Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:6].N1C=CC=CC=1.[CH3:25][C:26]([CH3:34])([CH3:33])[C:27]([NH:29][C:30]([NH2:32])=[S:31])=[O:28]>O.C(O)C>[CH3:25][C:26]([CH3:34])([CH3:33])[C:27]([NH:29][C:30]1[S:31][CH:2]=[C:3]([CH2:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:32]=1)=[O:28]
Reactant: O=C(CBr)CC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)C(=O)NC(N)=S
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)C(=O)Nc1nc(CC(=O)Nc2cccc(C(F)(F)F)c2)cs1
Yield: 88 %

Procedure:
A 500 ml reaction flask fitted with a magnetic stirrer, heating mantle, thermometer and water-cooled condenser was charged with 44.7 g (0.138 mole) of 4-bromo-3'-trifluoromethylacetoacetanilide, 350 ml of absolute ethanol and 15 g (0.19 mole) of pyridine. A 26 g sample (0.162 mole) of N-trimethylacetylthiourea [m.p. 140°-42°; prepared as described by Moore and Crossley in The Journal of the American Chemical Society, vol. 62, p. 3273 (1940)] was added to the reaction solution. As the substituted thiourea dissolved, the reaction temperature increased from 24° to 31°. The solution was refluxed for four hours and poured into 1.5 liters of water. With stirring, the residual oil crystallized. The product was collected and washed with water. There was obtained 46.8 g (88%) of white solid, m.p. 147°-52°. One recrystallization from ethyl acetate-heptane yielded material which melted at 153°-55°. N.M.R. (dimethyl-d6 sulfoxide) ∂ 1.3 (tert-butyl), 3.8 (CH2), 6.9 (hetero-aromatic), 7.3-8.1 (aromatic).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C@@H:10]2[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Solvent: CO
Product: COc1ccc2c(c1)[C@@H](C(=O)O)CCC2
Yield: 19.2 %

Procedure:
7-Methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (5.0 g) and (S)-(−)-1-phenethylamine (3.2 mL) were dissolved in methanol (50 mL), and the solvent was evaporated under reduced pressure to give crude crystals (7.33 g). This was recrystallized from a mixed solvent of methanol and isopropyl ether. The obtained crystals were partitioned between ethyl acetate and 1 mol/L-hydrochloric acid. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give (S)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.96 g).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[C:25]1([CH3:33])[CH:30]=[CH:29][C:28]([NH:31]N)=[CH:27][CH:26]=1>>[CH3:23][S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:31]([C:28]4[CH:29]=[CH:30][C:25]([CH3:33])=[CH:26][CH:27]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: Cc1ccc(NN)cc1
Product: Cc1ccc(-n2nccc2-c2nn(-c3cccc(S(C)(=O)=O)c3)ccc2=O)cc1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and p-tolyl-hydrazine according to example 43 gave the desired product. MS: M=407.3 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]3[OH:14])[C:4]=2[N:5]=[CH:6][N:7]=1.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[C:22]#[CH:23]>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:26]([O:25][C:21](=[O:24])[C:22]#[C:23][C:10]1[C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=2[N:8]([C@@H:12]2[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]2[OH:14])[CH:9]=1)[CH3:27]
Reactant: Nc1ncnc2c1c(I)cn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CC(=O)OCC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)C#Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2ncnc(N)c12
Temperature: 55 °C
Yield: 63.7 %

Procedure:
To a solution of the product from Step 5 (61 mg, 0.156 mmol) in DMF (2 mL) were added CuI (6 mg, 0.032 mmol) and TEA (45 μL, 0.323 mmol). The mixture was degassed with argon under sonication for 2-3 minutes and Pd(PPh3)4 (18 mg, 0.016 mmol) was added and the resulting mixture was heated at 55° C. for 15 min. Ethyl propiolate (4×5 μL, 0.197 mmol) was added to the reaction mixture at 55° C. in 30 minutes intervals. The crude mixture was concentrated and purified on silica gel with CH2Cl2/MeOH (100/1, 50/1, 25/1) as the eluents to afford 36 mg (64%) of the target compound.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:15])[NH:6][C:7](=[O:14])[N:8]2[CH2:13][CH2:12][CH2:11][S:10][C:9]=12)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][Cl:27]>CN(C)C=O>[Cl:27][CH2:26][CH2:25][CH2:24][CH2:23][N:6]1[C:5](=[O:15])[C:4]([CH:1]([CH3:3])[CH3:2])=[C:9]2[S:10][CH2:11][CH2:12][CH2:13][N:8]2[C:7]1=[O:14]
Reactant: ClCCCCBr
Reactant: CC(C)c1c2n(c(=O)[nH]c1=O)CCCS2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1c2n(c(=O)n(CCCCCl)c1=O)CCCS2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a suspension of 1.81 g (8 mmol) of 9-isopropyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione and 1.77 g (12.8 mmol) of potassium carbonate in 30 ml of N,N-dimethylformamide, 1.84 ml (16 mmol) of 1-bromo-4-chlorobutane was added at room temperature, followed by stirring at 60° C. for 2 hours and then at 100° C. for 3 hours. After cooling, the reaction mixture was concentrated to dryness. The residue was dissolved in dichloromethane-water; the organic layer was washed with water and dried. The oily substance obtained by distilling off the solvent was purified by column chromatography (eluent, n-hexane/ethyl acetate=5/1→2/1) to yield 2.12 g (83.6%, colorless oily substance) of the desired product. 1H-NMR (CDCl3, 200 MHz) δ 1.28 (6H, d, J=6.8 Hz), 1.77-1.86 (4H, m), 2.15-2.26 (2H, m), 3.08 (2H, t, J=6.8 Hz), 3.13 (1H, quint., J=7.0 Hz), 3.41-3.60 (2H, m), 3.95 (2H, t, J=7.2 Hz), 4.04-4.10 (2H, m); IR (neat) 2956, 1691, 1637, 1560, 1439, 777, 752 cm-1
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=4)[N:15]([CH2:20][C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:22])[C:16]3=[O:19])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>C(Cl)Cl>[Cl:33][C:29]1[CH:28]=[C:27]([C:14]2[N:15]([CH2:20][C:21]([NH:23][CH:24]([CH3:25])[CH3:26])=[O:22])[C:16](=[O:19])[C:17]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)[CH:4]=2)[CH:18]=3)[CH:32]=[CH:31][CH:30]=1
Reactant: C1CCNCC1
Reactant: CC(C)NC(=O)Cn1c(-c2cccc(Cl)c2)cc2ccc(-c3cccc(CCl)c3)cc2c1=O
Solvent: ClCCl
Product: CC(C)NC(=O)Cn1c(-c2cccc(Cl)c2)cc2ccc(-c3cccc(CN4CCCCC4)c3)cc2c1=O
Temperature: 23 °C
Reaction time: 18 h

Procedure:
To 2-[7-(3-chloromethylphenyl)-3-(3-chlorophenyl)-1-oxo-1H-isoquinolin-2-yl]-N-isopropylacetamide (19 mg, 0.04 mmol) in DCM (5 mL) was added piperidine (0.5 mL) and this was stirred at 23° C. for 18 h. The mixture was concentrated in vacuo, and the crude residue purified by preparative HPLC to yield the HCl salt of 2-[3-(3-chlorophenyl)-1-oxo-7-(3-piperidin-1-ylmethylphenyl)-1H-isoquinolin-2-yl]-N-isopropylacetamide (EXAMPLE 35) hydrochloride salt (7 mg, 0.013 mmol, 33%) as pale beige solid.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.CC1(C)[O:15][C:14](=O)[CH2:13][C:12](=[O:17])[O:11]1>C(OCC)(=O)C>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14](=[O:15])[CH2:13][C:12]([OH:17])=[O:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CCOC(C)=O
Product: O=C(O)CC(=O)Nc1ccc(I)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture containing 4-iodoaniline (400 g, 1.83 mol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (263 g, 1.83 mol) was stirred at 80° C. After 2 hours, the mixture was cooled to 23° C. and then ethyl acetate (5 L) was added. The mixture was extracted with aqueous sodium hydroxide solution (110 g of sodium hydroxide dissolved in 5 L of water). The basic aqueous layer was washed with ethyl acetate (3 L). The washed layer was brought to pH 2 with 6 M aqueous hydrochloric acid solution. The acidic aqueous solution was extracted with ethyl acetate (3×3 L). The organic layers were combined and the combined solution was dried with magnesium sulfate. The dried solution was filtered and the filtrate was concentrated to afford the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]([NH:13][S@@](C(C)(C)C)=O)[CH:11]=[CH2:12])[CH:5]=[C:6]([CH2:8][F:9])[CH:7]=1.Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]([NH2:13])[CH:11]=[CH2:12])[CH:5]=[C:6]([CH2:8][F:9])[CH:7]=1
Reactant: C=C[C@@H](N[S@](=O)C(C)(C)C)c1cc(F)cc(CF)c1
Agent: Cl
Solvent: CO
Product: C=C[C@@H](N)c1cc(F)cc(CF)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)—N—((R)-1-(3-fluoro-5-(fluoromethyl)phenyl)allyl)-2-methylpropane-2-sulfinamide (660 mg, 2.297 mmol) in MeOH (7.66 mL), was added HCl (4 M in dioxane) (5.742 mL, 22.97 mmol) at 0° C., the reaction mixture was stirred at room temperature for 2 h, The reaction mixture was concentrated to dryness. Sat. Na2CO3 was added, the reaction mixture was then extracted by EtOAc. The organic was dried and concentrated to yield the crude product. The crude product was used in next step reaction without purification. LCMS (m/z): 184.1 (MH+), 0.40 min.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[CH:11]([NH:13][NH2:14])=[O:12].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]([CH3:44])([C:28]2[N:32]([CH3:33])[C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]([F:43])([F:42])[F:41])=[N:30][N:29]=2)[CH3:27])=[C:20]([CH:24]=1)[C:21]([OH:23])=O.O>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]([CH3:27])([C:28]2[N:32]([CH3:33])[C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]([F:41])([F:43])[F:42])=[N:30][N:29]=2)[CH3:44])=[C:20]([CH:24]=1)[C:21]([NH:14][NH:13][CH:11]=[O:12])=[O:23]
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1C(=O)O
Reactant: NNC=O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1C(=O)NNC=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
WSC•monohydrochloride (130 mg), HOBt (110 mg) and formic hydrazide (60 mg) were sequentially added to a solution of 5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzoic acid (300 mg) in DMF (6 ml), followed by stirring at room temperature for 4 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was sequentially washed with saturated aqueous sodium bicarbonate solution, water and then saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure to obtain 5-chloro-N′-formyl-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzohydrazide (230 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:47])[C@@H:12]([NH:20][C:21](=[O:46])[C@H:22]([NH:38]C(OC(C)(C)C)=O)[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C@H:31]3[CH2:35][O:34]C(C)(C)[O:32]3)=[CH:25][CH:24]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:47])[C@@H:12]([NH:20][C:21](=[O:46])[C@H:22]([NH2:38])[C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][C@H:31]([OH:32])[CH2:35][OH:34])=[CH:27][CH:28]=2)[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(OC[C@H]3COC(C)(C)O3)cc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](N)c2ccc(OC[C@H](O)CO)cc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.8 %

Procedure:
To a solution of 2-((S)-2-{(R)-2-tert-butoxycarbonylamino-2-[4-((S)-2,2-dimethyl-[1,3]dioxolan4-ylmethoxy)-phenyl]-acetylamino}-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester (170 mg, 0.25 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.5 mL, 6.5 mmol) at 0° C. The reaction was warmed to room temperature and stirred for 4 hours. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate and the extracts were combined, washed with brine and dried over sodium sulfate to give 2-((S)-2-{(R)-2-amino-2-[4-((R)-2,3-dihydroxy-propoxy)-phenyl]-acetylamino}-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester as a foam (120 mg, 90%).
Reaction SMILES: [CH2:1](Br)[CH:2]([CH3:4])[CH3:3].[OH:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CBr
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(C)C)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 44 h
Yield: 87.3 %

Procedure:
Isobutyl bromide (10.5 mL, 95.8 mmol) was added to a suspension of methyl 4-hydroxy-3-nitrobenzoate (6.26 g, 31.8 mmol) and potassium carbonate (13.2 g, 95.5 mmol) in dry DMF (40 mL). The resulting mixture was stirred at 90° C. for 44 hours and then cooled to room temperature. Subsequently, ice-water (80 mL) was added to the cooled mixture. The precipitated crystalline product was collected by filtration, washed with water (50 mL), and dried for 30 min in air. The dried crystalline product was then washed with hexane (40 mL), and dried in air to give 7.03 g (yield 87%) of the desired compound in the form of a pale orange crystalline product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO>[CH:10](=[N:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[OH:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccc(O)c(N)c1
Reactant: O=Cc1ccccc1
Solvent: CO
Product: Cc1ccc(O)c(N=Cc2ccccc2)c1
Yield: 63.9 %

Procedure:
A solution of 2-amino-p-cresol (1.23 g, 10 mmol) and benzaldehyde (1.06 g, 10 mmol) in methanol (10 ml) was heated at reflux for 2 hrs then cooled in an ice bath. The product was filtered off, washed with a little cold methanol and dried to yield 1.35 g of 2-benzylideneamino-4-methylphenol 54.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][C:8]([NH:10][NH:11][C:12]([N:14]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][C:16]2[CH:25]=[CH:26][C:27]([N+:29]([O-])=O)=[CH:28][C:15]1=2)=[O:13])=[O:9])(=[O:5])=[O:4])[CH3:2].[H][H]>O1CCCC1.[Pd]>[CH2:1]([S:3]([CH2:6][CH2:7][C:8]([NH:10][NH:11][C:12]([N:14]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][C:16]2[CH:25]=[CH:26][C:27]([NH2:29])=[CH:28][C:15]1=2)=[O:13])=[O:9])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)CCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc([N+](=O)[O-])cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCS(=O)(=O)CCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(N)cc21

Procedure:
A solution of the title compound of Example 10 (4.0 g) in tetrahydrofuran (250 mL) was shaken in a Parr Hydrogenator at 38 psi hydrogen over 5% palladium on carbon for 18 hours. The catalyst was filtered from the reaction, and the solution was evaporated under vacuum. Crystallization of the residue from ethanol (3A) yielded the title compound as a yellow solid. Recrystallization of this from ethanol (3A) yielded the pure title compound as yellow crystals. Mp: 172°-179° C.
Reaction SMILES: [OH-].[Na+].[CH:3]1[N:7]2[C:8]3[C:13]([N:14]=[CH:15][C:6]2=[N:5][C:4]=1[C:16]([O:18]CC)=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=3.C(O)C>O>[CH:3]1[N:7]2[C:8]3[C:13]([N:14]=[CH:15][C:6]2=[N:5][C:4]=1[C:16]([OH:18])=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: CCOC(=O)c1cn2c(cnc3ccccc32)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn2c(cnc3ccccc32)n1
Yield: 107.8 %

Procedure:
10 ml of 1N sodium hydroxide solution were added to a suspension of 0.63 g of ethyl imidazo-[1,2-a]-quinoxaline-2-carboxylate, 10 ml of ethanol and 30 ml of water and the mixture was refluxed for one hour. The ethanol was evaporated under reduced pressure from the resulting clear yellow solution and the aqueous phase was acidified with concentrated hydrochloric acid. The mixture was filtered to obtain 0.6 g of imidazo-[1,2-a]-quinoxaline-2-carboxylic acid in the form of a buff crystalline solid melting at 274°-275° C.
Reaction SMILES: C1C2C(COC([NH:18][CH:19]([C:83]3[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=3)[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[C:22]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[C:21]=3[O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)(Cl)Cl.C(#N)C>[CH2:65]([O:64][C:21]1[C:22]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])=[C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]=[CH:25][C:20]=1[CH:19]([NH2:18])[C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1)[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(NC(=O)OCC2c3ccccc3-c3ccccc32)c2ccccc2)c(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(N)c2ccccc2)c(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
N-(9-Fluorenylmethoxycarbonyl)-2,3,4-tris(octadecyloxy)benzhydryl amine (3.37 g, 2.89 mmol) was dissolved in a mixed solvent of chloroform (30 mL) and acetonitrile (15 mL), 20% piperidine [1-methyl-2-pyrrolidone solution] (28.6 mL, 57.9 mmol) was added, and the mixture was stirred at room temperature for 30 min. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, methanol was added, and the precipitated solid was collected by filtration. The obtained solid was dried under reduced pressure to give the title compound (2.80 g, 97.9%) as a white solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:9])[CH:6]([CH3:8])[CH3:7].[C:11]1([S:17][CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)(Cl)Cl>[CH3:7][CH:6]([CH3:8])[C:5]([C:14]1[CH:15]=[CH:16][C:11]([S:17][CH3:18])=[CH:12][CH:13]=1)=[O:9]
Reactant: CC(C)C(=O)Cl
Reactant: CSc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CSc1ccc(C(=O)C(C)C)cc1
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
To a suspension of aluminum chloride (136 g, 1.02 mol) in chloroform (1.0 L) cooled to -10° C., was added dropwise isobutyrylchloride (115 mL, 1.10 mol). Then thioanisole (100 mL, 0.85 mol) was added dropwise. Upon completion of addition the reaction was allowed to proceed at r.t. for 1.5h. The reaction was cooled to 10° C. and quenched by addition of water (750 mL). The organic layer was separated, washed with water (2×500 mL), saturated NaHCO3 solution(2×500 mL), brine (1×500 mL), and then dried over Na2SO4. After concentration in vacuo., the resulting crude product crystallized upon standing under high vacuum for 30 min to give the title compound as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:12]([Cl:21])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Product: Cc1ccc(C(=O)Cl)cc1OCc1ccccc1
Temperature: 79 °C
Reaction time: 4 h

Procedure:
K2CO3 (18.1 g, 131.2 mmol) was added to a stirred solution of 3-hydroxy-4-methyl-benzoic acid (5 g, 33 mmol) in DMF (50 mL) followed by benzyl bromide (11.8 g, 69 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered, the filterate was diluted with water and extracted with EtOAc. The organic layer was collected, dried over sodium sulfate and concentrated under reduced pressure to afford 11.3 g (crude) of 3-benzyloxy-4-methyl-benzoic acid benzyl ester which was such taken for the next step without purification. NaOH (4.0 g, 102 mmol) was added to a stirred solution of 3-benzyloxy-4-methyl-benzoic acid benzyl ester (11.3 g, 34 mmol) in a mixture of MeOH (50 mL) and H2O (50 mL), stirring was continued at ambient temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure Cold water was then added and acidified it with 10% aqueous HCl, the precipitate was collected to afford 7.21 g (87.8% Yield) of 3-benzyloxy-4-methyl-benzoic acid. A mixture of 3-benzyloxy-4-methyl-benzoic acid (7.21 g, 29.7 mmol) in thionyl chloride (50 mL) was stirred at 79° C. for 4 hrs. The reaction mixture was concentrated under reduced pressure to afford 7.75 g (crude) of 3-benzyloxy-4-methyl-benzoyl chloride. A solution of 3-benzyloxy-4-methyl-benzoyl chloride (7.75 g) in THF (10 mL) was poured to cold aqueous solution of ammonia (50 mL) with stirring, The precipitate was collected to afford 6.7 g (94% Yield) of 3-benzyloxy-4-methyl-benzamide. A solution of 3-benzyloxy-4-methyl-benzamide (3.0 g, 12.4 mmol) in pyridine (4 mL) was cooled to −30° C. Imidazole (1.68 g, 24.8 mmol) followed by POCl3 (2.64 g, 49.6 mmol) were added to the cold solution with stirring and the reaction was continued at the same temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water followed by 110% aqueous HCl solution. The organic layer separated was dried over sodium sulfate and concentrated under reduced pressure to afford 2.46 g (89% Yield) of 3-benzyloxy-4-methyl-benzonitrile. Pd/C (476 mg) was added to a stirred solution of 3-benzyloxy-4-methyl-benzonitrile (2.46 g, 11.0 mmol) in MeOH (25 mL) in an inert atmosphere and stirring was continued under H2 gas atmosphere at ambient temperature, overnight. The reaction mixture was filtered through celite. The filtrate collected was concentrated under reduced pressure to afford 1.367 g (93.6% Yield) of 3-hydroxy-4-methyl-benzonitrile.