether, and the precipitate was collected by filtration to give the title compound (2.56 g).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[C:3]([O:5]CC)=[O:4].Cl>O1CCOCC1.[OH-].[Na+].C(OCC)(=O)C>[CH3:1][C:2]([CH3:19])([CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Cc1ccc2ccccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(Cc1ccc2ccccc2c1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
The crude ester (915 mg) was taken up in dioxane (4 mL) and 20% aqueous sodium hydroxide (8 mL). After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate. The aqueous fraction was acidified to pH=2 with concentrated hydrochloric acid and was then extracted with ethyl acetate. The combined organic fractions were dried over sodium sulfate and concentrated to yield 2,2-dimethyl-3-(naphthalene-2-yl)propanoic acid (211 mg, 40% yield for two steps) as a white solid, which was used directly in the next step.