Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47](O)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].O.O[N:52]1C2C=CC=CC=2N=N1.N>C1COCC1.[Pd]>[OH:1][C:2]1[C:7]2[C:8]3([OH:45])[C:21]([O:25][CH3:26])([CH:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([NH2:52])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[CH:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Reactant: On1nnc2ccccc21
Agent: [Pd]
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: COC1[C@@H](NC2=CC(=O)c3c(cc4c(c3O)C(=O)C3(OC)C(O)Cc5cc(C)c(C(N)=O)c(O)c5C3(O)C4=O)C2=O)O[C@@H](C)[C@H](OC)[C@H]1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 11.7 %

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (100 mg, 0.15 mmol) in THF (2 mL) was added 10% Pd/C and the reaction mixture was stirred at room temperature under hydrogen at 1 atmosphere for 4 h. The reaction mixture was filtered without exposure to air into another flask containing polystyrene-carbodiimide (260 mg, 0.29 mmol) and the mixture was stirred for 10 min. A solution of 1-hydroxybenzotriazole hydrate (40 mg, 22 mmol) in THF (1 mL) and ammonia (0.22 mL, 2.0 M solution in THF, 0.16 mmol) were added and the reaction mixture was stirred at room temperature under nitrogen for 4 h. The reaction was filtered through a micro filter and concentrated. The crude material was purified by preparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic) to afford 6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((2S,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide (12 mg, 15%) as a dark red solid: 1H NMR (500 MHz, CDCl3) δ 14.19 (s, 1H), 12.89 (s, 1H), 8.22 (s, 1H), 6.86 (d, J=8.5 Hz, 1H), 6.52 (s, 1H), 5.96 (s, 2H), 5.87 (s, 1H), 4.96 (d, J=6.0 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 3.79 (s, 3H), 3.78-3.66 (m, 3H), 3.61 (s, 3H), 3.59-3.50 (m, 2H), 3.40 (s, 3H), 3.37-3.30 (m, 3H), 3.13 (t, J=9.5 Hz, 1H), 2.46 (s, 3H), 1.36 (s, 3H); MS (ESI+) m/z 683 (M+H); HPLC 94.3% (AUC), tR 11.64 min.
Reaction SMILES: Br[C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:11].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:34][O:35][C:36](=[O:48])[C@H:37]([CH2:46]I)[NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>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].CC(N(C)C)=O>[CH3:34][O:35][C:36](=[O:48])[C@@H:37]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:46][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:11]
Reactant: COC(=O)[C@H](CI)NC(=O)OC(C)(C)C
Reactant: Cc1cc(C#N)cc(C)c1Br
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@H](Cc1c(C)cc(C#N)cc1C)NC(=O)OC(C)(C)C
Temperature: 35 °C
Reaction time: 8 h

Procedure:
A 5 L three-necked round-bottomed flask equipped with a nitrogen inlet, a mechanical stirred, an addition funnel and a thermocouple was charged with 4-bromo-3,5-dimethyl-benzonitrile (210 g, 1.0 mol) and DMAc (750 ml). The resulting suspension was stirred and heated to 35° C. to dissolve the solids. To the resulting mixture was then added P(o-tol)3 (6.0 g, 0.02 mol), Pd2(dba)3 (9.2 g, 0.01 mol) and the resulting mixture heated to about 75-80° C. The cooled mixture prepared in STEP A above was added by cannula to the reaction mixture at a rate which maintained the temperature at about 75-80° C. (about 2 hours). The resulting suspension was cooled to ambient temperature, then aged overnight with moderate agitation. The resulting suspension was then heated to about 35-40° C., filtered with silica (540 g). The silica bed was washed with DMAc (400 mL×2), the combined DMAc solutions cooled to about 0-5° C. and then added slowly to a mixture of ice and deionized water. The resulting mixture was maintained cold for 2 hours, over which time a white solid was observed to precipitate. The resulting mixture was then warmed to ambient temperature and aged overnight. The solid precipitate was cooled by vacuum filtration using a Buchner funnel. The filter cake was rinsed with deionized water (1 L×3), air dried overnight, then dried in a vacuum oven overnight. MeOH (1 L) was added to the solid and the resulting slurry was cooled to about 0-5° C., then aged at this temperature for 1 hour, with stirring. The solid was collected by filtration, washed with cold methanol (400 mL) and dried in a vacuum oven at 45° C. to yield the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19]C2C=C3C(=CC=2)N(C)C(=O)C=C3)[CH:13]=1)([CH2:10][CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3].C(Br)C=C>>[CH2:1]([C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)([CH2:10][CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCC(CC)(C(=O)OCC)c1cccc(OCc2ccc3c(ccc(=O)n3C)c2)c1
Solvent: C=CCBr
Product: C=CCC(CC)(C(=O)OCC)c1cccc(OC)c1

Procedure:
The ethyl 2-allyl-2-(3-hydroxyphenyl)butyrate used as a starting material was obtained using the procedures described in the portion of Example 1 which is concerned with the preparation of starting materials except that allyl bromide was used in place of ethyl iodide in the second alkylation step. The intermediate so obtained, ethyl 2-allyl-2-(3-methoxyphenyl)butyrate gave the following characteristic NMR signals: 0.76 (t, 3 H), 1.18 (t, 3 H), 2.05 (m, 2 H), 2.75 (m, 2 H), 3.80 (s, 3 H), 4.15 (q, 2 H), 5.15 (m, 2 H), 5.50 (m, 1 H), 6.80 (m, 3 H), 7.22 (m, 1 H). ##STR2##
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([C:18]([NH:21][CH2:22][CH2:23][CH2:24][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)([CH3:20])[CH3:19])[CH:14]=[CH:15][C:16]=1[Cl:17].Cl>ClCCl.C(N(CC)CC)C>[Cl:17][C:16]1[CH:15]=[CH:14][C:13]([C:18]([NH:21][CH2:22][CH2:23][CH2:24][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)([CH3:19])[CH3:20])=[CH:12][C:11]=1[NH:10][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(NCCCn1ccnc1)c1ccc(Cl)c(N)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NCCCn1ccnc1)c1ccc(Cl)c(NC(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Benzoyl chloride (0.21 ml) was added to a solution of N-[1-(3-amino-4-chlorophenyl)-1-methylethyl]-3-(imidazol-1-yl)propylamine (0.50 g) in dichloromethane (50 ml) and triethylamine (0.25 ml) with stirring at 0° C. The mixture was allowed to warm up to ambient temperature and stirred at this temperature for 18 hours. The mixture was washed with water, dried and evaporated. The residue was purified by flash column chromatography on silica using ethyl acetate/methanol/triethylamine (8:1:1) as the mobile phase. The product was obtained as an oil which was added to ethereal hydrogen chloride to produce a gum. The gum was triturated and then left standing for 18 hours. The resulting solid was ground up, filtered and dried to give 2'-chloro-5'-{1-[3-(imidazol-1-yl)propylamino]-1-methylethyl}benzanilide.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2].[CH3:13][O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1CCN>C(#N)C>[CH3:13][O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH2:11][CH2:12][NH:8][C:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2]
Reactant: COc1ccccc1CCN
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: COc1ccccc1CCNC(=S)n1ccnc1
Yield: 53.6 %

Procedure:
A solution of 1,1'-thiocarbonyldiimidazole (1.78 g, 10 mmol) and 2-methoxyphenethylamine (1.51 g, 10 mmol) in acetonitrile 25 mL) was stirred at room temperature for 20 h. The resulting precipitate was collected by filtration to provide 1.40 g (53%) of the titled product: IR (KBr, cm-1) 2944, 1563, 1493, 1409, 1282, 1246, 1031, 755; 1H NMR (300 MHz, DMSO-d6) δ 12.0 (br s, 1H), 7.65 (s, 1H), 7.25 (m, 2H), 7.05-6.9 (m, 4H), 3.8 (m, 2H), 3.8 (s, 3H), 2.95 (t, J=7 Hz, 2H); MS (FD) m/e 261 (M+); UV (EtOH) 278 nm (ε=7083), 216 nm (ε=12683), 203 nm (ε=22221).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:11]NC(=O)CCC(N)=O>C(Cl)(Cl)Cl>[Br:11][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: Clc1ncnc2[nH]ccc12
Solvent: ClC(Cl)Cl
Product: Clc1ncnc2[nH]cc(Br)c12
Temperature: 25 °C
Yield: 88.2 %

Procedure:
To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (30 g/0.02 mol) dissolved in 75 mL of chloroform was added 3.5 g (0.02 mol) of N-bromosuccinamide and the resulting mixture refluxed for 1 h. After cooling to room temperature, the precipitate was removed by filtration and dried under reduced pressure affording 4.1 g (89%) of the title compound. 1H NMR (400 MHz) (CDCl3) δ: 7.93 (d, 1H, J=2.8 Hz), 8.60 (s, 1H).
Reaction SMILES: Cl[CH:2]([C:7]([CH3:9])=O)[C:3]([O:5][CH3:6])=[O:4].[C:10]([NH2:18])(=[S:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCO>[CH3:9][C:7]1[N:18]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:17][C:2]=1[C:3]([O:5][CH3:6])=[O:4]
Reactant: NC(=S)c1ccccc1
Reactant: COC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: COC(=O)c1sc(-c2ccccc2)nc1C
Yield: 41.8 %

Procedure:
A solution of methyl 2-chloroacetoacetate (1.86 g, 12.4 mmol) and thiobenzamide (1.7 g, 12.4 mmol) in EtOH (50 mL) was refluxed for 18 h. The mixture was evaporated to dryness and the resulting oil was purified by flash chromatography to give methyl 4-methyl-2-phenylthiazole-5-carboxylate (1.21 g, 42%) as a colourless oil: 1H NMR (300 MHz, CDCl3) δ (TMS) 8.0-7.9 (m, 2H, arom), 7.5-7.4 (m, 3H, arom), 3.87 (s, 3H, OMe), 2.76 (s, 3H, Me-thiazole). Analysis calculated for C12H11NO2S: C 61.78; H 4.75; N 6.00; S 13.74. Found: C 61.56; H 4.71; N 5.82; S 14.61.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])[CH:9]([CH3:19])[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].C(=O)([O-])O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])[CH:9]([CH3:19])/[C:10](/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:29]\[OH:30])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)C(C)[C@H](c2ccc(Br)cc2)c2ccc(Cl)cc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(=N/O)C(C)[C@H](c2ccc(Br)cc2)c2ccc(Cl)cc2C)ccn1

Procedure:
In analogy to example 132, step 6, from (3R)-3-(4-bromophenyl)-3-(4-chloro-2-methyl-phenyl)-2-methyl-1-(2-methylpyridin-4-yl)propan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=457.0 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[OH:12]>[Pd]>[OH:12][C:3]1[C:2]([F:1])=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[NH2:9]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1O
Agent: [Pd]
Product: Nc1ccc(F)c(F)c1O
Reaction time: 12 h
Yield: 100.2 %

Procedure:
2,3 difluoro 6-nitro phenol (2 g, 11 mmol) was treated with 10%Pd/C (1 g) at 23 ° C. The reaction mixture was flushed with hydrogen gas and the reaction was allowed to stir 12 h before it was filtered through celite. The filtrate was concentrated in vacuo to afforded the title compound (1.6 g, 97%). EI-MS m/z 146 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[CH:6][C:7]=1[F:8].[Cl-].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH:24]=[N+:25]([CH3:27])[CH3:26].COC1C=C(C=CC=1OC)C=O.CNC>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:24]([N:25]([CH3:27])[CH3:26])[C:23]2[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:21]([O:20][CH3:19])[CH:22]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(-c2cc3ccccc3[nH]2)cc1Cl
Reactant: COc1ccc(C=[N+](C)C)cc1OC
Agent: CNC
Agent: COc1ccc(C=O)cc1OC
Agent: [Cl-]
Product: COc1ccc(C(c2c(-c3ccc(F)c(Cl)c3)[nH]c3ccccc23)N(C)C)cc1OC

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-(3-chloro-4-fluoro-phenyl)-1H-indole and (3,4-dimethoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 3,4-dimethoxy-benzaldehyde and dimethylamine.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:15]1([C:18]2[CH:22]=[C:21]([NH2:23])[N:20]([C:24]3[CH:33]=[CH:32][CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[N:29]4)[N:19]=2)[CH2:17][CH2:16]1.ClCCl.[OH-].[Na+]>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:23][C:21]2[N:20]([C:24]3[CH:33]=[CH:32][CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[N:29]4)[N:19]=[C:18]([CH:15]3[CH2:17][CH2:16]3)[CH:22]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(C2CC2)nn1-c1cccc2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(C3CC3)nn2-c2cccc3ncccc23)cc1
Temperature: 80 °C
Yield: 35 %

Procedure:
A mixture of 4-t-butylbenzenesulfonyl chloride (0.061 g, 0.26 mmol) and 3-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (0.05 g, 0.20 mmol) in pyridine (1 mL) was heated at 80° C. for 15 h with stirring. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous sodium hydrogen sulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude residue was dissolved in methanol (3 mL) and 1 M aqueous sodium hydroxide (1.0 mL, 1.0 mmol) and stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between dichloromethane (3 mL) and 1 M aqueous sodium hydrogen sulfate (3 mL). The phases were separated and the aqueous layer was extracted with dichloromethane (2×5 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.031 g, 0.070 mmol, 35%). 1H NMR (400 MHz, CDCl3) δ 8.84 (d, J=4.0 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.55-7.51 (m, 5H), 7.41 (s, 1H), 7.39 (s, 1H), 6.94 (d, J=7.2 Hz, 1H), 6.12 (s, 1H), 1.99-1.93 (m, 1H), 1.36 (s, 9H), 1.01-0.92 (m, 2H), 0.84-0.79 (m, 2H); MS: (ES) m/z calculated for C25H27N4O2S [M+H]+ 447.2. found 447.2.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.CCN(C(C)C)C(C)C.[C:27](Cl)(=[O:30])[CH2:28][CH3:29]>C1COCC1.C(OCC)(=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH:17][C:27](=[O:30])[CH2:28][CH3:29])[CH:14]=[CH:15][CH:16]=1
Reactant: CCC(=O)Cl
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(=O)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.8 %

Procedure:
To a solution of (3-quinoxalin-2-ylphenyl)amine (200 mg, 0.904 mmol) and DIEA (180 μL, 1.09 mmol) in THF (5 mL), propionyl chloride (87 μL, 1.0 mmol) was added and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate (20 mL), the organic phase was washed with water (10 mL), brine (10 mL), dried over MgSO4, and the solvent evaporated in vacuo. The resulting solid was triturated with diethyl ether and dried to afford 170 mg (67%) N-[3-(quinoxalin-2-yl)phenyl]propionamide. LCMS calculated for C17H15N3O (M+H): 278.12. found 276.00. 1H-NMR (CDCl3, 400 Mhz) δH: 9.44 (1H, br. s), 8.32 (1H, s), 8.14 (m, 2H), 7.41 (1H, d, J=7.5 Hz), 7.88-7.55 (4H, m), 7.52 (m, 1H), 7.40 (1H, br. S), 2.45 (2H, q, J=7 Hz), 1.28 (3H, t, J=7 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[O:9][CH3:10])[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:18]
Reactant: COc1ccccc1OC
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2ccccc2)cc1OC
Yield: 95.7 %

Procedure:
The process of Step 1, Example 4 was followed except that 292 grams of 1,2-dimethoxy benzene, 297 grams of benzoyl chloride, and 281 grams of aluminum chloride were used to yield 490 grams of 3,4-dimethoxy benzophenone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:12])[CH2:10][CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:13]Br.CCCCCC>C(Cl)Cl.BrBr>[Br:13][CH:10]([CH3:11])[C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:12]
Reactant: CCC(=O)c1ccc(Cl)c(Cl)c1
Reactant: BrBr
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(Br)C(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 3′,4′-dichloropropiophenone (81, 5.02 g, 0.247 mol) in CH2Cl2 (100 mL) was added ten drops of bromine. After stirring at room temperature under nitrogen for several min, the characteristic red color of bromine disappeared indicating initiation of the reaction. The remainder of the bromine (1.27 mL, 24.7 mmol) was added dropwise and the reaction solution was allowed to stir at room temperature under nitrogen atmosphere for 1.75 h. Analysis by TLC (silica, 2:1 hexane:CH2Cl2) indicated consumption of starting material. The reaction solution was quenched and brought to a pH of 9 with a saturated aqueous solution of NaHCO3 and concentrated NH4OH. The solution was extracted with CH2Cl2, dried (Na2SO4), filtered, concentrated, and dried to give 7.14 g (100%) of 2-bromo-(3′,4′-dichlorophenyl)propan-1-one as a white solid. Characterization data is similar with data reported in Anderson, W. K.; Jones, A. N., J. Med. Chem. 1984, 27, (12), 1559-1565.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:20][C:21]([NH:23][C@H:24]([C:28]([NH:30][C@H:31]([C:44]([O:46]CC1C=CC=CC=1)=[O:45])[CH2:32][CH2:33][C:34]([O:36]CC1C=CC=CC=1)=[O:35])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])(=[O:17])[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][CH3:16]>C(OCC)(=O)C.CO.O.[Pd]>[C:1]([O:18][CH:19]([CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:20][C:21]([NH:23][C@H:24]([C:28]([NH:30][C@H:31]([C:44]([OH:46])=[O:45])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])(=[O:17])[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][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)C(C)C
Yield: 100.1 %

Procedure:
Dibenzyl N-[N-(3-hexadecanoyloxyoctadecanoyl)-L-valyl]-L-glutamate (950 mg) prepared by the method of Example 2 was dissolved in a mixture of ethyl acetate (200 ml) and methanol (50 ml). A suspended mixture of palladium black (800 mg) in water (10 ml) was added thereto. The mixture was subjected to catalytic hydrogenation at 2.5 atmospheric pressure. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dried up by using high vacuum pump to afford amorphus N-[N-(3-hexadecanoyloxyoctadecanoyl)-L-valyl]-L-glutamic acid (770 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[C:18]1([C:24]2[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([NH:30][C:27]3[CH:26]=[CH:25][C:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:29][N:28]=3)=[O:17])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2ccc(CC(=O)O)cc2)ccn1
Reactant: Nc1ccc(-c2ccccc2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(-c4ccccc4)cn3)cc2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(4-(2-methylpyridin-4-yl)phenyl)acetic acid 26-3 (50 mg, 0.2 mmol), 5-phenylpyridin-2-amine (41 mg, 0.24 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (114 mg, 0.3 mmol) in 1.5 mL DMF was added N,N-diisopropylethylamine (DIEA, 104 μL, 0.6 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2-(4-(2-methylpyridin-4-yl)phenyl)-N-(5-phenylpyridin-2-yl)acetamide 26 as white solid. MS m/z 380.17 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 10.84(s, 1H), 8.60(d, 1H, J=2.4 Hz), 8.42(d, 1H, J=6.4 Hz), 8.10(d, 1H, J=8.8 Hz), 8.04(dd, 1H, J1=8.8 Hz, J2=2.4 Hz), 7.70(m, 2H), 7.65(m, 2H), 7.51(m, 1H), 7.44(m, 5H), 7.33(m, 1H), 3.76(s, 2H), 2.46(s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH:10][C:28]([C:23]2([C:20]3[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=3)[CH2:24][CH2:25][CH2:26][CH2:27]2)=[O:29])=[N:7][CH:6]=1
Reactant: COc1ccc(C2(C(=O)O)CCCC2)cc1
Reactant: Nc1ncc(Cc2ccccc2Cl)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C2(C(=O)Nc3ncc(Cc4ccccc4Cl)s3)CCCC2)cc1
Reaction time: 16 h

Procedure:
5-(2-Chloro-benzyl)-thiazol-2-ylamine (45 mg, 0.20 mmol) and 1-(4-Methoxy-phenyl)-cyclopentanecarboxylic acid (44 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (2 mL) containing triethylamine (84.1 L, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography. ESI-MS m/z calc. 426.1. found; 427.2 (M+1)+ Retention time 3.97 minutes. 1H NMR (400 MHz, MeOD) d 1.62-1.84 (m, 4H), 1.95-2.17 (m, 2H), 2.41-2.62 (m, 2H), 3.78 (s, 3H), 4.22 (s, 2H), 6.90 (d, J=8.8 Hz, 2H), 7.03-7.49 (m, 7H).