Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[C:22]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:23]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[C:22]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:23]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3cncc(S(C)(=O)=O)c3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(Nc3cncc(S(C)(=O)=O)c3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
To a solution of N-tert-butyl-2-(5-(methylsulfonyl)pyridin-3-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (125 mg, 241 mol) in dichloromethane was added trifluoroacetic acid (550 mg, 371 μL, 4.82 mmol) and the mixture stirred at room temperature for 16 h. The mixture was concentrated then re-dissolved in dichloromethane (3.7 mL), methanol (1.6 mL) and ammonium hydroxide (0.5 mL) and the mixture stirred at room temperature for 1 h. The mixture was concentrated in vacuo then triturated with water and filtered. The solid obtained was washed with ether then dried to give N-tert-butyl-2-(5-(methylsulfonyl)pyridin-3-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (92 mg, 237 mol, 98%) as a yellow solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.38 (s, 1H), 9.90 (s, 1H), 9.40 (d, J=2.5, 1 H), 8.55 (d, J=1.9, 1 H), 8.06 (t, J=2.2, 1H), 8.01 (s, 1H), 7.96 (s, 1H), 7.54 (s, 1H), 3.22 (s, 3H), 1.31 (s, 9H); MS (EI/CI) m/z: 389.1 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O>C(OCC)(=O)C>[O:18]=[C:17]1[C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][C:14](=[O:16])[O:19]1
Reactant: O=C(O)C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C1C[C@@H](NC(=O)OCc2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
A stirred suspension of N-(benzyloxycarbonyl)-D-aspartic acid (14.7 g, 55.1 mmol) in ethyl acetate (100 mL) was treated dropwise with thionyl chloride (40 mL, 511 mmol) and the resulting homogeneous mixture was stirred at room temperature for 16 hours, and concentrated. The resulting solid was triturated in 1:1 diethyl ether/hexanes (200 mL) for 2 hours and filtered. The solid was dried to provide the desired product (13.7 g, 99%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][C:29]1[C:34](=O)[NH:33][C:32]([NH:36][C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[N:43]=[CH:42][CH:41]=[CH:40]3)=[C:31]([C:47]#[N:48])[CH:30]=1>O1CCOCC1>[Cl:1][C:34]1[C:29]([F:28])=[CH:30][C:31]([C:47]#[N:48])=[C:32]([NH:36][C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[N:43]=[CH:42][CH:41]=[CH:40]3)[N:33]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1cc(F)c(=O)[nH]c1Nc1ccc2ncccc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: N#Cc1cc(F)c(Cl)nc1Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
A 1,4-dioxane (100 ml) solution containing N-chlorosuccinimide (4.15 g) was added dropwise to a 1,4-dioxane (50 ml) solution containing triphenylphosphine (8.58 g) at 50° C., followed by stirring for 30 minutes. 5-fluoro-6-oxo-2-(quinolin-6-ylamino)-1,6-dihydropyridin-3-carbonitrile (2.61 g) was added to the reaction mixture, followed by stirring at 70° C. for 3 hours. The reaction mixture was cooled to room temperature. Then solid matter was collected by filtration and was washed with tetrahydrofuran, and a gray solid of 6-chloro-5-fluoro-2-(quinolin-6-ylamino)nicotinonitrile (2.34 g) was thus obtained.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1.[Li+].CC([N-]C(C)C)C.[CH2:29]([Si:31]([CH2:35][CH3:36])([CH2:33][CH3:34])Cl)[CH3:30]>C1COCC1>[Br:13][C:14]1[CH:19]=[C:18]([Si:31]([CH2:35][CH3:36])([CH2:33][CH3:34])[CH2:29][CH3:30])[C:17]([F:20])=[CH:16][N:15]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: Fc1ccc(Br)nc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC[Si](CC)(CC)c1cc(Br)ncc1F
Yield: 96 %

Procedure:
To a solution of diisopropylamine (25.3 g, 250 mmol) in THF (400 ml) was added n-BuLi (100 ml, 2.5 mol/L in hexanes) below −50° C. A solution of 2-bromo-5-fluoropyridine (41.9 g, 238 mmol) in THF (60 ml) was added to the LDA-solution at −78° C. in a dropwise manner below −63° C. After 60 minutes at −78° C. triethylchlorosilane (44 ml, 262 mmol) was added in a fast manner keeping the temperature below −50° C. The cooling bath was removed and the reaction mixture was allowed to reach −20° C. The reaction mixture was poured on a mixture of 1M aq. HCl (250 ml) and aq. NH4Cl (10%). Tert.-butyl methyl ether was added and the layers were separated. The organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated to give a yellow liquid. Distillation (bp. 99-101° C., 0.5 mm Hg). afforded the title compound as a slightly yellow liquid: 66.26 g (96% yield)
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[CH3:6][O:7][C:8](=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=O>CS(C)=O>[CH3:6][O:7][C:8](=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:3][C:2]#[CH:1]
Reactant: [Li]CCCC
Reactant: COC(=O)CCCCCCCC=O
Solvent: CS(C)=O
Product: C#CC=CCCCCCCCC(=O)OC

Procedure:
n-Butyl lithium (750 μL, 2M) was added methyl sulfoxide (6 mL) under argon at room temperature. The solution was stirred for half an hour, and (3-trimethylsillyl-2-propynyl)-triphenylphosphonium bromide (1 mmole) in methyl sulfoxide was added and stirred for one hour. 9-Oxo-nonanoic acid methyl ester in methyl sulfoxide was added to the reaction mixture and stirred for 4.5 hours. The reaction mixture was poured onto ice water and extracted with ethyl acetate three times. The organic layers were combined and dried to obtain crude mixture, which was further purified through Si gel column chromatography. The product contained trans and cis isomers in about 8:2 ratio.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[CH:3]=1.[F:10][C:11]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=1[NH2:13]>>[F:10][C:11]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=1[NH:13][C:2]1[CH:3]=[C:4]([NH:8][CH3:9])[N:5]=[CH:6][N:7]=1
Reactant: Nc1ccc(F)cc1F
Reactant: CNc1cc(Cl)ncn1
Product: CNc1cc(Nc2ccc(F)cc2F)ncn1

Procedure:
The title compound is prepared analogously as described in Example 114A from (6-chloro-pyrimidin-4-yl)-methylamine and 2,4-difluoroaniline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:22]=[C:21]([CH2:23][N:24]([CH3:35])[S:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:20]=[CH:19][C:9]=2[O:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[CH:4][C:3]=1[S:36]([CH3:39])(=[O:38])=[O:37]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:22]=[C:21]([CH2:23][N:24]([CH3:35])[S:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)(=[O:26])=[O:27])[CH:20]=[CH:19][C:9]=2[O:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[S:36]([CH3:39])(=[O:38])=[O:37]
Reactant: CN(Cc1ccc(OCC(=O)OC(C)(C)C)c(-c2ccc(F)c(S(C)(=O)=O)c2)c1)S(=O)(=O)c1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1ccc(OCC(=O)O)c(-c2ccc(F)c(S(C)(=O)=O)c2)c1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
To a solution of TFA/DCM (1:3, 10 mL) was added intermediate 31 (150 mg, 0.26 mmol, 1 eq) and the mixture was stirred at room temperature for 2 h. The organic solvent was removed in vacuo and the crude product was purified by reversed phase semi-preparative HPLC to afford 100 mg (73%) of 2-((4-fluoro-3-(methylsulfonyl)phenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)acetic acid (Example 28). 1HNMR (CD3CN, 300 MHz): δ 8.08 (m, 1H), 7.95 (m, 1H), 7.88 (m, 2H), 7.26-7.44 (m, 5H), 7.00 (d, 1H), 4.71 (s, 2H), 4.18 (s, 2H), 3.25 (s, 3H), 2.55 (d, 3H). MS (ES-API): MH−=524.1. HPLC (Method A) tR=2.02 min.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>C1C=CC=CC=1.CO>[Br:1][CH:2]([CH3:6])[C:3]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[O:4]
Reactant: CC(Br)C(=O)Cl
Reactant: C1COCCN1
Solvent: CO
Solvent: c1ccccc1
Product: CC(Br)C(=O)N1CCOCC1

Procedure:
This compound is prepared by reaction of 2-bromopropionylchloride with morpholine under the experimental conditions of Example 10: b.p. 115°-120° C. (0.1-0.2 mm); Rf=0.52 (C6H6 -MeOH 80:20); IR (neat) νmax: 2860, 1660, 1470, 1440, 1280, 1260, 1125, 1040 cm-1. The product is very irritating to the skin and mucosae.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[C:9]([N:12]1[CH2:16][CH2:15][CH:14]([N:17]([CH3:39])[C:18]([C:20]2[O:21][C:22]3[C:28](F)=[C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:26]([CH3:36])=[C:25]([C:37]#[N:38])[C:23]=3[N:24]=2)=[O:19])[CH2:13]1)(=[O:11])[CH3:10].C(N(CC)CC)C>CS(C)=O>[C:9]([N:12]1[CH2:16][CH2:15][CH:14]([N:17]([CH3:39])[C:18]([C:20]2[O:21][C:22]3[C:28]([N:5]4[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]4)=[C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:26]([CH3:36])=[C:25]([C:37]#[N:38])[C:23]=3[N:24]=2)=[O:19])[CH2:13]1)(=[O:11])[CH3:10]
Reactant: CC(=O)N1CCC(N(C)C(=O)c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)C1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(N(C)C(=O)c2nc3c(C#N)c(C)c(-c4ccccc4)c(N4CC[C@H](N(C)C)C4)c3o2)C1
Reaction time: 0.75 h
Yield: 52.5 %

Procedure:
Under nitrogen atmosphere at 140 to 150° C., a dimethyl sulfoxide (1 ml) solution of (3S)-3-(dimethylamino)pyrrolidin (86 μl, 679 μmol) was added to a dimethyl sulfoxide (10 ml) solution of N-(1-acetylpyrrolidin-3-yl)-4-cyano-7-fluoro-N,5-dimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-206) (238 mg, 566 μmol) and triethylamine (103 μl, 736 μmol), followed by stirring at the same temperature for 45 minutes. After cooling, the solvent was evaporated away under reduced pressure, the residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine, then the aqueous layer was extracted with ethyl acetate. Next, saturated sodium hydrogencarbonate water was added to the aqueous layer, followed by extraction with chloroform. The combined organic layer was dried over anhydrous magnesium sulfate, then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with dichloromethane/methanol (10:1, v/v) gave the entitled compound (153 mg, 53%) as an amorphous substance.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=1)=[O:22]>>[CH2:1]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH2:17][N:33]1[CH2:34][CH2:35][CH:30]([C:26]2[CH:25]=[C:24]([NH:23][C:21](=[O:22])[CH:20]([CH3:19])[CH3:36])[CH:29]=[CH:28][CH:27]=2)[CH2:31][CH2:32]1)[CH2:2][CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)CCOc1ccc2ccccc2c1C=O
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)CCOc1ccc2ccccc2c1CN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure F and Scheme R using 2-(isopentyloxy)-1-naphthaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 473.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]([O:14][C:15](=[O:36])[CH2:16][O:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([C:25]2[O:26][C:27]3[N:28]=[C:29](Cl)[N:30]=[CH:31][C:32]=3[N:33]=2)=[CH:20][C:19]=1[CH3:35])([CH3:13])([CH3:12])[CH3:11]>CC(N(C)C)=O>[C:10]([O:14][C:15](=[O:36])[CH2:16][O:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([C:25]2[O:26][C:27]3[N:28]=[C:29]([O:9][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[N:30]=[CH:31][C:32]=3[N:33]=2)=[CH:20][C:19]=1[CH3:35])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1cc(-c2nc3cnc(Cl)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3cnc(Oc4ccccc4)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
19 mg of sodium hydride were added under an argon atmosphere to a solution of 38 mg of phenol in 5 ml of dimethylacetamide. After stirring for 30 min at room temperature, a solution of 156 mg of [4-(5-chloro-oxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethyl-phenoxy]-acetic acid tert-butyl ester in 3 ml of dimethylacetamide was added slowly. The mixture was allowed to stir for 1.5 h at room temperature. Upon consumption of the starting ester an aqueous solution of citric acid (100 g/l) was added until the pH was neutral. The aqueous layer was extracted twice with 15 ml ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the solvents were removed in vacuo. The title compound was isolated by silica gel chromatography (heptane/ethyl acetate gradient). Yield: 77 mg of a white solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:9]=3[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(O)(=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([O:17][C:14]2[CH:15]=[CH:16][C:9]3[CH2:8][CH2:7][N:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:12][CH2:11][C:10]=3[CH:13]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Oc1ccc2c(c1)CCN(C1CCCC1)CC2
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)CCN(C2CCCC2)CC3)CC1

Procedure:
3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E4) (1.1 g, 4.8 mmol), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.15 g, 5.7 mmol), di-tert-butyl azodicarboxylate (1.31 g, 5.7 mmol) and triphenylphosphine (1.5 g, 5.7 mmol) were stirred at room temperature for 16 hours in tetrahydrofuran (20 ml). The mixture was acidified with acetic acid and applied to a SCX ion exchange cartridge (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia:methanol (1:9). The combined basic fractions were concentrated in vacuo and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (1:9:90) to afford the title product (E5a); MS (ES+) m/e 415 [M+H]+.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[C:5]([OH:8])[C:4]2[O:9][C:10]([C:12]3[C:17]4[C:3]=2[C:2]=1[C:19](=[O:20])[O:18][C:16]=4[C:15]([OH:21])=[C:14]([OH:22])[CH:13]=3)=[O:11].C(O[C:27](=[O:29])[CH3:28])(=O)C>N1C=CC=CC=1>[CH3:5][C:6]([O:7][C:6]1[CH:1]=[C:2]2[C:19](=[O:20])[O:18][C:16]3[C:15]([O:21][C:4]([CH3:3])=[O:9])=[C:14]([O:22][C:10]([CH3:12])=[O:11])[CH:13]=[C:12]4[C:10]([O:9][C:4]([C:5]=1[O:8][C:27]([CH3:28])=[O:29])=[C:3]2[C:17]=34)=[O:11])=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1oc2c(O)c(O)cc3c(=O)oc4c(O)c(O)cc1c4c23
Solvent: c1ccncc1
Product: CC(=O)Oc1cc2c(=O)oc3c(OC(C)=O)c(OC(C)=O)cc4c(=O)oc(c1OC(C)=O)c2c34
Yield: 9.2 %

Procedure:
To a slurry of 10.0 g (29.6 mmol) of ellagic acid dihydrate in 250 mL of pyridine was added 100 mL of acetic anhydride. The solution was heated to reflux for 3 hours. The hot solution was filtered and upon cooling, crystals formed. The crystals were filtered, washed with hexane, and vacuum dried to give 1.28 g (9.2%) of pure ellagic acid tetraacetate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1.Cl[C:35]([C@@H:37]([O:39]C(=O)C)[CH3:38])=[O:36]>>[OH:39][C@@H:37]([CH3:38])[C:35]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1)=[O:36]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: O=C(NCC1CNCCO1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: C[C@H](O)C(=O)N1CCOC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (morpholin-2-ylmethyl)-amide (example A147) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+:11].CC(C)=O.[C:16](Cl)(=[O:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>O>[C:16]([NH:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5])(=[O:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[Na+:11].[Na+:11]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: CCCCCCCCCCCCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCC(=O)N[C@@H](CC(=O)[O-])C(=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a one L three-necked flask were placed 31.9 g (0.24 mol) of L-aspartic acid and an aqueous solution of 19.2 g (0.48 mol) of sodium hydroxide in 150 mL of water under stirring. After the L-aspartic acid was dissolved, 120 mL of acetone was added to the mixture in the flask. Then, to the resultant reaction liquid which had been cooled to 0° C. were added dropwise over a period of 30 minutes, 52.2 g (0.2 mol) of pentadecanoyl chloride and an aqueous solution of 0.2N sodium hydroxide in 30 mL of water simultaneously therewith, while maintaining the reaction temperature at 0 to 5° C. and pH at 11 to 12. Thereafter, by gradually raising the temperature of the reaction liquid to room temperature (25° C) under stirring over a period of 2 hours, a solution of disodium pentadecanoyl-L-aspartate was obtained. To the resultant solution was added 140 mL of 5N hydrochloric acid to lower the pH of the solution to 1. The crystal thus precipitated was separated from the solution by means of vacuum filtration, washed with water and dried under reduced pressure. The resultant crystal was washed with 500 mL of hexane, dried and recrystallized from a mixed solvent of ethanol/water (1:1 v/v). As a result 39.8 g (0.11 mol) of N-pentadecanoyl-L-aspartic acid was obtained in a yield of 55.6% based on the fed pentadecanoyl chloride. The physical properties of the objective N-pentadecanoyl-L-aspartic acid were as follows.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:12]([O:14][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[CH:13]=[C:4]([C:3]([O:2][CH3:1])=[O:15])[CH:5]=1
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCOc1cc(C(=O)OC)cc(C(=O)OC)c1
Yield: 85.3 %

Procedure:
The product was generated using general protocol D using dimethyl-5-hydroxyisophthalate (3.920 g, 18.7 mmol), 1-bromohexadecane (5.18 g, 17.0 mmol), K2CO3 (9.37 g, 67.8 mmol), CH3CN (100 mL) yielded 6.30 g (86.5%) of a white solid. 1H NMR (CDCl3, 600 MHz) δ: 8.26 (t, 3J=1.4 Hz, 1H, Ar—H), 7.74 (d, 3J=1.5 Hz, 2H, Ar—H), 4.03 (t, 3J=6.5 Hz, 2H, O—CH2), 3.94 (s, 6H, COO—CH3), 1.80 (p, 3J=7.3 Hz, 2H, OCH2CH2), 1.46 (p, 3J=7.6 Hz, 2H, OCH2CH2CH2), 1.26 (m, 24H), 0.88 (t, 3J=6.8, 3H, CH2—CH3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[C:12](=[O:23])[CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN.[CH3:38][N:39](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N1C=CC=CC=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[C:12](=[O:23])[CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([NH:39][CH3:38])=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N(CCc2ccc(C(F)(F)F)cc2)C(=O)C(C(=O)O)c2ccccc2)cc1OC
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CNC(=O)C(C(=O)N(CCc1ccc(C(F)(F)F)cc1)c1ccc(OC)c(OC)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.3 %

Procedure:
A mixture of 16.2 mg (0.033 mmol) N-(3,4-Dimethoxy-phenyl)-2-phenyl-N-[2-(4-trifluoromethyl-phenyl)-ethyl]-malonamic acid, 15.5 mg (0.049 mmol) methylamine (commercially available), 13.8 mg (0.043 mmol) TBTU and 7.8 mg (0.09 mmol) pyridine in 2 mL DMF was shaken for 4 h at room temperature. The mixture was evaporated to dryness, taken up in methanol, formic acid and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and acetic acid. The combined product fractions were evaporated to dryness to yield 2.7 mg (16%) of the title compound. MS(m/e): 501.3 (MH+), MH+ found: 501.3.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[Br-].O=[C:14]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:15][CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][C:17]1=[N+]1CCCC1>C(O)(=O)C>[C:7]([C:6]1[CH:10]=[C:2]([N:1]2[C:17]3[CH2:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:16]=3[CH:15]=[C:14]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:3]=[CH:4][C:5]=1[OH:11])([OH:9])=[O:8]
Reactant: O=C(CC1C(=[N+]2CCCC2)CCc2ccccc21)c1ccccc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Agent: [Br-]
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)ccc1O
Temperature: 60 °C

Procedure:
304 g of 5-aminosalicylic acid are added to 3800 ml of acetic acid while stirring. The stirred suspension is heated to 60° C. and 791 g of tautomeric 1-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]pyrrolidinium bromide in equilibrium with 1-phenacyl-2-(1-pyrrolidino)-3,4-dihydronaphthalene hydrobromide are added. An additional 150 ml of acetic acid are added to the reaction mixture, which is stirred at 70° C. for 3 to 4 hours and then cooled to ambient temperature. A solid appears and is collected by filtration, washed successively with acetic acid and petroleum ether and dried for 16 hours under vacuum to give 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole.