Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([C@@H:12]1[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14][CH2:13]1)([CH3:11])([CH3:10])[CH3:9].[CH2:19]([C:21]1[C:26]([Cl:27])=[C:25](Cl)[N:24]2[N:29]=[CH:30][N:31]=[C:23]2[N:22]=1)[CH3:20]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:8]([C@@H:12]1[CH2:13][CH2:14][C@H:15]([NH:18][C:25]2[N:24]3[N:29]=[CH:30][N:31]=[C:23]3[N:22]=[C:21]([CH2:19][CH3:20])[C:26]=2[Cl:27])[CH2:16][CH2:17]1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)[C@H]1CC[C@@H](N)CC1
Reactant: CCc1nc2ncnn2c(Cl)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCc1nc2ncnn2c(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1Cl

Procedure:
0.280 g (2.76 mmol) Triethylamine, a spatula tip of tetrabutylammonium iodide and 0.393 g (2.53 mmol) of cis-4-tert-butylcyclohexylamine were added successively to a solution of 0.500 g (2.3 mmol) of 5-ethyl-6,7-dichloro-[1,2,4]triazolo[1,5-a]pyrimidine in 10 ml of toluene under stirring. The reaction mixture was heated at reflux for 5 hours and then stirred for another 12 hours at room temperature. The solvent was evaporated under reduced pressure and dichloromethane was added to the resulting residue. The resulting reaction mixture was washed with 2N hydrochloric acid and water. The organic phase was separated, dried and the solvent was evaporated under reduced pressure. Treatment of the resulting residue with hexane yielded 0.420 g (1.2 mmol, 52% of theory) of the title compound having a melting point of 120-122° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[S:8][C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:18].C(Cl)(Cl)Cl.CCCCCC>C(OC(=O)C)(=O)C>[Cl:18][C:4]1[C:5]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[S:8][C:6]=2[N:7]=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1nc2sc3c(c2c(=O)[nH]1)CCCC3
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(Cl)c2c3c(sc2n1)CCCC3
Yield: 81 %

Procedure:
To a 50 mL flask was added 5 (220 mg, 1 mmol) and 5 mL POCl3. The resulting mixture was refluxed for 2 h, and the solvent was removed under reduced pressure to afford a dark residue. To this was added 30 mL of CHCl3 and 300 mg of silica gel. The solvent was evaporated to afford a plug. Column chromatography of the plug with hexane: acetyl acetate=20:1 as eluent afford 192 g (81%) of 6 as a yellow solid: 1H NMR (DMSO-d6) δ 1.82 (m, 4H), 2.63 (s, 3H), 2.84 (m, 2H), 2.96 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:19]=2)[N:14]=[CH:13]1.Br[CH2:30][CH:31]1[CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].CO>CN(C=O)C.C(OCC)(=O)C>[CH:31]1([CH2:30][N:26]2[CH2:27][CH2:28][N:23]([C:18]3[CH:19]=[C:20]4[C:15](=[CH:16][CH:17]=3)[N:14]=[CH:13][N:12]([C:3]3[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=3[CH3:1])[C:6]([O:8][CH3:9])=[O:7])[C:21]4=[O:22])[CH2:24][CH2:25]2)[CH2:33][CH2:32]1
Reactant: BrCC1CC1
Reactant: COC(=O)c1ccc(C)c(-n2cnc3ccc(N4CCNCC4)cc3c2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)c(-n2cnc3ccc(N4CCN(CC5CC5)CC4)cc3c2=O)c1

Procedure:
Methyl 4-methyl-3-(4-oxo-6-piperazin-1-ylquinazolin-3(4H)-yl)benzoate (1.41 g), (bromomethyl)cyclopropane (0.40 ml), and potassium carbonate (2.1 g) were stirred in DMF (9.4 ml) at 60° C. for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with water (×3). The combined aqueous layers was extracted with EtOAc and the organic layers combined, washed with brine, dried (magnesium sulphate) and concentrated to yield a brown glass. MeOH was added and the resultant solid collected by filtration and washed with ethyl acetate to yield methyl 3-[6-[4-(cyclopropylmethyl)piperazin-1-yl]-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoate as a white solid (0.39 g); NMR Spectrum: (DMSOd6) 0.00 (m, 2H), 0.38 (m, 2H), 0.76 (m, 1H), 2.05 (s, 3H), 2.14 (d, 2H), 2.52 (m, 4H) 3.17 (m, 4H), 3.75 (s, 3H), 7.36 (s, 1H), 7.51 (m, 3H), 7.85 (s, 1H), 7.90 (d, 1H), 7.97 (s, 1H); Mass Spectrum: M+H+ 433.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[CH3:12][C:11]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:13]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc([N+](=O)[O-])c1
Product: CC(=O)Nc1cccc([N+](=O)[O-])c1
Yield: 89.4 %

Procedure:
To 10 g (72 mmol) of 3-nitroaniline, 10 ml (106 mmol) of acetic anhydride were added, followed by stirring. White crystals were precipitated with exotherm. After stirring for 10 minutes, ice water was poured into the reaction mixture. The crystals were dissolved in chloroform, followed by washing successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was distilled out under reduced pressure. The residue was washed with ethyl ether, whereby 11.6 g of white powder were obtained (yield: 89%).
Reaction SMILES: [NH2:1][C@:2]([CH3:13])([CH2:5][CH2:6][C:7]1[N:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)[CH2:3][OH:4].[C:14](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:15].C(N(CC)CC)C.O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:13][C@@:2]1([CH2:5][CH2:6][C:7]2[N:8]([CH3:12])[CH:9]=[CH:10][CH:11]=2)[CH2:3][O:4][C:14](=[O:15])[NH:1]1
Reactant: Cn1cccc1CC[C@@](C)(N)CO
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cccc1CC[C@]1(C)COC(=O)N1
Yield: 53.1 %

Procedure:
Subsequently, to a suspension of (2R)-2-amino-2-methyl-4-(1-methylpyrrol-2-yl)butan-1-ol 1/2 D-(−)tartrate (41.4 mg, 0.16 mmol) obtained above in dichloromethane (1.6 ml) was added successively di-t-butyl dicarbonate (0.1758 g, 0.81 mmol), triethylamine (0.225 ml, 1.62 mmol) and 4-dimethylaminopyridine (2.0 mg, 0.016 mmol) with stirring, and the resulting mixture was stirred at room temperature for 30 minutes. After stirring, water was added to the reaction mixture, and the resulting mixture was evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (3:2-2:1) as the eluent to afford (4R)-4-methyl-4-[2-(1-methylpyrrol-2-yl)ethyl]-1,3-oxazolidin-2-one (17.7 mg, yield: 53%).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:7]1[C:20]2[CH:19]=[CH:18][C:17]([CH2:21]O)=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6].CN(C=O)C>C(Cl)Cl>[Cl:3][CH2:21][C:17]1[CH:18]=[CH:19][C:20]2[N:7]([CH2:5][CH3:6])[C:8]3[C:13]([S:14][C:15]=2[CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: CCN1c2ccccc2Sc2cc(CO)ccc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN1c2ccccc2Sc2cc(CCl)ccc21
Reaction time: 1 h
Yield: 95.7 %

Procedure:
In an atmosphere of argon, thionyl chloride (0.65 ml, 8.86 mmol) was added at 0° C. to a mixture of 10-ethyl-3-hydroxymethylphenothiazine (1.14 g, 4.43 mmol), DMF (0.1 ml) and methylene chloride (12 ml), and the mixture was stirred for 1 hour and then at room temperature for 1 hour. The reaction mixture was concentrated under a reduced pressure, and chloroform and a saturated sodium bicarbonate aqueous solution (each 20 ml) were added to the residue in that order. The reaction product was extracted with ethyl acetate, and the extract was washed with saturated sodium chloride aqueous solution. The extract was dried over anhydrous magnesium sulfate, and then concentrated under a reduced pressure to give 3-chloromethyl-10-ethylphenothiazine (1.17 g, 4.24 mmol, 96%) as brown oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.O[C:14]1[C:15]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH2:26])=[O:25])[C:16]=2[N:17]=[N:18][N:19]=1>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][NH:10][C:14]2[C:15]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH2:26])=[O:25])[C:16]=3[N:17]=[N:18][N:19]=2)=[CH:7][CH:8]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Product: NC(=O)c1cccc2c(NCc3ccc(C(F)(F)F)cc3)nnnc12

Procedure:
Compound 8 was prepared following general synthetic scheme 7 wherein (4-(trifluoromethyl)phenyl)methanamine was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [348 (M+1)], 1H NMR (400 MHz, DMSO-d): δ 9.40-9.37 (m, 2H), 8.56-8.51 (m, 2H), 8.05 (s, 1H), 8.01 (t, 1H), 7.70 (d, 2H), 7.62 (d, 2H), 4.99 (d, 2H).
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:5]=[C:6]([CH:24]=[C:25]([Br:27])[CH:26]=1)[CH2:7][O:8][C@@H:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:10]1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C.Cl[CH2:38][C:39]1[NH:40][C:41](=[O:44])[NH:42][N:43]=1>CN(C)C=O.ClCCl>[Br:3][C:4]1[CH:5]=[C:6]([CH:24]=[C:25]([Br:27])[CH:26]=1)[CH2:7][O:8][C@@H:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:10]1[N:18]1[CH2:23][CH2:22][N:21]([CH2:38][C:39]2[NH:40][C:41](=[O:44])[NH:42][N:43]=2)[CH2:20][CH2:19]1
Reactant: O=c1[nH]nc(CCl)[nH]1
Reactant: Brc1cc(Br)cc(CO[C@@H]2Cc3ccccc3[C@H]2N2CCNCC2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1[nH]nc(CN2CCN([C@@H]3c4ccccc4C[C@H]3OCc3cc(Br)cc(Br)c3)CC2)[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
After reconversion to the base, the compound obtained in Step C of Example 1 (2.14 mmol) is dissolved in 30 ml of dimethylformamide. There are added 0.75 ml (4.28 mmol) of diisopropylethylamine and 314 mg (2.35 mmol) of 5-(chloromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one prepared according to the method described in Tetrahedron Letters, 2000, 41, 8661. The mixture is stirred for 12 hours at ambient temperature and then evaporated to dryness. The residue obtained is taken up in dichloromethane, washed, dried, filtered and evaporated. The oil obtained is purified by flash chromatography on silica to yield the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[C:16]([O:18][CH:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:20](=O)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=O)[CH:6]=[CH:7][CH:8]=1.C([O-])(=O)C.[NH4+:38].O.ClCCl>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[C:16]2[O:18][C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:38]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: [NH4+]
Reactant: COc1cccc(CC2CCCCC2C(=O)OC(C(=O)c2ccccc2)c2ccccc2)c1
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(CC2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
A solution of 2-oxo-1,2-diphenylethyl 2-[(3-methoxy-phenyl)methyl]cyclohexanecarboxylate (440 mg) and ammonium acetate (593 mg) in acetic acid (2.4 ml) was refluxed for 3 hours and cooled to room temperature, and a mixture of water and dichloromethane was added thereto. The organic layer was washed with water and sodium bicarbonate aqueous solution, dried over magnesium sulfate, and evaporated in vacuo to afford 2-[2-[(3-methoxyphenyl)methyl]cyclohexyl]-4,5-diphenyloxazole (394 mg).
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[C:3]#[C:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([CH2:25][N:26]=[N+:27]=[N-:28])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[OH:1][CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[C:3]1[N:26]([CH2:25][C:24]2[CH:29]=[CH:30][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[N:27]=[N:28][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C#CC(O)c1ccccc1[N+](=O)[O-]
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1C(O)c1ccccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
To a solution of diisopropylamine (6.6 ml, 47.1 mmole) in tetrahydrofuran (80 ml) at -78° C. under an argon atmosphere was added 2.5N butyllithium (17.4 ml, 43.5 mmole), and the mixture was stirred for 30 minutes. To this reaction mixture were next added a solution of ethyl propionate (4.0 ml, 39.5 mmole) in tetrahydrofuran (20 ml) and a solution of 2-nitrobenzaldehyde (4.0 g, 26.5 mmole) in tetrahydrofuran (20 ml) in this sequence, and the resulting mixture was further stirred at -78° C. for 30 minutes. To the reaction mixture were added tetrahydrofuran (10 ml) followed by water, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous saline in this sequence. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to give ethyl 4-hydroxy-4-(2-nitrophenyl)-2-butynoate as an oily product. After the ethyl 4-hydroxy-4-(2-nitrophenyl)-2-butynoate thus obtained was dissolved in toluene (80 ml), 4-methoxybenzylazide (13.0 g, 79.7 mmole) was added to the solution and stirred under heating at 100° C. for 3 hours. The reaction mixture was then cooled to room temperature. Precipitates were collected by filtration, washed with toluene and desiccated to give ethyl 5-[hydroxy-(2-nitrophenyl)methyl]-1-(4-methoxybenzyl)-1,2,3-triazole-4-carboxylate (a-2: highly polar product (MP)) (2.55 g, 15.7%). Furthermore, the filtrate was concentrated and purified by silica gel column chromatography (toluene:ethyl acetate=1:1) to give a 3:1 mixture (6.09 g, 37.4%) of ethyl 4-(hydroxy-(2-nitrophenyl)methyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate (a-1: low polar product (LP)) and a compound a-2.
Reaction SMILES: NC1C=C(C=CC=1OC)C(O)=O.Cl.[C:14]([NH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:21]([OH:23])=[O:22])(=[O:16])[CH3:15].[N+:29]([O-])([OH:31])=[O:30]>>[N+:29]([C:24]1[CH:25]=[C:26]([O:27][CH3:28])[C:18]([NH:17][C:14](=[O:16])[CH3:15])=[CH:19][C:20]=1[C:21]([OH:23])=[O:22])([O-:31])=[O:30]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C(=O)O)cc1NC(C)=O
Agent: COc1ccc(C(=O)O)cc1N
Agent: Cl
Product: COc1cc([N+](=O)[O-])c(C(=O)O)cc1NC(C)=O
Temperature: 0 °C
Yield: 72 %

Procedure:
3-amino-4-methoxybenzoic acid ("19") (Aldrich Chemical; Milwaukee, Wis.) (5 g or 29.9 mmol) was suspended in 40 ml acetic acid. Acetic anhydride (3 ml or 1:04 eq) was added by stirring. The reaction mixture was stirred for 2 hours at room temperature. 25 ml of 0.1N HCl was added and the precipitate was filtered off and washed with 3×10 ml of 0.1N HCl and 5×10 ml water to produce 5.97 g (about 95%). 3-(N-acetyl) amino-4-methoxybenzoic acid ("20") (5 g or 23.5 mmol) was added to 20 ml of fuming nitric acid at 0° C. on vigorous stirring. The solution was stirred at 0° C. for an additional hour and poured onto 200 g of ice. Precipitate was filtered off, washed with 5×20 mls of water and dried to produce 4.38 g (about 72%) of 2-nitro-4-methoxy-5(N-acetyl)aminobenzoic acid ("21"), which was converted into 2-nitro-4-methoxy-5-(N-acetyl)aminoacetophenone ("22") (about 63% yield) as described. 2-nitro-4-methoxy-5-(N-acetyl)aminoacetophenone ("22") (1 g or 4,76 mmol) was dissolved in 5 ml of DMF and the solution was added to 5-biotinamidocaproyl chloride prepared separately from 5-biotinamidocaproic acid (1.55 g or 1 eq.) and 5 ml thionyl chloride. The reaction mixture was stirred overnight at room temperature and added to 100 ml of diethyl ether. Precipitate was purified using small silica gel column and a step gradient of MeOH in CHCl3 to give 1.16 g (about 47%) of 2-nitro4-methoxy-5-(5-biotinamidocaproamido) acetophenone ("23"). This intermediate was converted into its corresponding alcohol (about 85% yield) and into the reactive NHS ester derivative 5-(5-biotinamidocaproamido)-4-methoxy-1-(2-nitro)phenylethyl-N-hydroxysuccinimidyl carbonate ("25") with about a 69% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]([C:9]2[O:10][C:11]3[C:16]([C:17](=[O:19])[CH:18]=2)=[CH:15][CH:14]=[C:13]([NH2:20])[CH:12]=3)=[CH:7][CH:6]=1)=[O:4].[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([NH:20][C:13]1[CH:12]=[C:11]2[C:16]([C:17](=[O:19])[CH:18]=[C:9]([C:8]3[CH:21]=[CH:22][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[O:10]2)=[CH:15][CH:14]=1)(=[O:25])[CH3:24]
Reactant: COC(=O)c1ccc(-c2cc(=O)c3ccc(N)cc3o2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2cc(=O)c3ccc(NC(C)=O)cc3o2)cc1
Yield: 56 %

Procedure:
The mixture consisting of 2 g of 7-amino-4'-flavonecarboxylic acid methyl ester thus prepared, 30 cc of pyridine, 15 cc of acetic anhydride is heated at 40° for 2 hours with stirring. Completion of the reaction is verified by thin-layer chromatography (benzene (90)-dioxane (25)-acetic acid (4) elution solvent). The reaction mixture is poured in 500 cc of ice water. The solid that is formed is filtered, washed with water and dried by formation of an azeotropic system with benzene. Yield 56%.
Reaction SMILES: [OH:1][CH:2]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][CH2:22][CH3:23])[CH:16]=[C:15]2[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][C:26]=1[O:35][CH3:36])[CH:3]([C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH3:10])[CH2:4][CH3:5].[C:37](OC(=O)C)(=[O:39])[CH3:38].C(N(CC)CC)C.C(Cl)Cl>C(OCC)(=O)C>[C:37]([O:1][CH:2]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][CH2:22][CH3:23])[CH:16]=[C:15]2[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][C:26]=1[O:35][CH3:36])[CH:3]([C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH3:10])[CH2:4][CH3:5])(=[O:39])[CH3:38]
Reactant: CCCNC(=O)C(CC)C(O)c1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2CCC
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)C(CC)C(OC(C)=O)c1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2CCC

Procedure:
Methyl 4-[5-[1-hydroxy-2-(propylcarbamoyl)butyl]-1-propylindol-3-ylmethyl]-3-methoxybenzoate (0.75 g, as a mixture of diastereomers) was combined with acetic anhydride (0.31 g), triethylamine (0.152 g), and methylene chloride (20 ml), under a nitrogen atmosphere, and the mixture heated under reflux for 20 hr. The cooled mixture was diluted with ethyl acetate, washed (1M hydrochloric acid (twice), water, brine), dried (MgSO4) and evaporated to give a dark oil. The product was purified by flash chromatography, eluting with 8:2 methylene chloride:ethyl acetate, to give methyl 4-[5-[1-acetoxy-2-(propylcarbamoyl)butyl]-1-propylindol-3-ylmethyl]-3-methoxybenzoate (0.69 g, 85%, as a mixture of diastereomers) as an oil: partial NMR (300 MHz, DMSO-d6): 0.40(t, 3H, CH3, one isomer), 0.66(t, 3H, CH3, other isomer), 0.79(m, 12H, 2×CH3, one isomer, 2×CH3, other isomer), 1.84(s, 3H, OCOCH3, one isomer), 1.97(s, 3H, OCOCH3, other isomer), 5.66 (d, 1H, CHOCOCH3, one isomer), 5.79(d, 1H, CHOCOCH3, other isomer), 7.67(br t, 1H, NH, one isomer), 8.04(br t, 1H, NH, other isomer).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH3:12])=[CH:6][CH:5]=1.[CH2:14](Cl)[CH2:15]O.C(N(C(C)C)CC)(C)C.[OH2:27]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:14][CH3:15])[CH2:11][CH2:12][OH:27])=[CH:6][CH:5]=1
Reactant: OCCCl
Reactant: O
Reactant: CCNc1ccc(C(=O)OC)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCO)c1ccc(C(=O)OC)cc1
Temperature: 25 °C

Procedure:
A mixture of 15 g (84 mmol) of 4-(ethylamino)benzoic acid methyl ester, 15 mL (0.224 mol) of ethylene chlorohydrine and 14.5 mL (84 mmol) of diisopropyl ethyl amine was refluxed for 5 hours. During the reflux, the temperature rose from 105° C. to 140° C. The reaction mixture was allowed to cool down to room temperature and 100 mL of water and 250 mL of ethyl acetate was added. After extraction, the organic fraction was isolated, washed 3 times with 50 mL of water, once with 50 mL of brine and dried over MgSO4. The solvent was removed under reduced pressure and N-ethyl-N-(2-hydroxyethyl)-4-aminobenzoic acid methyl ester was isolated by preparative column chromatography on Kieselgel 60 (Aldrich) using cyclohexane/ethyl acetate 1/1 as eluent. 5.0 g of N-ethyl-N-(2-hydroxyethyl)-4-aminobenzoic acid methyl ester was isolated (m.p. 61-64° C.)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]([NH:18][C:19](=[O:21])[CH3:20])[CH:11]=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15].C=O.[BH3-][C:25]#N.[Na+]>CC#N.CC(O)=O>[CH3:25][N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]([NH:18][C:19](=[O:21])[CH3:20])[CH:11]=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15]
Reactant: [BH3-]C#N
Reactant: CC(=O)Nc1ccc(C(F)(F)F)c(OC[C@H]2CCCN2)c1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(F)(F)F)c(OC[C@H]2CCCN2C)c1
Reaction time: 1 h

Procedure:
To a solution of (R)-N-[3-(pyrrolidin-2-ylmethoxy)-4-trifluoromethyl-phenyl]-acetamide (0.85 g, 2.81 mmol) in 25 mL CH3CN was added 1.13 mL formaldehyde (37% in H2O) and NaBH3CN (0.28 g, 4.50 mmol). The reaction was stirred for 1 h, and the pH of the reaction was neutralized every 15 min by introducing several drops of AcOH. The reaction was concentrated in vacuo and dissolved into Et2O and 6 N NaOH. The layers were separated, and the organic layer was washed twice with 6N NaOH and extracted with 6 N HCl twice. The acidic aqueous layer was basified with NaOH pellets and extracted 4 times with CH2Cl2. The CH2Cl2 layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to yield the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[C:7]([C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][OH:24])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH:25]=[O:26])=[CH:11][N:10]=1)=[O:8])[CH3:2].O.P([O-])(O)(O)=[O:32].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[C:7]([C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][OH:24])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([C:25]([OH:32])=[O:26])=[CH:11][N:10]=1)=[O:8])[CH3:2]
Reactant: O=P([O-])(O)O
Reactant: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OCCO)c(OC)cc23)c1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OCCO)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 57.2 %

Procedure:
To a stirred solution of 1-(3-ethoxy-benzoyl)-6-(2-hydroxy-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde (70 mg, 0.17 mmol) in t-butanol (1 mL) and water (1 mL) solution was added sodium dihydrogenphosphate monohydrate (97 mg, 0.71 mmol), 2-methyl-2-butene (0.12 mL, 1.06 mmol) and sodium chlorite (98.0 mg, 1.06 mmol) at room temperature. The reaction suspension was then stirred at room temperature for 14 hrs. The resulting two-phase mixture was partitioned between dichloromethane and water and acidified to pH=3 by addition of acetic acid. The aqueous phase was then extracted with dichloromethane (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a brown semi-solid oil. The crude product was recrystallized in ethyl acetate to afford 1-(3-ethoxy-benzoyl)-6-(2-hydroxy-ethoxy)-7-methoxy-isoquinoline-4-carboxylic acid (40 mg, 57% yield) as a light yellow solid. HR-MS m/e calcd for C24H25N1O7 (M−H+) 412.1391, found 412.1394; 1H NMR (300 MHz) compatible.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]Br.[O-:11][C:12]#[N:13].[K+].[CH3:15][OH:16]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:13][C:12]([O:16][CH3:15])=[O:11]
Reactant: CO
Reactant: N#C[O-]
Reactant: COC(=O)CCCCCBr
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCNC(=O)OC
Yield: 77 %

Procedure:
The reaction of 10.45 grams of 6-bromohexanoic acid methyl ester with 6.08 grams of potassium cyanate and 2.7 grams of methanol in 50 ml DMF following the procedure of Example 1 gave 7.82 grams (76.9%) of 6-methoxycarbonylaminohexanoic acid methyl ester having a boiling point of 104° C./0.0013 mbar.