Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:23]([CH3:24])=[CH:22][C:21]([Cl:25])=[CH:20][C:9]=1[C:10]([N:12]=[S:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])=[O:11].[Cl:26][C:27]1[C:28]([N:33]2[C:37]([C:38](Cl)=[O:39])=[CH:36][C:35]([C:41]([F:44])([F:43])[F:42])=[N:34]2)=[N:29][CH:30]=[CH:31][CH:32]=1>ClCCl>[Cl:26][C:27]1[C:28]([N:33]2[C:37]([C:38]([NH:7][C:8]3[C:9]([C:10](=[O:11])[N:12]=[S:13]([CH:17]([CH3:18])[CH3:19])[CH:14]([CH3:16])[CH3:15])=[CH:20][C:21]([Cl:25])=[CH:22][C:23]=3[CH3:24])=[O:39])=[CH:36][C:35]([C:41]([F:44])([F:42])[F:43])=[N:34]2)=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cc(Cl)cc(C(=O)N=S(C(C)C)C(C)C)c1N
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(Cl)cc(C(=O)N=S(C(C)C)C(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 2 h
Yield: 54.1 %

Procedure:
To a suspension of potassium carbonate (1.79 g, 10 mmol, 1.30 equiv) and 2-amino-3-methyl-5-chloro-N-(bis-2-propyl-λ4-sulfanylidene)benzamide (3.00 g, 9.97 mmol) in dichloromethane (20 mL) was added a solution of 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carbonyl chloride (4.000 g, 10.97 mmol, 1.10 equiv.) in dichloromethane (10 mL) at room temperature. After 2 h at this temperature, the solids were filtered off. The resulting filtrate was washed with water and dried over Na2SO4. After filtration, the filtrate was concentrated in vacuum and the resulting solids were crystallized from diisopropyl ether to yield the title compound (3.1 g, 54%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]([C:14]([O:16]CC)=[O:15])[C:7]2=[O:19])[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[N:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]([C:14]([OH:16])=[O:15])[C:7]2=[O:19])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2ccc(OCC)nc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccc2[nH]cc(C(=O)O)c(=O)c2n1
Yield: 90.9 %

Procedure:
A mixture of ethyl 6-ethoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (2.98 g), 1N NaOH (50 mL), and ethanol (10 mL) was heated at reflux for 2 h. The reaction mixture was cooled in an ice bath, acidified, and the resulting precipitate collected, rinsed with water and dried to give 2.42 g of 6-ethoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[NH:14][CH:13](Cl)[C:12]=2[CH2:11][CH2:10]1.[CH3:28][NH2:29]>>[CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13]([NH:29][CH3:28])[C:12]=2[CH:11]=[CH:10]1
Reactant: Cc1cc(F)ccc1N1CCC2=C1c1cccc(OC(F)(F)F)c1NC2Cl
Reactant: CN
Product: CNc1nc2c(OC(F)(F)F)cccc2c2c1ccn2-c1ccc(F)cc1C
Temperature: 180 °C

Procedure:
1-(2-Methyl-4-fluorophenyl)-4-chloro-6-trifluoromethoxy-2,3,4,5-tetrahydropyrrolo[3,2-c]quinoline(394 mg, 1.0 mmol) was dissolved in aqueous solution of methylamine (40%, 10 ml) in the pressure tube. The reaction mixture was refluxed at 180° C. for 3 hours. After removing the reaction solvent of the above mixture, the residue was diluted in dichloromethane(20 ml), and washed with water(15 ml) for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 301 mg of desired compound as solid in 77% of yield.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH2:17]=[C:18]([CH3:20])[CH3:19].C([O-])(O)=O.[Na+]>O1CCOCC1>[C:18]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:2]=1[OH:1])([CH3:20])([CH3:19])[CH3:17]
Reactant: O=C(O)c1ccc(O)cc1O
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(O)cc1O
Temperature: -50 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4-dihydroxy benzoic acid (3.08 g; 20 mmol) in dioxane (50 mL) was added conc. H2SO4 (3 mL) and the solution was cooled to −50° C. Isobutene (40 g) was added, the reaction flask sealed and allowed to warm to room temperature. The reaction mixture was stirred overnight, cooled to −30° C. and pH adjusted to 8 using saturated NaHCO3 (aq). The organic phase was Isolated, dried, evaporated to dryness and purified by column chromatography (SiO2-heptane/EtOAc=4:1) to yield 2.3 g (54%). MS (LC-MS): 209 (MH−).
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([C:13]2[C:14](=[O:23])[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][C:7]1=[O:24])(=O)[CH2:2][CH2:3][CH3:4].[CH2:25]([O:27][NH2:28])[CH3:26]>CO>[CH2:25]([O:27][NH:28][C:1](=[C:6]1[C:11](=[O:12])[CH2:10][CH:9]([C:13]2[C:14](=[O:23])[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][C:7]1=[O:24])[CH2:2][CH2:3][CH3:4])[CH3:26]
Reactant: CCCC(=O)C1C(=O)CC(c2cc3ccccc3[nH]c2=O)CC1=O
Reactant: CCON
Solvent: CO
Product: CCCC(NOCC)=C1C(=O)CC(c2cc3ccccc3[nH]c2=O)CC1=O

Procedure:
10 parts by weight of 2-butyryl-5-(2-oxoquinol-3-yl)-cyclohexane-1,3-dione, 2.0 parts by weight of ethoxyamine and 100 parts of methanol were stirred for 8 hours at room temperature. The solvent was distilled off under reduced pressure, the residue was taken up in 200 parts of dichloromethane, and the solution was washed with 5% strength hydrochloric acid, dried over sodium sulfate and evaporated down under reduced pressure. 2-(1-Ethoxyaminobutylidene)-5-(2-oxoquinol-3-yl)-cyclohexane-1,3-dione of melting point 155°-157° C. was obtained (active ingredient No. 2).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C@@H:8]([OH:11])[C:9]#[CH:10])=[CH:4][CH:3]=1.[N+:14]([C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([N+:26]([O-:28])=[O:27])[CH:25]=1)[C:20](Cl)=[O:21])([O-:16])=[O:15].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C@@H:8]([O:11][C:20](=[O:21])[C:19]2[CH:18]=[C:17]([N+:14]([O-:16])=[O:15])[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=2)[C:9]#[CH:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: C#C[C@H](O)COc1ccc(F)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#C[C@@H](COc1ccc(F)cc1)OC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (3S)-4-(4-fluorophenoxy)-3-hydroxy-1-butyne (est. 490 mmol) in methylene chloride (1 L) was added 3,5-dinitrobenzoyl chloride (125 g, 539 mmol) at between −5° C. and 0° C. , followed by slow addition of triethylamine (10.8 mL, 77 mmol) and a catalytic amount of dimethylaminopyridine (DMAP) (20 mg). After the mixture was stirred at ambient temperature for 40 minutes, the reaction mixture was cautiously partitioned between methylene chloride and aqueous NaHCO3. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with water and brine, and dried over Na2SO4. The solution was filtered through a pad of silica gel with methylene chloride which gave crude product as a tan solid. Rapid recrystallization from 99:1 mixture of methanol:acetic acid (5 L) gave 101 g of the enantiomerically enriched product, (3S)-4-(4-fluorophenoxy)-3-(3′,5′-dinitrobenzoyl)oxy-1-butyne, a compound of formula (BBa) as fluffy white needles. This material was determined to have greater than 98% ee by analytical HPLC using a Diacel Chiralpak AD® (4.6×250 mm, 60% 2-propanol/hexane, 1 mL/min), which separates the (R) (11.5 min) and the (S) (19.3 min) enantiomers; 1H NMR (CDCl3) δ2.65 (s, 1H), 4.40 (m, 2H), 6.05 (m, 1H), 6.90 (m, 2H), 7.0 (t, 2H), 9.15 (s, 2H), 9.25 (s, 1H) ppm.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]([CH2:14]C(O)=O)#[N:13].O.Cl>N1C=CC=CC=1>[C:12]([CH:14]=[C:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:6]1)#[N:13]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: N#CCC(=O)O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: N#CC=C1OC(=O)c2ccccc21
Reaction time: 6 h

Procedure:
A finely powdered mixture of phthalic anhydride (34 g.; 0.23 mole) and cyanoacetic acid (22 g.; 0.26 mole) was dissolved in dry pyridine (28 ml) and the mixture stirred for 6 hours at 60°-70° C. After cooling overnight the dark solid was treated with water (800 ml) and brought to pH 4-5 with hydrochloric acid. The resulting yellow solid was filtered off, washed well with water and recrystallised from glacial acetic acid, m.p. 178°-180° C (lit. m.p. 195° C).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:22])[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1.C[O:24][C:25](=[O:48])[C@H:26]([C@@H:45]([CH3:47])O)[NH:27]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([O:22][C@H:45]([CH3:47])[C@@H:26]([C:25]([OH:48])=[O:24])[NH2:27])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:7][CH:8]=1
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Reactant: COc1ccc(C2(O)c3ccccc3-c3ccccc32)cc1
Product: COc1ccc(C2(O[C@H](C)[C@H](N)C(=O)O)c3ccccc3-c3ccccc32)cc1

Procedure:
from 9-(4-methoxyphenyl)-9H-fluoren-9-ol (Example 3n) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
Reaction SMILES: [CH:1](=[C:8]1[C:12]2=[N:13][C:14]3[CH:15]=[C:16]([NH:22][C:23](/[CH:25]=[CH:26]\[C:27]([OH:29])=[O:28])=[O:24])[CH:17]=[CH:18][C:19]=3[C:20](=[O:21])[N:11]2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.[CH3:34]COCC>CO>[CH:1](=[C:8]1[C:12]2=[N:13][C:14]3[CH:15]=[C:16]([NH:22][C:23](/[CH:25]=[CH:26]\[C:27]([O:29][CH3:34])=[O:28])=[O:24])[CH:17]=[CH:18][C:19]=3[C:20](=[O:21])[N:11]2[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C\C(=O)Nc1ccc2c(=O)n3c(nc2c1)C(=Cc1ccccc1)CC3
Reactant: CCOCC
Agent: FB(F)F
Solvent: CO
Product: COC(=O)/C=C\C(=O)Nc1ccc2c(=O)n3c(nc2c1)C(=Cc1ccccc1)CC3

Procedure:
(Z)-3-[N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-2-propenoic acid (1.22 g) was heated in anhydrous methanol (190 ml) containing boron trifluoride etherate (1.58 ml) at reflux temperature for 8 hours. The reaction mixture was concentrated to a small volume in vacuo and the precipitate was filtered and washed with water until neutral to give 1.1 g of (Z)-3-[N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-2-propenoic acid, methyl ester, m.p. 233°-235° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[N:17][NH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[I:25]I>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16]([I:25])=[N:17][NH:18]3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]ncc23)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]nc(I)c23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
A solution of 4-[4-(t-butoxycarbonyl)piperazin-1-yl]-1H-indazole (5.00 g, 16.5 mmol) in N,N-dimethylformamide is treated with powdered potassium hydroxide (1.85 g, 33.07 mmol) and iodine (4.61 g, 18.2 mmol), stirred at room temperature for 16 h, diluted with ethyl acetate and quenched with 15% aqueous sodium metabisulfite. The phases are separated and the aqueous phase is extracted with ethyl acetate. The extracts and the organic phase are combined, washed with brine, dried over sodium sulfate and concentrated in vacuo to afford a crude solid. This solid is purified by column chromatography (silica gel, 10:90 to 15:85 to 20:80 ethyl acetate/hexanes) to afford the title product as a yellow solid, 2.40 g (35% yield) identified by HNMR and mass spectral analyses.
Reaction SMILES: [NH:1]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](O)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:24][CH:23]=1.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>C(O)(=O)C>[NH:1]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH:6][C:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:25]1[CH:24]=[CH:23][C:22]([CH3:21])=[CH:27][CH:26]=1
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Cc1ccc(C(O)(c2ccccc2)c2ccccc2)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(C(NC(=O)CC[C@H](NC(=O)OCc2ccccc2)C(=O)O)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
A mixture of 140.14 g Z-Gln-OH (0.5 mole) and 274.4 g 4-methyltriphenylcarbinol (1 mole) in 1.5 l acetic acid and 93.4 ml acetic anhydride (1 mole) is stirred at room temperature for 7 minutes. Upon addition of 2.5 ml concentrated sulfuric acid the temperature is raised to 50° C.; a clear, yellow solution results after 15 minutes. After 21/2 hrs the solution is allowed to cool and poured into 5 l ice-cold water. The precipitate formed is filtered off, washed thoroughly with water and dissolved in 1 l ethylacetate. The resulting solution is washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to an oil (400 ml) which crystallized on addition of diisopropylether.
Reaction SMILES: [N:1]1C=CC=CC=1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>C(Cl)Cl>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH2:1])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: c1ccncc1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(Br)cc1
Reaction time: 8 h

Procedure:
The optically pure resin-bound secondary amine resin (from Step C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) and then 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.
Reaction SMILES: [C:1]([BH3-])#N.[Na+].C=O.[C:7]([O:11][C:12]([NH:14][CH:15]([CH2:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C:16]([O:18][CH3:19])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[C:7]([O:11][C:12]([NH:14][CH:15]([CH2:20][N:21]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[CH3:1])[C:16]([O:18][CH3:19])=[O:17])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: COC(=O)C(CNCc1ccc(Cl)c(Cl)c1)NC(=O)OC(C)(C)C
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COC(=O)C(CN(C)Cc1ccc(Cl)c(Cl)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
Sodium cyanoborohydride (121 mg) was added to a solution of formaldehyde (570 mg), methyl 2-(tert-butoxycarbonylamino)-3-(3,4-dichlorobenzylamino)propionate (720 mg) and acetic acid (0.1 ml) in acetonitrile and the mixture was stirred at room temperature for 30 minutes. Aqueous sodium hydrogen carbonate (10 ml) was added and the mixture was extracted with ethyl acetate (3×20 ml). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colourless oil (722 mg). NMR δH (360 MHz, CDCl3) 1.45 (9H, s), 2.21 (3H, s), 2.73 (2H, d, J=7.0 Hz), 3.46 (2H, m), 3.75 (3H, s) 4.37 (1H, m), 5.19 (1H, br s), 7.10 (1H, dd, J=11.0 and 1.0 Hz), 7.36 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:6]([O:8][C:9](=[O:10])[C:4]=12)=[O:7].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.Cl>C(Cl)Cl.C(O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[C:6]([C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([O:2][CH3:1])[C:4]=1[C:9]([OH:8])=[O:10])=[O:7]
Reactant: COc1ccc(OC)cc1
Reactant: COc1cccc2c1C(=O)OC2=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(OC)c(C(=O)c2cccc(OC)c2C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.1 %

Procedure:
3-Methoxyphthalic anhydride (17.8 g, 0.1 mole) was suspended in 100 ml. dry methylene chloride (previously distilled over anhydrous potassium carbonate). To the suspension was added anhydrous aluminum chloride (30.5 g, 0.23 mole) in one portion. The suspension quickly became bright yellow and was stirred at room temperature for 2 hours. A solution of p-dimethoxybenzene (27.6 g, 0.2 mole) in methylene chloride (100 ml) was added slowly to the vigorously stirred solution. The reaction mixture was stirred overnight at 25° and poured onto ice (300 g) and concentrated hydrochloric acid (50 ml). The slurry was stirred for 30 minutes and extracted with chloroform (4 × 150 ml). A white precipitate suspended in the aqueous layer is collected by filtration. The organic extract was washed once with water (200 ml) and washed with saturated sodium bicarbonate (4 × 150 ml). The aqueous bicarbonate extract was washed once with chloroform (150 ml) and acidified with concentrated hydrochloric acid, the mixture cooled on an ice bath and filtered. The residue was washed well with water and dried under reduced pressure and combined with the white precipitate to yield 2-(2',5'-dimethoxybenzoyl)-6-methoxybenzoic acid (I) as a pale yellow solid (13 g, 41% yield), m.p. 180°-182° C (from ethanol); IR (KBr) 2.95, 5.72μ; NMR (CDCl3) δ, 7.60-6.80 (m, 6H), 6.10 (s, 1H), 3.75 (s, 3H), 3.70 (s, 3H), 3.49 (s, 3H).
Reaction SMILES: N[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1C(O)[CH2:13][CH:12]([OH:17])[CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.C(#N)C1[C:20](=CC=CC=1)[NH2:21]>>[O:17]=[C:12]1[CH2:11][CH2:10][CH2:15][C:2]([C:3]2[C:8]([NH2:9])=[C:7]([CH:6]=[CH:5][CH:4]=2)[C:20]#[N:21])=[CH:13]1
Reactant: N#Cc1ccccc1N
Reactant: Nc1c2c(nc3ccccc13)CC(O)CC2O
Product: N#Cc1cccc(C2=CC(=O)CCC2)c1N

Procedure:
To gain entry into the 9-amino-1,2,3,4-tetrahydroacridin-1,3-diol series, i.e., to prepare diols of formula 15, an anthranilonitrile 10 is condensed with a 5-(phenyldialkylsilyl)-1,3-cyclohexanedione 11 to afford a 3-(oxocyclohex-1-enyl)-2-aminobenzonitrile 12, which is cyclized to a 9-amino-3-(phenyldialkylsilyl)acridinone 13 and, in turn, converted to a 9-amino-3-hydroxyacridinone 14 and reduced to a diol 15.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C@H:11]([OH:17])[C:12]([CH3:16])([CH3:15])[C:13]#[N:14])C1C=CC=CC=1>[OH-].[OH-].[Pd+2].O1CCCC1>[OH:8][CH2:9][CH2:10][C@H:11]([OH:17])[C:12]([CH3:16])([CH3:15])[C:13]#[N:14]
Reactant: CC(C)(C#N)[C@@H](O)CCOCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C#N)[C@@H](O)CCO
Reaction time: 7.5 h

Procedure:
16 g of Pearlman's catalyst (Pd(OH)2 on carbon, 20%) is added to 11.13 g (47.70 mmol) of 5-benzyloxy-2,2-dimethyl-3(S)-hydroxy-pentane-nitrile of the title compound of Example 1c, dissolved in 110 ml of tetrahydrofuran. It is now hydrogenated for 7.5 hours at 10 bar and at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.
Reaction SMILES: [C:1]([N:4]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:18]=[CH:19][C:20](=[O:32])[N:21]([CH2:23][CH2:24][C:25]([CH3:31])([CH3:30])[C:26]([O:28]C)=[O:27])[CH:22]=2)=[O:16])[C@@H:7]([CH3:33])[CH2:6]1)(=[O:3])[CH3:2].CO.[OH-].[Na+].Cl>O1CCCC1>[C:1]([N:4]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:18]=[CH:19][C:20](=[O:32])[N:21]([CH2:23][CH2:24][C:25]([CH3:31])([CH3:30])[C:26]([OH:28])=[O:27])[CH:22]=2)=[O:16])[C@@H:7]([CH3:33])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(C)(C)CCn1cc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)ccc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(=O)n(CCC(C)(C)C(=O)O)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}-2-oxopyridin-1(2H)-yl]-2,2-dimethylbutanoic acid was prepared from methyl 4-[5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}-2-oxopyridin-1(2H)-yl]-2,2-dimethylbutanoate. methyl 4-[5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}-2-oxopyridin-1(2H)-yl]-2,2-dimethylbutanoate (0.010 g, 0.017 mmol) was hydrolyzed to the acid by dissolving in tetrahydrofuran and methanol and sodium hydroxide (1N) was added. The mixture was stirred at room temperature overnight. The mixture was cooled to rt, acidified to pH=5 with 1N HCl to form a white precipitate (0.006 g, 63%). The solid was filtered to give 4-[5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}-2-oxopyridin-1(2H)-yl]-2,2-dimethylbutanoic acid.
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=[C:5]2[C:4]1=[O:16].[SH:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)C>[N+:13]([C:10]1[CH:9]=[C:6]2[C:7](=[O:8])[N:3]([CH2:2][S:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:4](=[O:16])[C:5]2=[CH:12][CH:11]=1)([O-:15])=[O:14]
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1CCl
Reactant: Sc1ccncc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1CSc1ccncc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
N-Chloromethyl-4-nitrophthalimide [2.89 g (12 mmol)] was added under ice-cooling with stirring to a suspension of 1.11 g (10 mmol) of 4-mercaptopyridine and 1.4 ml (12 mmol) of triethylamine in 50 ml of ethanol. The mixture was stirred at room temperature for 16 hours. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 1.99 g of the desired compound (yield: 63.1%, yellow crystals).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C@@H:3]([C:14]([OH:16])=[O:15])[NH:4][C:5]([N:7]([CH3:13])[CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[O:6].[C:19](Cl)(=O)CCCC=C>>[CH3:1][C:2]([CH3:18])([CH3:17])[C@@H:3]([C:14]([OH:16])=[O:15])[NH:4][C:5]([N:7]([CH3:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:19])=[O:6]
Reactant: C=CCCCN(C)C(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: C=CCCCC(=O)Cl
Product: C=CCCCCN(C)C(=O)N[C@H](C(=O)O)C(C)(C)C

Procedure:
3-Methyl-N-{[methyl(hex-5-enyl)amino]carbonyl}-L-valine was prepared according to the procedure for 3-methyl-N-{[methyl(pent-4-enyl)amino]carbonyl}-L-valine (Steps 1-5) by using 5-hexenoyl chloride instead of 4-pentenoyl chloride in Step 1. LRMS (ESI) m/z 271 [(M+H)+; calcd for C14H27N2O3: 271].
Reaction SMILES: N[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[C:8](=[O:13])[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:6]2.[N+]([O-])([O-])=O.[Na+].[BrH:31]>O>[Br:31][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[C:8](=[O:13])[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:6]2
Reactant: Br
Reactant: Cc1cc(CN)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(CBr)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reaction time: 0.5 h
Yield: 70 %

Procedure:
5-Aminomethyl-7-methyl-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one (0.5 g, 1.43 mmol) was dissolved in a solution of water (10 mL) and 48% HBr (1 mL). The solution was chilled in an ice bath. A solution of sodium nitrate (0.17 g, 2.4 mmol) in water (5 mL) was added dropwise. A white solid formed. The reaction was allowed to stand for 30 minutes, and then the water was decanted off. The solid was chromatographed on silica gel, eluting with methylene chloride, to give 0.42 g (70% yield) of the title compound as a white solid. 1H NMR (300.132 MHz, CDCl3) δ 7.23-7.15 (m, 4H), 7.35-7.30 (m, 2H), 4.76 (s, 2H), 4.48 (s, 2H), 4.22 (s, 2H), 2.75 (s, 3H)