Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]1[CH:4]=[CH:5][C:6]([O:14][CH3:15])=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[CH:9]=[CH:8]2.[OH-].[Na+]>[Pd].CO>[CH3:15][O:14][C:6]1[CH:5]=[CH:4][CH:3]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([CH3:13])=[N:11]2
Reactant: COc1ccc(Cl)c2nc(C)ccc12
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cccc2nc(C)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.5 %

Procedure:
A 1000-mL round-bottom flask was charged with 8-chloro-5-methoxy-2-methylquinoline hydrochloride (50.0 g, 204.8 mmol), methanol (300 mL), aqueous sodium hydroxide solution (3 M, 205 mL), and 10% palladium on active carbon (25 g). The system was purged with hydrogen gas, and the resulting mixture was stirred under a hydrogen atmosphere for 3 h at room temperature. The reaction mixture was filtered through a pad of Celite and concentrated under vacuum to remove most of methanol. The resulting solution was extracted with ethyl acetate (2×2000 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (gradient elution with 0-20% ethyl acetate/petroleum ether) to afford 5-methoxy-2-methylquinoline (36 g, 63%) as a yellow solid. MS (ES, m/z): 174 [M+H]+
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:7]=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]2[S:13][CH2:12][C:11]([CH3:15])([CH3:14])[C:10]=2[CH:16]=1>CCOCC>[C:17]([C:8]1[C:9]2[S:13][CH2:12][C:11]([CH3:14])([CH3:15])[C:10]=2[CH:16]=[C:6]([NH:5][C:3]([NH:2][CH3:1])=[O:4])[CH:7]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1cc(N)cc2c1SCC2(C)C
Reactant: CN=C=O
Solvent: CCOCC
Product: CNC(=O)Nc1cc(C(C)(C)C)c2c(c1)C(C)(C)CS2

Procedure:
Methylisocyanate (0.14 mL, 2.28 mmol) is added dropwise to a solution of 5-amino-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzothiophene (550 mg, 2.33 mmol) in Et2O (5 mL). A solid gradually forms and the reaction is quenched with H2O (10 mL). The reaction is extracted with Et2O (3×10 mL) and the organic layers dried (MgSO4) and evaporated to a tan solid. This solid is recrystallized from EtOAc to give the product as white prisms, mp>150° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH:8]=[C:7](C3C=CC=C[N+]=3[O-])[C:6]=2[CH:20]=1.ClC1C=CC(C2C=CC=CC=2)=CN=1.CC(O)(C#C)C.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:11][C:9]([CH3:12])([O:10][C:5]1[CH:6]=[CH:20][C:2]([Br:1])=[CH:3][CH:4]=1)[C:8]#[CH:7]
Reactant: CC1(C)C=C(c2cccc[n+]2[O-])c2cc(Br)ccc2O1
Agent: C#CC(C)(C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Clc1ccc(-c2ccccc2)cn1
Solvent: ClCCl
Product: C#CC(C)(C)Oc1ccc(Br)cc1
Reaction time: 8 h

Procedure:
The 6-bromo-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran used as the starting material was prepared as follows: (A) 69.2 g of p-bromophenol and 33.6 g of 2-methylbut-3-yn-2-ol were dissolved in 600 ml of dichloromethane and 75 ml of diethyl azodicarboxylate were added. 126 g of triphenylphosphine were added portionwise and the mixture was stirred overnight. The mixture was washed with dilute hydrochloric acid and 2M sodium hydroxide solution, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:10) for the elution. There was obtained an oil which was distilled to give 14.4 g of 4-(1,1-dimethyl-2-propynyloxy)bromobenzene of boiling point 96°-106° C./1 mmHg. (B) In an analogous manner to that described in Example 6(A), from 4-(1,1-dimethyl-2-propynyloxy)bromobenzene and 2-iodopyridine there was obtained 6-bromo-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran.
Reaction SMILES: [NH2:1][C:2](N)=[O:3].O1C=CN=C1.Cl.[OH-].[Na+].C(=O)(O)[O-].[Na+].[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)(=O)C>[C:2]([NH2:1])(=[O:3])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccccc1
Reactant: NC(N)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NC(=O)c1ccccc1

Procedure:
The reaction of the aliphatic carboxylic acid derivative (III) with the isocyanoacetate compound (IV) is carried out in a solvent (e.g., tetrahydrofuran, dioxane, dimethylformamide) in the presence of a base such as sodium methoxide, potasium t-butoxide or 1,8-diazabicyclo(5.4.0)undecene-7 at -50° to 50° C. The oxazole derivative (V) thus obtained is saponified with an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide) at 20° to 50° C., and the reaction mixture is acidified to give the oxazolecarboxylic acid derivative (VI) which is then treated with a mineral acid (e.g., 2N hydrochloric acid-methanol) at 40° to 80° C. to give the aminoketone compound (VII). Alternatively, the aminoketone compound (VII) may be prepared by hydrolyzing the compound (V) with a mineral acid, for example, by treating the compound (V) with 4N hydrochloric acid at 50° to 80° C. The subsequent reaction of the aminoketone compound (VII) with the benzoyl halide (VIII) is carried out in a solvent (e.g., ethyl acetate, benzene) in the presence of an acid acceptor (e.g., sodium hydroxide, sodium bicarbonate) at -20° to 20° C. The N-benzoylamine derivative (IX) thus obtained is then reacted with the halogenoacetate compound (X) in a solvent (e.g., tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile) in the presence of an acid acceptor (e.g., potassium hydroxide, sodium ethoxide, potassium t-butoxide, sodium hydride) at -50° to 30° C. to give the 3-benzoylaminopropionate derivative (II).
Reaction SMILES: C(N(CC)CC)C.O1CCOCC1.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15].[CH2:26]([O:44][C:45](=[O:48])[NH:46][OH:47])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>C(Cl)(Cl)Cl.O>[CH2:26]([O:44][C:45](=[O:48])[NH:46][O:47][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:25][CH:24]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)NO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCCCOC(=O)NOC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 7.5 parts of triethylamine in 25 parts of dioxan is added over 2 hours to a stirred suspension of 13.5 parts of p-nitrobenzoyl chloride and 24.2 parts of octadecyl-N-hydroxycarbamate in 125 parts of dioxan at 5° C. keeping the pH in the range pH3 to pH5. The temperature is raised to 25° C. and the mixture is stirred for a further 24 hours and then added to 1000 parts of water to give a waxy solid. The solid is dissolved in 250 parts of chloroform and the solution is washed with 200 parts of water, dried, filtered and is evaporated to constant weight at 40° C. under reduced pressure to give 31.5 parts of n-octadecyl-N-(p-nitrobenzoyloxy)carbamate as a waxy solid m.p. 84° C.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[CH:4]=[C:5]([NH:10][NH3+:11])[CH:6]=[CH:7][C:8]=1[CH3:9].[C:12](OCC)(=[O:17])[CH2:13][C:14]([CH3:16])=O.C([O-])(=O)C.[Na+].C(O)(=O)C>C(O)C>[CH3:2][C:3]1[CH:4]=[C:5]([N:10]2[C:12]([OH:17])=[CH:13][C:14]([CH3:16])=[N:11]2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N[NH3+])cc1C
Reactant: CCOC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(O)n(-c2ccc(C)c(C)c2)n1
Yield: 71 %

Procedure:
2-(3,4-Dimethylphenyl)hydrazinium chloride (900 g, 5.21 mol), ethyl acetoacetate (678 g, 5.21 mol), sodium acetate (428 g, 5.21 mol) and glacial acetic acid (10 L) were stirred at 118° C. for about 24 hours. The resulting mixture was cooled and concentrated, and the residue was dissolved in dichloromethane (10 L) and carefully washed with saturated sodium bicarbonate (3×3 L). The organic layer was concentrated to afford a solid. The solid was dissolved in ethanol (450 mL) under reflux. Petroleum ether (7.2 L) was slowly added, and the resulting mixture was cooled and filtered to afford the title compound (748 g, 71%). PXRD analysis provided the diffractogram as shown in FIG. 31.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20].CCO>C(CC(C)(C)C)(C)C>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:21][CH2:17][CH2:18][CH2:19][CH3:20])[O:8][C:7]=2[CH:9]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Reactant: CCCCN
Solvent: CC(C)CC(C)(C)C
Solvent: CCO
Product: CCCCNCC1OCc2ccc(S(C)(=O)=O)cc2O1
Temperature: 130 °C

Procedure:
A mixture of 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (30 mg, 0.10 mmol), n-butan-1-amine (0.50 ml, 5.1 mmol) and EtOH (1.0 ml) was heated under microwave radiation at 130° C. for 30 min. MS m/z (rel. intensity, 70 eV) 299 (M+, 1), 123 (8), 86 (bp), 77 (9), 72 (10).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:20]([O:21][CH3:22])=[CH:19][C:12]2[CH2:13][C:14](=O)[NH:15][CH:16]=[CH:17][C:11]=2[CH:10]=1.O.[Cl-].[NH4+]>O1CCOCC1>[CH3:22][O:21][C:20]1[C:9]([O:8][CH3:7])=[CH:10][C:11]2[CH2:17][CH2:16][NH:15][CH:14]=[CH:13][C:12]=2[CH:19]=1
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc2c(cc1OC)CCNC=C2

Procedure:
A boiling suspension of lithium aluminum hydride (0.8 g) in absolute dioxan (100 ml) is mixed with 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (2.2 g, 0.01 mol) and then refluxed for 3 hours. While cooling with iced water, 10% ammonium chloride solution is added and the precipitate formed is suction filtered. The filtrate is concentrated (to about 20 ml) in vacuo, the white precipitate obtained is suction filtered and washed with a little dioxan. Yield: 0.9 g. Mp: 162°-163° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:22])=[C:17]([CH:21]=1)[C:18](O)=O>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:22])=[C:17]([CH2:18][C:9]2[S:8][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:11][CH:10]=2)[CH:21]=1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: Clc1ccc(-c2cccs2)s1
Product: Clc1ccc(-c2ccc(Cc3cc(Br)ccc3Cl)s2)s1

Procedure:
2-(5-Chloro-2-thienyl)thiophene and 5-bromo-2-chlorobenzoic acid were treated in a manner similar to Reference Example 5 to give the target compound.
Reaction SMILES: FC(F)(F)C([N:5]([C:22]1[CH:23]=[C:24]([C:27](Cl)=[O:28])[S:25][CH:26]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=O.C(N(CC)CC)C.[C:39]([O:50][CH2:51][CH3:52])(=[O:49])[CH:40]([CH:42]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[OH:43])[OH:41]>CCOCC>[CH2:6]([NH:5][C:22]1[CH:23]=[C:24]([C:27]([O:41][CH:40]([CH:42]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[OH:43])[C:39]([O:50][CH2:51][CH3:52])=[O:49])=[O:28])[S:25][CH:26]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1csc(C(=O)Cl)c1
Reactant: CCOC(=O)C(O)C(O)C(=O)OCC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)OC(C(=O)OCC)C(O)C(=O)OCC)c1

Procedure:
A mixture of 4-[N-(trifluoroacetyl)-N-(hexadecyl)amino]-2-thiophenecarbonyl chloride and 1.2 g. of triethylamine in 100 ml. of warm ether is treated with 2.5 g. of diethyl tartarate and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the product as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:32][CH2:33][CH2:34][CH3:35])[N:21]([CH2:22][CH2:23][NH:24]C(=O)OC(C)(C)C)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1>C(#N)C>[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:32][CH2:33][CH2:34][CH3:35])[N:21]([CH2:22][CH2:23][NH2:24])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCN
Temperature: 25 °C
Yield: 81.7 %

Procedure:
Trifluoroacetic acid (100 mL) was added with stirring to a solution of 1,1-dimethylethyl N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (30.0 g, 78.2 mmol) in acetonitrile (100 mL). The reaction mixture was maintained at ambient temperature for 24 hours and then it was concentrated under vacuum. The residue was dissolved in a minimal amount of water and the pH of the solution was adjusted to pH 13 using 10% sodium hydroxide. The resulting precipitate was isolated by filtration and dried under high vacuum to provide 18.1 g of 2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethaneamine as an off-white solid, m.p. 196-199° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[F:26][C:27]([F:45])([F:44])[C:28]1[CH:29]=[C:30]([C:38]([CH3:43])([CH3:42])[C:39](Cl)=[O:40])[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1.C(OCC)(=O)C>CN(C)C=O.O1CCCC1>[F:26][C:27]([F:45])([F:44])[C:28]1[CH:29]=[C:30]([C:38]([CH3:43])([CH3:42])[C:39]([N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:40])[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1
Reactant: CNc1ccncc1-c1ccccc1C
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cnccc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of 140 mg (0.71 mmol) methyl-(3-o-tolyl-pyridin-4-yl)-amine in 1 ml N,N-dimethylformamide at 0° C. were added dropwise 0.71 ml (0.71 mmol) of 1 M potassium hexamethyldisilazide solution in tetrahydrofuran. Stirring was continued for 1 h at room temperature and the reaction mixture was cooled to 0° C. again. At this temperature, a solution of 270 mg (0.85 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 0.5 ml tetrahydrofuran was added. After stirring for 18 h at room temperature, ethyl acetate was added and the organic phase was washed with brine, dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 211 mg (58%) of the title compound as white foam.
Reaction SMILES: P(OCC)(OCC)OCC.[N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[C:24](=[O:30])[N:23]([CH2:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[C:22]1[C:40]3[CH:41]=[C:42]4[O:50][CH2:49][O:48][C:43]4=[CH:44][C:45]=3[C:46](=[O:47])[C:21]2=1)=[N+]=[N-]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[NH2:11][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[C:24](=[O:30])[N:23]([CH2:31][CH2:32][CH2:33][N:34]1[CH2:35][CH2:36][O:37][CH2:38][CH2:39]1)[C:22]1[C:40]3[CH:41]=[C:42]4[O:50][CH2:49][O:48][C:43]4=[CH:44][C:45]=3[C:46](=[O:47])[C:21]2=1
Reactant: COc1cc2c(=O)n(CCCN3CCOCC3)c3c(c2cc1OCCCN=[N+]=[N-])C(=O)c1cc2c(cc1-3)OCO2
Agent: CCOP(OCC)OCC
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: COc1cc2c(=O)n(CCCN3CCOCC3)c3c(c2cc1OCCCN)C(=O)c1cc2c(cc1-3)OCO2

Procedure:
Triethyl phosphite (0.022 mL, 0.183 mmol) was added to a solution of the compound 21 (0.040 g, 0.073 mmol) in benzene (4 mL), and the mixture was heated at reflux for 24 h. The mixture was diluted to a volume of 200 mL with CHCl3, washed with H2O (2×50 mL) and saturated aq NaCl (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by flash column chromatography (SiO2, ˜40 g), eluting with a gradient of 0.5% MeOH in CHCl3, to yield the title compound as a solid. The solid (0.015 g, 0.023 mmol) was diluted with benzene (4 mL), and 2 M HCl in methanol (6 mL) was added to the solution. The mixture was heated at reflux for 3 h. The reaction mixture was allowed to cool to room temperature and the precipitate was filtered to provide the desired compound 22 as a solid (0.007 g, 58%): mp>350° C. IR (film) 3413, 2346, 1751, 1651, 1559, 1437, 1309, 737 cm−1; 1H NMR (D2O) δ 6.77 (s, 1H), 6.62 (s, 1H), 6.56 (s, 1H), 6.16 (s, 1H), 5.96 (s, 2H), 4.86-4.82 (m, 2H), 4.01 (s, 6H), 3.78 (s, 2H), 3.67 (s, 3H), 3.32 (s, 4H), 3.24-3.19 (t, J=7.5 Hz, 2H), 2.19-2.17 (m, 4H); ESIMS m/z 522 (MH+); HRESIMS m/z 522.2249 (MH+), called for C28H32N3O7 522.2246; HPLC purity: 95.23% (C-18 reverse phase, MeOH—H2O, 85:15).
Reaction SMILES: [Cl-].CC1C=C(C)C=C(C)C=1[N+]1C=CN(C2C(C)=CC(C)=CC=2C)C=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:32]1[N:37]=[C:36]([CH:38]([S:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])=[C:46]([CH3:57])[CH:45]=2)[CH2:39][O:40][CH2:41][CH3:42])[CH:35]=[CH:34][CH:33]=1.[F:58][C:59]([F:72])([F:71])[C:60]1[CH:65]=[CH:64][C:63](B2OCCO2)=[CH:62][CH:61]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:41]([O:40][CH2:39][CH:38]([S:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])=[C:46]([CH3:57])[CH:45]=1)[C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([C:63]2[CH:64]=[CH:65][C:60]([C:59]([F:72])([F:71])[F:58])=[CH:61][CH:62]=2)[N:37]=1)[CH3:42]
Reactant: CCOCC(Sc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)n1
Reactant: FC(F)(F)c1ccc(B2OCCO2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1cc(C)c(-n2cc[n+](-c3c(C)cc(C)cc3C)c2)c(C)c1
Solvent: C1COCCO1
Product: CCOCC(Sc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24.5 %

Procedure:
To a mixture of palladium (II) acetate (6 mg, 0.027 mmol), 1,3-bis(2,4,6-trimethylphenyl)imidazoliumchloride (9 mg, 0.026 mmol) and Cs2CO3 (266 mg, 0.816 mmol) in 1,4-dioxane (1 mL) was added ethyl [(4-{[1-(6-bromo-2-pyridinyl)-2-(ethyloxy)ethyl]thio}-2-methylphenyl)oxy]acetate (125 mg, 0.275 mmol) in 1,4-dioxane (1.75 mL) and the resulting mixture stirred under nitrogen at ambient temperature for 10 min. 2-[4-(Trifluoromethyl)phenyl]-1,3,2-dioxaborolane (69 mg, 0.300 mmol) was then added and the resulting mixture heated to 85° C. and kept at this temperature for 16 h. The reaction mixture was then reduced and the residue partitioned between EtOAc (15 mL) and saturated aqueous NH4Cl (15 mL) and the layers separated. The aqueous layer was then re-extracted with EtOAc (15 mL) and the combined organic layers washed with brine (50 mL) dried (MgSO4) and filtered. The mixture was then reduced under vacuum and the resulting residue purified by SPE (silica, 10 g cartridge), eluting with cyclohexane:EtOAc (gradient 50:1 to 3:1). Further purification by mass directed autoprep HPLC afforded the title compound as an oil (35 mg).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].N([O-])=O.[Na+].[C:17](Cl)(=[O:20])[CH:18]=[CH2:19].CCOCC>C([O-])([O-])=O.[K+].[K+]>[C:17]([NH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])(=[O:20])[CH:18]=[CH2:19]
Reactant: NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: C=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [K+]
Solvent: CCOCC
Product: C=CC(=O)NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
1-Amino-1-deoxy-D-glucitol (0.16 mol; 29 g) and 0.2 g NaNO2 were dissolved under a nitrogen atmosphere at 0° C. in 100 ml of a 0.3M K2CO3 solution. Acryloyl chloride (0.32 mol; 28.96 g) was added under vigorous stirring. The reaction was carried out similar to the synthesis of 1. After addition of ether, white crystals and a yellow oil were formed. The crystals were separated and gave the product, while the oil was discharged. Stepwise addition of 2 l of ether to the mother liquid and storing it in the refrigerator gave more of the desired product. For further purification the crystals were recrystallized twice from water/ethanol/ether. Yield: 22.2 g (59%), m.p.: 125° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][CH2:6][C@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH3:15])[C:3]1=[O:16].[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][C@H:29]([C:31](O)=[O:32])[CH3:30])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1>>[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][C@H:29]([C:31]([NH:1][C@@H:2]2[CH2:8][CH2:7][CH2:6][C@H:5]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:4]([CH3:15])[C:3]2=[O:16])=[O:32])[CH3:30])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1
Reactant: CN1C(=O)[C@H](N)CCC[C@@H]1c1ccccc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1CCC[C@H](c2ccccc2)N(C)C1=O

Procedure:
Using a procedure similar to that described in example 3, except using (3R,7R)-3-amino-1-methyl-7-phenylazepan-2-one (3f) (60 mg) to couple with N-[(3,5-difluorophenyl)acetyl]-L-alanine (1e) (67 mg), the title compound was obtained as a white solid (100 mg, 84%). 1H NMR (300 MHz, CDCl3) δ 1.39 (d, 3H), 1.57 (m, 1H), 1.94 (m, 3H), 2.14 (m, 2H), 2.51 (s, 3H), 3.56 (s, 2H), 4.51-4.56 (m, 1H), 4.92-4.95 (m, 2H), 6.24 (bd, 1H), 6.70-6.75 (m, 1H), 6.83-6.85 (bd, 2H), 7.28-7.39 (m, 6H). MS APCI, m/z=444 (M+1). LC/MS 2.33 min., Method A.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[CH:7][C:6]=1[NH:16][C:17]([C:19]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][C:24]([O:30]C)=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:18])([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[CH:7][C:6]=1[NH:16][C:17]([C:19]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][C:24]([OH:30])=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:18])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc2c(=O)c(C(=O)Nc3cc(O)c(C(C)(C)C)cc3C(C)(C)C)c[nH]c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(C)(C)C)c(NC(=O)c2c[nH]c3cc(O)ccc3c2=O)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2,4-di-tert-butyl-5-hydroxy-phenyl)-7-methoxy-4-oxo-1H-quinoline-3-carboxamide (120 mg, 0.28 mmol) in DCM (1.5 mL) was added BBr3 (1.5 mL, 15.23 mmol) dropwise at −78° C. After the addition was complete the cooling bath was removed and the resulting reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with sat. solution of NaHCO3. The aqueous layer was extracted with DCM and the combined organic layer was dried over MgSO4, filtered and concentrated. The residue was purified via reverse phase HPLC to give N-(2,4-ditert-butyl-5-hydroxy-phenyl)-7-hydroxy-4-oxo-1H-quinoline-3-carboxamide. LC/MS: m/z 409.5 (M+H)+ at 1.83 min (10%-99% CH3 CN (0.035% TFA)/H2O (0.05% TFA)).