Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[N:20]3)[CH:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].C1COCC1.Cl>CO>[N:19]1([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C@H:9]3[CH2:8][CH2:7][C@H:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]3)[N:18]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[N:20]1
Reactant: CCOC(=O)[C@H]1CC[C@H](Nc2nccc(-n3ncc4ccccc43)n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)[C@H]1CC[C@H](Nc2nccc(-n3ncc4ccccc43)n2)CC1
Reaction time: 8 h

Procedure:
A mixture of trans-4-(4-indazol-1-ylpyrimidin-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (2.88 g, 7.9 mmol), aqueous NaOH (2 M, 65 mL) and THF (65 mL) was stirred overnight. MeOH (40 mL) was added, and the reaction mixture stirred for an additional 105 min. Aqueous HCl (1M) was added to reach pH 3, and the resulting solid collected by filtration to give trans-4-(4-indazol-1-yl-pyrimidin-2-ylamino)-cyclohexanecarboxylic acid (2.739 g) without further purification.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[CH:7][N:8]([C:11]3[CH:24]=[CH:23][C:14]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:13][CH:12]=3)[N:9]=2)[CH:5]=[CH:4][C:3]=1[O:25][CH2:26][CH:27]1[CH2:29][CH2:28]1.[CH3:30][N:31](C)C(=O)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N.[Zn]>[C:30]([C:2]1[C:10]2[C:6](=[CH:7][N:8]([C:11]3[CH:24]=[CH:23][C:14]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:13][CH:12]=3)[N:9]=2)[CH:5]=[CH:4][C:3]=1[O:25][CH2:26][CH:27]1[CH2:29][CH2:28]1)#[N:31]
Reactant: CC(=O)N(C)C
Reactant: CC(=O)N[C@@H](C)COc1ccc(-n2cc3ccc(OCC4CC4)c(Br)c3n2)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(=O)N[C@@H](C)COc1ccc(-n2cc3ccc(OCC4CC4)c(C#N)c3n2)cc1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
A mixture of N-[(1S)-2-{4-[7-bromo-6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}-1-methylethyl]acetamide (150 mg), tris(dibenzylideneacetone)dipalladium(0) (45 mg), 1,1′-bis(diphenylphosphino)ferrocene (54.4 mg), zinc cyanide (57.7 mg), zinc powder (10.7 mg) and N,N-dimethylacetamide (3 mL) was stirred at 120° C. for 1.5 hr under an argon atmosphere. The reaction mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The combined organic layer was washed three times with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as colorless crystals (54.5 mg).
Reaction SMILES: [Na].[CH:2]1([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Br[C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[CH:2]1([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc(C=NC2CCCCC2)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(C=NC2CCCCC2)cc1
Reaction time: 15 h
Yield: 50.7 %

Procedure:
(a) To 70 ml of absolute ethanol is added 872 mg of sodium, and 7 g of 4-(N-cyclohexylformimidoyl)phenol is added to the solution. Subsequently, 7.4 g of ethyl 2-bromo-2-methylpropionate is further added. The mixture is refluxed under heating and with stirring for 15 hours. After distilling off the ethanol from the reaction mixture, water is added to the residue, and the solution is extracted three times with benzene. The extract is washed with water twice, with cooled dilute aqueous solution of sodium hydroxide three times and then with water twice. After drying the resulting solution over magnesium sulfate, the solvent is distilled off to give 5.54 g of ethyl 2-[4-(N-cyclohexylformimidoyl)phenoxy]-2-methylpropionate as an oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:10][C:9]([CH:11](N2C(=O)C3C(=CC=CC=3)C2=O)[CH2:12][CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:26].O.[NH2:28]N>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:10][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][NH2:28])=[CH:8][C:7]=1[CH3:26]
Reactant: CCCC(c1cc(C)c(C2OCCO2)s1)N1C(=O)c2ccccc2C1=O
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CCCCN)sc1C1OCCO1

Procedure:
N-[[5-(1,3-Dioxolan-2-yl)-4-methyl-2-thienyl]-4-butyl]-isoindole-1,3(2H)-dione (16.1 g) and hydrazine hydrate (8 ml) were stirred at room temperature in tetrahydrofuran (150 ml) for 24 h. The mixture was filtered and the filtrate was distilled to give the title compound as a red-brown oil (5.34 g), b.p. 230°/0.1 mm.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6](O)[C:7]([OH:9])=O)=[CH:4][CH:3]=1.[C:13]1([CH:19]2[CH2:23][CH2:22][CH2:21][NH:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C.C(Cl)Cl.CCN(CC)CC.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:7]2=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(O)C(O)c1ccc(Br)cc1
Reactant: c1ccc(C2CCCN2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1C(c2ccc(Br)cc2)c2ccccc2C2CCCN12
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.8 %

Procedure:
To a stirred solution of 4-bromomandelic acid (832 mg, 3.6 mmol), 2-phenylpyrrolidine (530 mg, 3.6 mmol), BOP reagent (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphonate, 1.53 g, 3.6 mmol) in 25 mL of anhydrous acetonitrile was added triethylamine (1.06 mL, 7.2 mmol) at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 4 h, concentrated under reduced pressure, then dissolved in methylene chloride (50 mL). The methylene chloride solution was washed with 1N HCl solution, water, saturated sodium bicarbonate solution, water, brine, and dried over anhydrous MgSO4, concentrated under reduced pressure to afford a syrup in a flask. PPA (polyphosphoric acid, 10 g) was added to the flask. The reaction mixture was heated on a rotavap in boiling water bath for 1 h, cooled to room temperature, solublized in ice water, extracted with methylene chloride (4×15 mL). The methylene chloride extract was washed with saturated sodium bicarbonate solution, water, brine, and dried over anhydrous MgSO4, concentrated under reduced pressure to afford a crude product mixture. Flash chromatography (silica gel, 0.5% MeOH, 0.01% Et3N in methylene chloride) to afford 860 mg of 4 (70% yield for two steps) as a mixture of trans and cis isomers with trans to cis ratio 2:1 (estimated by 1H NMR integration). Recrystallization with THF isolated trans isomer as a yellow solid, mp 204-206° C. 1H NMR (CDCl3) δ 1.96-2.22 (m, 3H, C2H2 & C1H), 2.66-2.78 (m, 1H, C1H), 3.48-3.58 (m, 1H, C3H), 3.732 (dd, 1H, J=7.5, 11.7 Hz, C3H), 4.610 (s, 1H, C6H), 4.64-4.70 (m, 1H, C10bH), 6.591 (d, 1H, J=7.8 Hz, aryl), 7.104 (d, 2H, J=8.1 Hz, C6 phenyl aryl), 7.12-7.28 (m, 3H, 8, 9, aryl), 7.520 (d, 2H, J=8.4 Hz, C6 phenyl aryl); 13C NMR (CDCl3) δ 23.06 (C2), 31.21 (C1), 45.07 (C3), 52.99 (C10b), 58.62 (C6), 121.10 (C4'), 123.58 (aromatic), 126.74 (aromatic), 127.38 (aromatic), 131.38 (aromatic), 132.60 (aromatic), 136.15 (aromatic), 136.55 (aromatic), 136.79 (aromatic), 167.36 (C5). HRMS calculated 341.0415 (for C18H16NOBr), measured 341.0427 (relative error 3.4 ppm).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH:23]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:16][C:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:30])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: O=C(O)C1CCCCC1
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)N)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)NC(=O)C3CCCCC3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example 26b) and cyclohexanecarboxylic acid as brown solid (28%). MS 414 (MH+).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][N:6]2[C:8](=[O:20])[C@@H:9]([NH:10][C:11](=[O:19])[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:5]2[S:4][CH2:3]1.C(OC(=O)C)(=O)C.C(Cl)(Cl)Cl>CS(C)=O.C(OCC)(=O)C.C1C=CC=CC=1>[O:1]=[C:2]1[CH2:7][N:6]2[C:8](=[O:20])[C@@H:9]([NH:10][C:11](=[O:19])[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:5]2[S:4][CH2:3]1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C[C@@H](O)CS[C@H]12
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: O=C1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2C1
Reaction time: 16 h
Yield: 23.8 %

Procedure:
To a solution of (3R,6R,7R)-3-hydroxy-7-phenylacetamidocepham (1.4 g., 4.78 mmole) in dimethylsulphoxide (25 ml.) was added acetic anhydride (5 ml.). The reaction mixture was kept at 22° for 16 hours, diluted with ethyl acetate, and washed with water and sodium bicarbonate solution. Removal of the solvent gave a crystalline solid (1.23 g.) which was dissolved in benzene:ethyl acetate: chloroform = 2:2:1 (10 ml.) and adsorbed on a 10 × 2.5 cm column of silica gel. Elution with the same solvent mixture gave (6R,7R)-3-oxo-7-phenylacetamidocepham (0.33 g., 23%), as plates from isopropyl alcohol, m.p. 183.4° (Mettler), [α]D22 + 472.5° (c, 1.0, N,N-dimethylformamide), λmaxEtOH 250, 257, 263 nm (ε 280, 280, 190), νmaxnujol 3287 (NH), 1764 (β-lactam), 1712 (ketone), and 1650 and 1524 cm-1 (CONH), NMR (d6 -DMSO, τ) 0.85 (d, J 9 Hz, NH), 2.67 (C6H5), 4.61 (dd, J 4.5 and 9 Hz, 7-H), 4.86 (d, J 4 Hz, 6-H), 6.60 and 6.1 (q, J 19 Hz, 2-CH2), 6.10 and 6.86 (q, J 15 Hz, 4-CH2), 6.39 (Ph.CH2). (Found: C, 57.4; H, 4.9; N, 9.6; S, 10.9. C14H14N2O3S requires C, 57.9; H, 4.9; N, 9.6; S, 11.0%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[C:13]1([CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH3:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:22]
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2C)c(C)c1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 108.2 %

Procedure:
A mixture of methyl 4-bromo-3-methylbenzoate (25.0 g, 110 mmol), o-tolylboronic acid (16.5 g, 120 mmol) and potassium carbonate (50 g, 360 mmol) in dioxane/water (300 mL:200 mL) was purged with nitrogen for 1 hour. [1,-bis(Diphenylphosphino) ferrocene]dichloropalladium [II] (4.5 g, 5.5 mmol) was added. The reaction mixture was heated to 100° C. with vigorous stirring for 3.5 hours, then cooled and filtered through Celite® (Celite Corp., Santa Barbara, Calif.). The cake was washed with ethyl acetate (500 mL). The combined organic phases were washed with 1N sodium hydroxide (500 mL) and brine (500 mL), dried over anhydrous potassium carbonate, and concentrated in vacuo to afford a dark oil (28.6 g). Purification by flash chromatography using 2% ethyl acetate in hexanes as solvent provided the title compound (24.7 g, 93%) as a pale yellow oil. MS [(+)ESI, m/z]: 241 [M+H]+ HRMS [(+)ESI, m/z]: 241.12205 [M+H]+. Calcd for C16H17O2: 241.12286 Anal. Calcd for C16H16O2: C, 79.97; H, 6.71. Found: C, 79.67; H, 6.61.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8]([OH:15])=[CH:7][CH:6]=1.[I-].[K+].Br[CH:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)[C:20]([O:22][CH3:23])=[O:21]>C1C=CC=CC=1.O>[Cl:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8]([O:15][CH:19]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)[C:20]([O:22][CH3:23])=[O:21])=[CH:7][CH:6]=1
Reactant: Oc1ccc(Cl)c2c1CCCC2
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)C(Oc1ccc(Cl)c2c1CCCC2)c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 1.19 g of sodium methoxide, 4.57 g of 4-chloro-5,6,7,8-tetrahydro-1-naphthol, and 100 mg of potassium iodide was added 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate in 10 ml of benzene. The mixture was heated at reflux overnight, cooled to room temperature, and poured into 100 ml of water. The mixture was then extracted with 2×75 ml of ether. The combined extracts were washed with 2×50 ml of 5% NaOH, 2×50 ml of water, 50 ml of saturated brine, and dried (MgSO4). Evaporation of the solvent yielded an oil which was chromatographed over 100 g of silica gel (benzene). Concentration of cuts yielded a yellow gum which solidified on standing to give the product as a white solid, mp 87.5°-90° C. (6.4 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH2:23])=[N:14][C:15]=3[N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[S:10][N:9]=2)=[CH:4][CH:3]=1.[C:24]1([CH3:33])[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>ClCCl>[NH2:23][C:13]1[N:12]=[C:11]2[S:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:16]2=[C:15]([N:17]2[CH2:18][CH2:19][N:20]([C:31]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([CH3:33])=[CH:25][CH:26]=3)=[O:32])[CH2:21][CH2:22]2)[N:14]=1
Reactant: Nc1nc(N2CCNCC2)c2c(-c3ccc(F)cc3)nsc2n1
Reactant: Cc1ccc(N=C=O)cc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)N2CCN(c3nc(N)nc4snc(-c5ccc(F)cc5)c34)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a suspension of Example 15 (0.2 mmol) in dichloromethane (5 mL) was added p-tolyl isocyanate (0.2 mmol). The reaction mixture was stirred at room temperature for 30 minutes. After concentration under reduced pressure, the residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1:50), yielding the pure title compound (66 mg, 71%) as a yellowish solid. MS (m/z) 464.1 [M+H]+ (100%). δH (300 MHz, DMSO-d6, 25° C.) 8.36 (s, 1H, NH), 7.72 (dd, J 8.4, 5.6 Hz, 2H), 7.38 (t, J 8.7 Hz, 2H), 7.26 (d, J 8.4 Hz, 2H), 7.06 (s, 2H, NH2), 7.01 (d, J 8.4 Hz, 2H), 3.36 (br s, 4H), 3.17 (br s, 4H), 2.20 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1B(O)O>CCOCC>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:26]3[CH:27]=[C:22]([O:21][CH3:20])[CH:23]=[CH:24][C:25]=3[O:28][CH3:29])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: CCCNC(=O)c1nnc2c(I)c(F)ccc2c1N
Reactant: COc1ccc(OC)c(B(O)O)c1
Solvent: CCOCC
Product: CCCNC(=O)c1nnc2c(-c3cc(OC)ccc3OC)c(F)ccc2c1N
Yield: 71.5 %

Procedure:
The title compound was prepared from 4-amino7-fluoro-8-iodo-N-propylcinnoline-3-carboxamide (200 mg, 0.535 mmol) and 2,5-dimethoxyphenyl boronic acid (194 mg, 1.07 mmol) according to Method A. The off-white solid from chromatography was slurried in ether, filtered and dried under vacuum at room temperature to afford the desired product (147 mg, 71%). 1H NMR (300.132 MHz, CDCl3) δ 8.50 (t, J=4.7 Hz, 1H), 7.89 (dd, J=9.3, 5.1 Hz, 1H), 7.52 (t, J=8.8 Hz, 1H), 6.98 (m, 2H), 6.91 (dd, J=2.4, 0.9 Hz, 1H), 3.79 (s, 3H), 3.67 (s, 3H), 3.44 (q, J=6.7 Hz, 2H), 1.64 (sextet, J=7.3 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H). MS APCI, m/z=385 (M+H). HPLC 2.62 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=4)=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(F)c(Cl)c1
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(F)c(Cl)c4)nc23)ccn1
Yield: 42.3 %

Procedure:
Reaction of 1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (134 mg, 0.5 mmol), prepared from commercially available 3-chloro-4-fluoro-acetophenone according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (86 mg, 42%). MS (ISP) 407.3 [(M+H)+]; mp 292° C.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[O:17]C2CCCCO2)[C:10]([O:12][CH3:13])=[O:11])[CH2:3][CH2:2]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CO>[O:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[OH:17])[C:10]([O:12][CH3:13])=[O:11])[CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(OC2CCCCO2)c(C2=CCOCC2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC(=O)c1ccc(O)c(C2=CCOCC2)c1
Temperature: 45 °C
Reaction time: 19 h
Yield: 67 %

Procedure:
To a stirred mixture of 66.46C (0.73 g, 2.30 mmol) in MeOH (10 mL) was added PPTS (58.8 mg, 0.234 mmol). The mixture was heated to 45° C. and monitored with TLC and LCMS. After 19 hours, the organic solvent was removed under reduced pressure and the residue was purified on silica gel (0-25% EtOAc in hexanes) to afford 66.46D (361 mg, 67% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.87 (2H, td, J=8.7, 2.2 Hz), 6.95 (1H, d, J=8.6 Hz), 6.00 (1H, m), 5.94 (1H, s), 4.34 (2H, q, J=2.7 Hz), 3.97 (2H, t, J=5.5 Hz), 3.89 (3H, s), 2.47 (2H, ddd, J=9.8, 5.5, 2.7 Hz).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13](OC)=[O:14])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C=O>O>[CH2:1]([N:8]1[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cncn1Cc1ccccc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCc1cncn1Cc1ccccc1

Procedure:
To a suspension of 2.16 g (0.01 mol) of 1-benzyl-5-carbmethoxyimidazole in 5 ml of water are succesively added 0.8 g (0.02 mol) of sodium hydroxide and 4 ml of ~37% aqueous formaldehyde. The resultant mixture is heated to reflux for 2 hours. After completion of the reaction, the solvent is stripped off, and the residual solid is extracted with ethyl acetate. The ethyl acetate extract is concentrated to give 1-benzyl-5-hydroxymethylimidazole as a solid, m.p. 138°-140° C.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][CH:4]=[C:3]([C:7](OC)=[O:8])[CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[OH:8][CH2:7][C:3]1[CH2:2][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][CH:4]=1
Reactant: COC(=O)C1=CCCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC=C(CO)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a cold (−20° C.) solution of 1-tert-butyl 3-methyl 5,6-dihydro-1,3(2H)-pyridinedicarboxylate (700.0 mg, 2.90 mmol) in dry toluene (40 mL) was added a solution of diisobutylaluminum hydride in toluene (1.5M, 4.83 mL, 7.25 mmol) dropwise under an argon atmosphere. The reaction mixture was stirred at 0° C. for 30 min and then stirred at room temperature. The reaction was quenched by an addition of water and the stirring was continued for additional 1 hr. The precipitated aluminum salts were filtered off. The filtrate was diluted with saturated NH4Cl solution, extracted with ethyl acetate. The separated organic phase was washed with brine, dried over MgSO4, filtered and evaporated to give tert-butyl 5-(hydroxymethyl)-3,6-dihydro-1(2H)-pyridinecarboxylate, which was used for the next reaction without further purification. (580.0 mg, yield 94%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[N+:12]([O-])=O.Cl.C(=O)(O)[O-].[K+]>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[NH2:12]
Reactant: C#CCSc1ccc(N)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: C#CCSc1ccc(N)c(N)c1
Reaction time: 0.5 h

Procedure:
4.8 G. of 1-amino-2-nitro-4-(prop-2-yn-1-ylthio)benzene in 14 ml. concentrated hydrochloric acid is treated with a solution of 24 g. stannous chloride in 14 ml. concentrated hydrochloric acid at 20°-30° C. After about 30 minutes, the mixture is neutralized with a saturated solution of potassium bicarbonate and chloroform added. The mixture is filtered, the chloroform layer separated, dried and evaporated yielding 1,2-diamino-4-(prop-2-yn-1-ylthio)benzene.
Reaction SMILES: [CH3:1][S:2]([CH3:4])=[O:3].CN(P(N(C)C)(N(C)C)=O)C.[Li]CCCC.Br[CH2:22][C:23]1[C:24]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[N:25][C:26]2[C:31]([C:32]=1[C:33]([NH:35][C@H:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:37][CH3:38])=[O:34])=[CH:30][CH:29]=[CH:28][CH:27]=2>C1COCC1>[CH3:1][S:2]([CH2:4][CH2:22][C:23]1[C:24]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[N:25][C:26]2[C:31]([C:32]=1[C:33]([NH:35][C@H:36]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:37][CH3:38])=[O:34])=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:3]
Reactant: CS(C)=O
Reactant: CC[C@H](NC(=O)c1c(CBr)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)c1c(CCS(C)=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
A solution of DMSO (0.075 mL, 1.05 mmol) and HMPA (0.38 mL, 2.2 mmol) in anhydrous THF (3 mL) was prepared under N2 and cooled to −78° C. To this was added a solution of n-BuLi (0.71 mL, 1.6 M in hexanes, 1.13 mmol), the reaction allowed to stir for 10 min., then 3-(bromomethyl)-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide (8) (200 mg, 0.44 mmol) was added as a solution in anhydrous THF (1 mL). The reaction was allowed to stir 10 min., additional anhydrous THF (1 mL) added, and reaction allowed stirring another 10 min. The cooling bath was then removed, saturated aqueous NH4CI (1 mL), H2O (1 mL), and Et2O (1 mL) added, the layers shaken together, and then separated. The organics were then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc/CH2Cl2) to give the desired product (170 mg, 85% yield) as a solid. 1H NMR (300 MHz, CDCl3, 52° C.) δ 8.10 (d, J=8.0 Hz, 1H), 7.86-7.61 (m, 2H), 7.55-7.25 (m, 12H), 5.29-5.16 (m, 1H), 3.44-3.07 (m, 2H), 2.73-2.37 (m, 2H), 2.27-2.15 (m, 3H), 2.15-1.86 (m, 2H), 1.02 (t, J=7.4 Hz, 3H); LCMS: m/z 457 (MH+). HRMS m/z 457.1927, calcd. 457.1950.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[C:11](Cl)(=O)C(Cl)=O>ClCCl.C(OCC)(=O)C.CN(C=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)nn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 6-chloropyridazine-3-carboxylic acid (4.2 g, 26.5 mmol) in a mixture of dichloromethane (100 mL) and ethyl acetate (30 mL) and a few drops of DMF was added oxalyl chloride (3 mL, 34 mmol). The mixture was stirred at room temperature for 4 h until solution was attained, then quenched with 20 mL of methanol. After 15 min, the mixture was concentrated, and the resulting solid was swirled in ether and filtered. The solid was triturated with dichloromethane and the filtrate was evaporated to provide the title compound. 1H NMR (400 MHz, acetone-d6): δ 4.04 (s, 3H), 8.05 (d, 1H), 8.31 (d, 1H).