Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][NH2:3].[C:4]([NH:6][C:7](=[N:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][N:19]=[C:20]2[N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)SC)#[N:5]>CN(C=O)C>[NH2:5][C:4]1[N:6]=[C:7]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][N:19]=[C:20]3[N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[N:2]([CH3:1])[N:3]=1
Reactant: CSC(=NCCCOc1cccc2c(N3CCCCC3)nccc12)NC#N
Reactant: CNN
Solvent: CN(C)C=O
Product: Cn1nc(N)nc1NCCCOc1cccc2c(N3CCCCC3)nccc12
Temperature: 40 °C
Reaction time: 24 h

Procedure:
Methyl hydrazine (5.7 ml) is added to a stirred suspension of 1-cyano-3-[3-(1-piperidino-5-isoquinolyloxy)propyl]-2-methylpseudothiourea (7.77 g) in 62 ml of DMF under nitrogen. The reaction mixture is stirred at 40° C. under nitrogen for 24 hours, cooled to RT, evaporated under vacuo and the residue dissolved in warm absolute ethanol. The resulting precipitate is collected, washed with absolute ethanol and dried in air. The filtrate is evaporated in vacuo and the residue crystallized from acetonitrile and dried overnight, yielding 5.3 g of the crude product as an off-white solid, M.P. 173°-175°0 C. The crude product is placed on a silica gel column and eluted with methylene chloride/methanol. The combined pure fractions are evaporated and recrystallized from acetonitrile, yielding the desired product, M.P. 181°-182° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH:34]([F:36])[F:35])=[C:6]([C:8]2[N:12](COCC[Si](C)(C)C)[N:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[N:29][C:28]=23)=[O:23])[CH:7]=1.Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH:34]([F:36])[F:35])=[C:6]([C:8]2[C:9]([NH:21][C:22]([C:24]3[CH:25]=[N:26][N:27]4[CH:32]=[CH:31][CH:30]=[N:29][C:28]=34)=[O:23])=[CH:10][NH:11][N:12]=2)[CH:7]=1
Reactant: C[Si](C)(C)CCOCn1ncc(NC(=O)c2cnn3cccnc23)c1-c1cc(Cl)ccc1OC(F)F
Agent: Cl
Solvent: CO
Product: O=C(Nc1c[nH]nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 60 °C
Yield: 96.4 %

Procedure:
A suspension of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazol-4-yl]amide (59.0 g, 110 mmol) in methanol (420 mL) was treated with 6N HCl (80 mL) and the mixture heated at 60° C. for 4 hours. The solvent was evaporated and the residue triturated with water. The solid was collected by filtration, washed with water and left to air dry. The solid was triturated with a minimum volume of acetonitrile, collected by filtration, washed with diethyl ether and dried at 60° C. under high vacuum to afford the title compound as a yellow solid (42.9 g, 96%). 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.71 (s, 1H), 9.34 (dd, 1H), 8.68-8.69 (m, 1H), 8.66 (s, 1H), 8.25 (s, 1H), 7.62 (dd, 2H), 7.43-7.46 (m, 1H), 7.29 (dd, 1H), 7.23 (d, 1H).
Reaction SMILES: NC[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.CN=C=S.N1C2C=CC=CC=2NC=1CN[CH2:31][CH2:32][CH2:33][NH:34][C:35]([NH:38][C:39]#[N:40])=[N:36]C>>[N:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[NH:11][C:7]=1[CH2:6][NH:5][CH2:4][CH2:3][NH:36][C:35]([NH:38][C:39]#[N:40])=[N:34][CH2:33][CH2:32][CH3:31]
Reactant: CN=C(NC#N)NCCCNCc1nc2ccccc2[nH]1
Reactant: NCCCNCc1nc2ccccc2[nH]1
Agent: CN=C=S
Product: CCCN=C(NC#N)NCCNCc1nc2ccccc2[nH]1

Procedure:
Using in the abovve procedure, 2-[(3-aminopropyl)aminomethyl]benzimidazole (prepared by reacting 2-chloromethylbenzimidazole with 1.3-diaminopropane) and methyl isothiocyanate, the product is N-[3-(2-benzimidazolylmethylamino)propyl]-N'-cyano-N"-methylguanidine.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:12][C:13](=[O:16])[CH:14]=[CH2:15])[CH2:9][CH2:10][CH3:11].C(N(C(C)C)C(C)C)C.CN(C=O)C>C(OCC)(=O)C.[Pd]>[C:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:16])/[CH:14]=[CH:15]/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: C=CC(=O)OCCCC
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCCOC(=O)/C=C/c1ccccc1
Reaction time: 24 h
Yield: 71 %

Procedure:
The Pd/C monolith (42 mg of a 1% Pd/C monolith, 2 mol % Pd) prepared according to the method described in Example 2 was added to a 1 dram glass vial in air followed by iodobenzene (28 μL, 0.25 mmol), n-butylacrylate (54 μL, 0.375 mmol), ethyldiisopropylamine (1.5 equiv, 0.375 mmol, 65 μL) and 1 mL DMF. The vial was sealed under air with a rubber septum cap and placed in an oil bath preheated to 80° C. for 24 hours. After the allotted time, the reaction mixture was dissolved in ethyl acetate. Gas chromatographic analysis indicated a 71% yield of (E)-n-butyl cinnamate.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:7]([CH3:17])=[N:6][CH:5]=1)([O-:3])=[O:2].[CH3:18][N:19]([CH:21](N(C)C)OC(C)(C)C)[CH3:20]>CN(C)C=O>[N+:1]([C:4]1[N:8]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:7]([CH:17]=[CH:18][N:19]([CH3:21])[CH3:20])=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ncc([N+](=O)[O-])n1CCN1CCOCC1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1ncc([N+](=O)[O-])n1CCN1CCOCC1

Procedure:
2.4 g. (0.01 mole) of 5-nitro-2-methyl-1-(2-morpholinoethyl)-imidazole and 2.1 g. (0.012 mole) of bis-dimethylaminotert.-butoxymethane were heated in 9 ml. of dimethylformamide to 130° C. for 60 minutes. After removal of the solvent by evaporation, the residue was crystallized with isopropanol; m.p. 105°-106° C.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([N:18]1[CH2:26][CH:25]2[CH:20]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:22][CH2:23][C:24]2=[O:27])[CH2:19]1)=[O:17])=O)(C)(C)C.[ClH:40]>O1CCOCC1>[ClH:40].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([N:18]1[CH2:26][CH:25]2[CH:20]([C:21]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:22][CH2:23][C:24]2=[O:27])[CH2:19]1)=[O:17]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1

Procedure:
(3aRS,7aRS)-2-[(2-tert-Butoxycarbonylaminophenyl)acetyl]-7,7-diphenylperhydro-4-isoindolone (1.5 g) is treated with a 5.7N solution (15 cc) of hydrochloric acid in dry dioxane at 20° C. for 4 hours. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue purified by dissolution in acetonitrile (20 cc) and precipitation with isopropyl ether (30 cc). The solid is drained, washed with isopropyl ether and dried. (3aRS,7aRS)-2-[(2-Aminophenyl)acetyl]-7,7-diphenylperhydro-4-isoindolone hydrochloride (1.1 g) is obtained in the form of a slightly pinkish solid.
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:2][C:3]([N:5]1[CH2:13][CH2:12][CH2:11][C@H:6]1[C:7]([O:9][CH3:10])=[O:8])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1(C)C=CC=CC=1>[CH3:10][O:9][C:7](=[O:8])[C@@H:6]1[CH2:11][CH2:12][CH2:13][N:5]1[C:3](=[S:30])[CH2:2][NH:1][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CCCN1C(=S)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 132.2 %

Procedure:
To Boc-Gly-Pro-OMe (2.78 g, 9.72 mmol) in toluene (200 mL) was added Lawesson's reagent (2.36 g, 5.83 mmol). The mixture was heated to reflux for 2 h, then allowed to cool to RT and concentrated under vacuum to give a yellow residue. Flash chromatography (30% EtOAc/hexanes, silica gel) gave 2.33 g (76%) of the desired compound as a yellow oil. This was homogeneous by TLC and 1H NMR analysis and was used without further purification.
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=[O:2].CO[CH:8]([O:14]C)[CH2:9][CH2:10][CH2:11][CH:12]=O>CCOC(C)=O.CCCCCC>[N+:1](/[C:4](/[CH3:5])=[CH:12]/[CH2:11][CH2:10][CH2:9][CH:8]=[O:14])([O-:3])=[O:2]
Reactant: CC[N+](=O)[O-]
Reactant: COC(CCCC=O)OC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C/C(=C\CCCC=O)[N+](=O)[O-]
Yield: 62.8 %

Procedure:
Prepared according to the general procedure A from nitroethane 112b (80 mmol) and 5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound as yellow oil (1.58 g, 63% yield) after silica gel chromatography (EtOAc/Hexane).
Reaction SMILES: [N+:1]([C:4]1[C:9]2[NH:10][C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)([C:14]([OH:16])=O)[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].F[P-](F)(F)(F)(F)F.[CH3:30][N+:31](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN.C(O)C>CN(C)C=O>[CH3:30][NH:31][C:14]([C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[NH:10][C:9]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][C:8]=2[O:13][CH2:12]1)=[O:16]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Reaction time: 1 h
Yield: 42.4 %

Procedure:
5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxylic acid (0.044 g. 0.15 mmol) in N,N-dimethylformamide (3 mL) was combined with N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate [Oakwood #: 023926](160 mg, 0.42 mmol) and N,N-diisopropylethylamine (100 μL, 0.6 mmol) at room temperature. 3.0 M methylamine in ethanol (0.2 mL, 0.6 mmol) was added, and the resulting mixture was stirred for 1 h, at which time the mixture was partitioned between water and ethyl acetate. The organic layer was washed with 1 N HCl, washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude N-methyl-5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide solid (0.020 g. 30%). LCMS calculated for C15H15N4O4 (M+H)+: m/z=315.1. found: 315.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](O)([CH3:12])([CH3:11])[CH3:10].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([OH:8])[CH:3]=1
Reactant: CC(C)(C)O
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(C)(C)c1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 84 h

Procedure:
To a solution of 29.46 g (170.3 mmol) of 3-bromophenol (distilled) and 16.41 g (20.9 ml, 221.3 mmol) of t-butanol in 100 ml of carbon tetrachloride was added 20 ml of conc. sulfuric acid. The clear, colorless solution turned a dark magenta color and became hot. The solution was cooled in water (ambient temperature) and allowed to stir at room temperature for 84 hours. The reaction mixture was neutralized with sat. NaHCO3 solution (pH ~7.0), partitioned between 300 ml of water and 500 ml of dichloromethane, and the organic and aqueous layers were separated. The aqueous phase was washed with 2×500 ml-portions of dichloromethane. All organic phases were combined, washed with 400 ml of brine solution, dried over MgSO4, filtered and concentrated in vacuo to a purple oil. Purification by flash chromatography (silica, 5% ethyl acetate in hexane) followed by kugelrohr distillation (85-95° C., 2 mm Hg) yielded the title compound as a clear, slightly yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>CN(C)C1C=CN=CC=1.ClCCl>[C:37]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])(=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reactant: CCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCC(=O)OC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 49 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 172 mg (1 mmole) of n-decanoic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 217 mg (Yield: 49%) of the title compound having the following structure as a red oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[NH:13][CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[CH:10]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[NH:13][CH:12]=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=1
Reactant: COC(=O)c1c[nH]c(Sc2ccccc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1Sc1cc(C(=O)O)c[nH]1

Procedure:
Methyl 5-(2-methylphenylthio)pyrrole-3-carboxylate (1.1 g.) was combined with 20 ml. of 1N sodium hydroxide and 50 ml. of methanol and refluxed for 2.5 hours, at which time thin layer chromatography with hexane-5/ethyl acetate-1/5% acetic acid as eluant indicated reaction to be complete. Methanol was removed by evaporation, the aqueous residue was diluted with approximately one volume of water, and extracted with ether. The aqueous phase was acidified with 6N hydrochloric acid and the product extracted into ethyl acetate. The ethyl acetate was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to crude product (1.0 g.). Recrystallization from methylene chloride/hexane gave purified 5-(2-methylphenylthio)pyrrole-3-carboxylic acid (590 mg., m.p. 151°-153° C., m/e 233).
Reaction SMILES: ClCCl.[CH3:4][S:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])(=[O:7])=[O:6].CS(C)=O>C(N(CC)CC)C>[CH3:4][S:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[O:13])(=[O:7])=[O:6]
Reactant: CS(=O)(=O)CCCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CS(=O)(=O)CCCCC=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.6 %

Procedure:
To a dichloromethane (15 ml) solution of 5-(methylsulfonyl)-1-pentanol (344 mg, 2.07 mmol), dimethylsulfoxide (0.441 ml, 6.21 mmol) and triethylamine (1.15 ml, 8.28 ml) was added a sulfur trioxide pyridine complex (659 mg, 4.14 mmol) at 0° C. and the mixture was stirred at room temperature for 3 hours. After the reaction mixture was washed with water, the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, and the fraction obtained from the ethyl acetate eluate was concentrated under reduced pressure, whereby the title compound (183 mg, 1.11 mmol, 54%) was obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:20][N:21]([CH3:31])[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:20][N:21]([CH3:31])[C:22]1[CH:27]=[CH:26][C:25]([C:2]2[N:3]=[C:4]3[C:10]([C:11]([C:13]4([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)=[CH:24][CH:23]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Product: CN(C)c1ccc(-c2cnc3[nH]cc(C(=O)C4(C)CCCCC4)c3n2)cc1

Procedure:
[2-(4-Dimethylamino-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-(1-methyl-cyclohexyl)-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone and 4-(dimethylamino)phenylboronic acid following general procedures as described in these Examples. MP 272-274° C., M+H=363.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:19]CC3C=CC(OC)=CC=3)=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH2:19])=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2c(C)c(-c3ccccn3)nc3cc(F)ccc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N

Procedure:
A solution of 7-fluoro-N-(4-methoxybenzyl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (0.900 g, 2.410 mmol), trifluoroacetic acid (2.8 mL, 36.2 mmol), and DCM (4 mL) was stirred at 23° C. for 1 hour. Upon completion, the reaction was concd, and the resulting residue was partitioned between EtOAc and 1 N HCl. The aqueous layer was then basified, and the product extracted twice with EtOAc. The combined organics were dried over magnesium sulfate and concd, affording 7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine as a beige amorphous solid. Mass Spectrum (ESI) m/e=254.2 (M+1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].O[CH:13]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(Cl)Cl>[OH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]=1[CH:13]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Oc1ccc2ccccc2c1
Reactant: CCOC(=O)CCCCCC(O)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)CCCCCC(c1ccccc1)c1c(O)ccc2ccccc12
Reaction time: 5 h

Procedure:
2-Naphthol (1.152 g) and ethyl 7-hydroxy-7-phenyl-heptanoate (2g) were dissolved in methylene chloride (20 ml) followed by dropwise addition of boron trifluoride-ether complex (0.56 g). After 5 hours of stirring, the reaction mixture was extracted with chloroform and the extract was washed with water, dried, and concentrated. The residue was applied to a silica gel column (hexane-ethyl acetate) to provide the title compound (1.94 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2([C:21](O)=O)[CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].C(OC1C=CC(S(N[C@H]2CCC[C@H]2[C:44]([NH:46][OH:47])=[O:45])(=O)=O)=CC=1)C#CC>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([NH:15][C@H:16]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:21]2[C:44]([NH:46][OH:47])=[O:45])(=[O:13])=[O:14])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N[C@H]2CCC[C@H]2C(=O)NO)cc1
Reactant: CC#CCOc1ccc(S(=O)(=O)NC2(C(=O)O)CCCC2)cc1
Product: CC#CCOc1ccc(S(=O)(=O)N[C@H]2CCCC[C@H]2C(=O)NO)cc1
Yield: 63.5 %

Procedure:
(1R,2S)-2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}aminocyclopentanecarboxylic acid (0.506 g, 1.5 mmol) was converted to (1R, 2S)-2-[{[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxycyclopentanecarboxamide (0.28 g) as described in Example 21 to give an off-white solid (0.185 g), mp 140-145° C. Electrospray Mass Spec 353.4 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:3][O:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[NH:7].[OH-].[Na+].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]\[C:41]([OH:43])=[O:42]>C1C=CC=CC=1>[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]\[C:41]([OH:43])=[O:42].[C:23]([O:1][CH:2]([CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:3][O:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[NH:7])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N=C(NOCC(O)CN1CCCCC1)c1cccnc1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: N=C(NOCC(CN1CCCCC1)OC(=O)c1ccccc1)c1cccnc1
Reaction time: 2 h

Procedure:
20.9 g (75.0 mmol) of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-3-pyridine-carboximidamide [Hung. Pat. 177.578 (1976)] was dissolved in 300 ml of benzene. To this solution 150 ml of 1 N sodium hydroxide solution was added, followed by dropwise addition of 19.5 ml (168 mmol) of benzoyl chloride. After stirring the mixture intensively for 2 hours, 7.1 g (67 mmol) of sodium carbonate and a further portion of benzoyl chloride (9.75 ml; 84 mmol) was added, and the stirring was continued overnight. The phases were then separated, the organic layer was extracted with 1 N sodium hydroxide solution and water, dried and evaporated to dryness. The residue (41 g oil) was dissolved in 150 ml of acetone, and 8.7 g (75 mmol) maleic acid was added. The obtained precipitate was filtered off, washed with acetone, and dried.
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:30])[C:27]([OH:29])=O)=[CH:22][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)(=O)C(Cl)=O.[NH:37]([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][N:37]([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:27](=[O:29])[C:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:25][CH:24]=1)=[O:30])[CH3:43]
Reactant: CCOC(=O)CNCC(=O)OCC
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)C(=O)N(CC(=O)OCC)CC(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a suspension of 1.99 g (4.75 mmol) of 4-(octadecyloxy)-alpha-oxobenzeneacetic acid in 100 ml of methylene chloride and 3 drops of DMF stirred and cooled in an ice bath was added 2.1 ml (23.8 mmol) of oxalyl chloride. After 5 minutes the ice bath was removed and stirring was continued at room temperature for 1 hour. The reaction mixture was concentrated at reduced pressure and the resultant acid chloride was dissolved in 75 ml of anhydrous methylene chloride and added dropwise to an ice cooled solution of 1.25 ml (7.1 mmol) of diethyl iminodiacetate and 1.3 ml (9.5 mmol) of triethylamine in 25 ml of methylene chloride. The reaction mixture was stirred at room temperature for 17 hours and washed with NaHCO3 solution, dried and concentrated at reduced pressure. The resultant solid was recrystallized from methanol to give 2.4 g (86% yield, mp 63°-64°) of N-(2-ethoxy-2-oxoethyl)-N-[2-[4-(octadecyloxy)phenyl] -1,2-dioxoethyl]glycine ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:15])[C:9]([NH:11][C:12](=[O:14])[CH3:13])=[CH:10][C:5]=2[O:4][N:3]=1.[Li+].CC([N-]C(C)C)C.Cl[CH2:25][C:26]1[S:27][C:28]2[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:29]=2[C:30]=1[CH:31]([CH3:33])[CH3:32].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH:31]([C:30]1[C:29]2[CH:34]=[CH:35][C:36]([C:38]([F:41])([F:39])[F:40])=[CH:37][C:28]=2[S:27][C:26]=1[CH2:25][CH2:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:15])[C:9]([NH:11][C:12](=[O:14])[CH3:13])=[CH:10][C:5]=2[O:4][N:3]=1)([CH3:33])[CH3:32]
Reactant: CC(C)c1c(CCl)sc2cc(C(F)(F)F)ccc12
Reactant: CC(=O)Nc1cc2onc(C)c2cc1C
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1cc2onc(CCc3sc4cc(C(F)(F)F)ccc4c3C(C)C)c2cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.5 %

Procedure:
To a suspension of N-(3,5-dimethylbenzisoxazol-6-yl)acetamide (381 mg, 1.87 mmol) in anhydrous THF (15 mL) was added dropwise 2M LDA (2.3 mL, 4.6 mmol) for 30 min at −78° C. under N2 atmosphere. The mixture was stirred for 30 min at −78° C., to which a solution of 2-chloromethyl-3-isopropyl-6-(trifluoromethyl)benzothiophene (655 mg, 2.24 mmol) in THF (5.0 mL) was added dropwise for 30 min. The mixture was stirred for 2 h at the same temperature, and then warmed to room temperature. A saturated aqueous ammonium chloride and ethyl acetate were added to the reaction mixture. The organic layer was washed with water, brine, and dried over anhydrous sodium sulfate. After the solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate, 1:1) to give the titled compound as a pale yellow crystal (426 mg, yield. 50%).