Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[O:14][CH3:15])=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[Br:20][CH2:21][C:22](Br)=[O:23].Cl>ClCCl>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([C:22](=[O:23])[CH2:21][Br:20])[CH:10]=[CH:9][C:8]=2[O:14][CH3:15])=[O:4]
Reactant: COC(=O)c1cc2cccc(OC)c2[nH]1
Reactant: O=C(Br)CBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1cc2c(C(=O)CBr)ccc(OC)c2[nH]1
Temperature: 0 °C

Procedure:
A-2. A solution of 1.02 g of 7-methoxyindole--2carboxylic acid methyl ester in 25 ml of dichloromethane is combined with 2 g of aluminum chloride and 0.65 ml of bromoacetyl bromide and the mixture is heated for 3 hours under reflux. The reaction mixture is allowed to cool and poured into 100 ml of a mixture of equal parts of ice water and concentrated hydrochloric acid. The organic phase is separated, concentrated to dryness under vacuum, and recrystallization from acetonitrile yields 650 mg of 4-bromoacetyl-7-methoxyindole-2-carboxylic acid methyl ester, mp 197°-201° C.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[C:43]([NH2:47])[CH:44]=[N:45][CH:46]=2)[CH2:37][CH2:36]1.Cl[C:49]1[C:58]2[C:53](=[CH:54][C:55]([F:60])=[CH:56][C:57]=2[F:59])[N:52]=[C:51]([C:61]2[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][N:62]=2)[C:50]=1[CH3:68].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[F:59][C:57]1[CH:56]=[C:55]([F:60])[CH:54]=[C:53]2[C:58]=1[C:49]([NH:47][C:43]1[CH:44]=[N:45][CH:46]=[C:41]([N:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)[CH:42]=1)=[C:50]([CH3:68])[C:51]([C:61]1[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][N:62]=1)=[N:52]2
Reactant: Cc1ccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)nc1
Reactant: Nc1cncc(N2CCOCC2)c1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)nc1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.023 g, 0.047 mmol), 5-morpholinopyridin-3-amine (0.064 g, 0.35 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(5-methylpyridin-2-yl)quinoline (0.09 g, 0.30 mmol) Pd2dba3 (0.011 g, 0.012 mmol) and sodium tert-butoxide (0.071 g, 0.74 mmol) in toluene (2.7 mL) at 120° C. for 10 days. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product 5,7-difluoro-3-methyl-2-(5-methylpyridin-2-yl)-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.55 (1H, d, J=4.9 Hz), 7.95 (1H, d, J=2.5 Hz), 7.81 (1H, d, J=2.3 Hz), 7.63 (2H, m), 7.19 (1H, m), 6.98-7.07 (2H, m), 6.62 (1H, app t, J=2.4 Hz), 3.86 (4H, app t, J=4.9 Hz), 3.19 (9H, app t, J=4.9 Hz), 2.48 (3H, s), 2.15 (3H, s). Mass Spectrum (ESI) m/e=448.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)(Cl)Cl>[C:21]([NH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: COc1ccc(CCN)cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(C)=O)cc1OC
Reaction time: 8 h
Yield: 91 %

Procedure:
To a stirred solution of β-(3,4-dimethoxyphenyl)ethylamine (100 g, 0.552 m) and triethylamine (66.6 g, 0.66 m) in CHCl3 (1 liter) was added acetyl chloride (47.1 g, 0.60 mole) dropwise over a period of 30 min. and the mixture stirred overnight. The mixture was washed with 3×500 ml H2O, dried over MgSO4 and evaporated to a solid. The solid was dissolved in 500 ml hot CCl4, 300 ml cyclohexane added and allowed to cool slowly. The crystallized solid was collected by filtration and dried to afford N-acetyl-3,4-dimethoxyphenethylamine as a white solid, 112.1 g (91% yield). m.p. 99°-100°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[Br:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.CN(C=O)C.[H-].[Na+]>O>[Br:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][C:2]1[CH:3]=[C:4]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: COc1cccc(Sc2cc(Br)cnc2C#N)c1
Reactant: Oc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(Sc2cc(Oc3cccc(Br)c3)cnc2C#N)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.7 %

Procedure:
A 10 mL round-bottomed flask was charged with 5-bromo-3-(3-methoxyphenylthio)picolinonitrile (214 mg, 0.666 mmol), 3-bromophenol (138 mg, 0.800 mmol), and DMF (6 mL). NaH (24.0 mg, 0.999 mmol) was added and reaction stirred at room temperature for 24 hours. The reaction was poured into water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was purified on silica gel (10% EtOAc in Hexanes) to afford the title compound (225 mg, 81.7% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]([O:17]CC)=O)=[N:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH3:21][O:22][C:23](=[O:29])[C@H:24]([CH:26]([CH3:28])[CH3:27])[NH2:25]>CCN(CC)CC>[CH3:27][CH:26]([CH3:28])[CH:24]([NH:25][C:15]([C:13]1[O:14][C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:11][N:12]=1)=[O:17])[C:23]([O:22][CH3:21])=[O:29]
Reactant: CCOC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)o1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)o1)C(C)C
Temperature: 110 °C
Yield: 15.5 %

Procedure:
An ethanolic solution of Ethyl 5-(4-nitrophenyl)oxazole-2-carboxylate (step D product, 3.4 g) and L-valine methyl ester hydrochloride (5.43 g) previously neutralized with Et3N (4.52 ml), was heated in a sealed tube at 110° C. for 2 days. EtOH was removed under reduced pressure and the crude material was chromatographed on silica gel in 1:9 EtOAc:Pet ether to get cream colored solid which was crystallized in EtOAc/pet ether to yield 700 mg (31%) of the title compound. 1HNMR (DMSO-d6, 300 MHz): δ 9.2 (d, 1H), 8.37 (d, 2H), 8.24 (s, 1H), 8.14 (d, 2H), 4.32 (m, 1H), 3.68 (s, 3H), 2.26 (m, 1H), 0.96 (t, 6H); MS (ES+): m/z 348 (M+1).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12]([N+:19]([O-:21])=O)=[C:13]([NH:15][C:16](=O)[CH3:17])[CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S1C=CC=C1.[ClH:27].[H][H]>CO.[Pt].CC(O)C>[ClH:27].[OH:21][N:19]1[C:12]2[CH:11]=[CH:10][C:9]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])=[CH:14][C:13]=2[N:15]=[C:16]1[CH3:17]
Reactant: CC(=O)Nc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pt]
Agent: Cl
Solvent: CO
Solvent: c1ccsc1
Solvent: CC(C)O
Product: Cc1nc2cc(C(=O)c3ccccc3)ccc2n1O
Yield: 73 %

Procedure:
(a-2) A mixture of 5.6 parts of N-(5-benzoyl-2-nitrophenyl)acetamide, 2 parts of a solution of thiophene in methanol 4%, 200 parts of methanol and 7 parts of 2-propanol, saturated with hydrogen chloride was hydrogenated at normal pressure and at room temperature with 1 part of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was washed with 2-propanone and dried, yielding 4.2 parts (73%) of (1-hydroxy-2-methyl-1H-benzimidazol-5-yl) phenylmethanone monohydrochloride as a residue (int. 49).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9].C1(C)C=CC=CC=1.C([O:19][C:20](=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])C.[OH-].[Na+]>C(OCC)(=O)C.O>[CH3:9][N:5]1[CH2:6][CH2:7][CH2:8][CH:4]1[CH2:3][CH2:2][NH:1][C:20](=[O:19])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCC(=O)OCC
Reactant: CN1CCCC1CCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCC(=O)NCCC1CCCN1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.7 %

Procedure:
Toluene (1.00 ml), dried using MS 4A, was mixed with 1.00 ml of a n-hexane solution of 15% Me3Al. With the mixture being cooled in an ice-methanol bath, 0.17 ml (0.78 mmol) of 2-(2-aminoethyl)-1-methylpyrrolidine was added dropwise over about 2 minutes. After stirring for 20 minutes, the temperature was raised to room temperature, and 0.5 ml of a toluene solution of 0.2 g (0.78 mmol) of myristic acid ethyl ester was added dropwise over 1 minute. After stirring for 2 hours at 70° C., the mixture was cooled with ice, and 1N NaOH solution was added dropwise. The mixture was stirred for 10 minutes, and water and ethyl acetate were added. Then, the mixture was separated into respective layers, and the organic layer was washed twice with 20 ml of a saturated aqueous solution of sodium chloride. After this layer was dried over anhydrous magnesium sulfate, it was concentrated under reduced pressure on a 30° C. water bath to obtain the captioned compound (yield 0.25 g). This compound was subjected to silica gel column chromatography (mobile phase: CHCl3:MeOH (19:1→9:1)) for purification. NMR and mass spectrum confirmed the purified compound to have the following structure:
Reaction SMILES: [CH:1]([O:4][C:5]([NH:7][C@H:8]([C:12]([OH:14])=O)[CH:9]([CH3:11])[CH3:10])=[O:6])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:41][C:42]1[CH:53]=[CH:52][C:45]2[N:46]=[C:47]([C@@H:49]([NH2:51])[CH3:50])[S:48][C:44]=2[CH:43]=1>C1(C)C=CC=CC=1>[F:41][C:42]1[CH:53]=[CH:52][C:45]2[N:46]=[C:47]([C@@H:49]([NH:51][C:12]([C@@H:8]([NH:7][C:5](=[O:6])[O:4][CH:1]([CH3:2])[CH3:3])[CH:9]([CH3:10])[CH3:11])=[O:14])[CH3:50])[S:48][C:44]=2[CH:43]=1
Reactant: CC(C)OC(=O)N[C@H](C(=O)O)C(C)C
Reactant: C[C@H](N)c1nc2ccc(F)cc2s1
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CN1CCOCC1
Product: CC(C)OC(=O)N[C@H](C(=O)N[C@@H](C)c1nc2ccc(F)cc2s1)C(C)C
Yield: 80.8 %

Procedure:
In 250 ml of toluene, 13.4 g (0.066 mol) of N-isopropoxycarbonyl-L-valine was dissolved. Thereto was added 14.3 g (0.144 mol) of N-methylmorpholine. Then was dropwise added at −10° C., 8.6 g (0.063 mol) of isobutyl chlorocarbonate. Thereto was added 22 g (0.06 mol) of (S)-1-(6-fluoro-2-benzothiazolyl)ethylamine p-toluenesulfonate. A reaction and a post-treatment were conducted in the same manner as in Reference Example 1, and the suspension of a solid in toluene was filtered at 70° C. to collect the solid. The solid was washed with water and toluene and dried to obtain 18.5 g (yield: 81.1%) of isopropyl {(S)-1-[(S)-1-(6-fluorobenzothiazol-2-yl)ethylcarbamoyl]-2-methylpropyl}carbamate. The compound obtained was confirmed for the structure by IR analysis and NMR analysis in comparison with its authentic material and identified.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([OH:13])[CH3:12])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([OH:13])[CH3:12])=[CH:8][CH:9]=1
Reactant: CC(O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(O)Cc1ccc(N)cc1
Yield: 78 %

Procedure:
A mixture of 1-(4-nitrophenyl)-2-propanol (Schadt, F. J. Am. Chem. Soc., 1978, 100, 228., 2.2 g, 12.3 mmol), iron powder (3.3 g, 59.1 mmol), ammonium chloride (370 mg, 6.9 mmol), ethanol (48 mL) and water (24 mL) was heated at reflux temperature for 2 h. The mixture was cooled and filtered through a pad of Celite. The filtrate was concentrated. The residue was diluted with ethyl acetate (200 mL) and washed with water (2×100 mL). The organic layer was dried (MgSO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 1.45 g (78%) of the title compound as a yellow oil: 1H-NMR (CDCl3) δ 7.00 (2H, d, J=8.6 Hz), 6.64 (2H, d, J=8.8 Hz), 3.99-3.89 (1H, m), 3.60 (2H, br s), 2.72-2.52 (2H, m), 1.22 (3H, d, J=6.2 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7](=O)[CH2:8][O:9][N:10]=[C:11]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:5])[CH3:2].Cl.[O:30]([NH2:32])[CH3:31].C(OCC)(=O)C>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([CH2:6][C:7](=[N:32][O:30][CH3:31])[CH2:8][O:9][N:10]=[C:11]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CC(=O)CON=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(CON=C(c1ccc(OC)cc1)c1ccc(OC)cc1)=NOC
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
3.85 g of the 4,4'-dimethoxybenzophenone O-(3-ethoxycarbonyl-2-oxopropyl)oxime as obtained in Example 1 was dissolved in 5 ml of pyridine and 1 g of methoxylamine hydrochloride was added thereto. Then the obtained mixture was stirred at room temperature. After two hours, the reaction mixture was poured into ethyl acetate, washed with diluted hydrochloric acid and then with a saturated saline solution and purified by silica gel chromatography. Thus 4 g of the title compound was obtained in the form of a colorless oily product.
Reaction SMILES: C(OC[N:11]1[CH:18]=[C:17]([F:19])[C:15](=[O:16])[N:14]([CH2:20][O:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12]1=[O:13])(=O)C1C=CC=CC=1.[OH-].[Na+]>N1C=CC=CC=1.O>[C:22]([O:21][CH2:20][N:14]1[C:15](=[O:16])[C:17]([F:19])=[CH:18][NH:11][C:12]1=[O:13])(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(OCn1cc(F)c(=O)n(COC(=O)c2ccccc2)c1=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: O=C(OCn1c(=O)[nH]cc(F)c1=O)c1ccccc1
Reaction time: 4 h

Procedure:
In a mixture of 10 ml of pyridine and 10 ml of water was dissolved 4 g (0.01 mol) of 1,3-bis(benzoyloxymethyl)-5-fluorouracil. A 5% aqueous caustic soda solution was slowly added dropwise to the solution under agitation while maintaining the pH value of the liquid at 10~11. The mixture was kept for 4 hours at 60° C. whereby alkaline hydrolysis of the starting 1,3-bis(benzoyloxymethyl)-5-fluorouracil was effected. After completion of the hydrolysis reaction, the reaction liquid was concentrated under reduced pressure and cooled. Any remaining unreacted 1,3-bis(benzoyloxymethyl)-5-fluorouracil was then precipitated out and filtered off and the filtrate was subjected to a column chromatographic treatment using a column packed with silica gel. Using a mixture (3:1 in mixing ratio) of benzene and ethyl acetate as eluent, 1-benzoyloxymethyl-5-fluorouracil aimed at was separated as a first elution component. 3-Benzoyloxymethyl-5-fluorouracil formed as by-product was also separated as a second elution component. The yields of 1-benzoyloxymethyl-5-fluorouracil and 3-benzoyloxymethyl-5-fluorouracil were 0.92 g (yield: 35%) and 0.65 g, respectively. After recrystallization from benzene of the crude product, the desired 1-benzoyloxymethyl-5-fluorouracil was obtained as white crystals melting at 179°~180° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:21]=1[C:22]#[N:23]>C1COCC1>[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:22](=[NH:23])[C:21]2[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:20]=2[Cl:19])=[CH:14][CH:13]=1
Reactant: Cc1cccc(Cl)c1C#N
Reactant: Nc1ccc(Br)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(Cl)c1C(=N)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 69.8 %

Procedure:
Under N2 atmosphere at room temperature to a solution of lithium bis(trimethylsilyl)amide (9.7 mL, 1.0 M solution in THF, 9.7 mmol) was added a solution of 4-bromoaniline (1.67 g, 9.7 mmol) in 10 mL anhydrous THF. After the mixture was stirred at ambient temperature for 40 min, a solution of 2-chloro-6-methylbezonitrile (1.55 mg, 10.2 mmol) in 10 mL anhydrous THF was added. The reaction mixture was stirred at room temperature overnight, and then poured into 300 mL ice water. The orange precipitate was collected by filtration, washed with hexane and air dried to give a light orange solid (2.19 g, 66% yield), which was used directly for the next step without further purification.
Reaction SMILES: [O:1]=[CH:2][CH:3]([CH2:5][OH:6])[OH:4].Cl.[CH2:8]([NH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(Cl)(Cl)Cl>CN(C)C1C=CN=CC=1.O>[CH2:8]([NH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([C:2]([CH:3]([CH2:5][OH:6])[OH:4])=[O:1])=[O:30])=[CH:27][CH:26]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Reactant: O=CC(O)CO
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)C(=O)C(O)CO)cc1
Reaction time: 4 h

Procedure:
To a mixture of 3.6 g. of glyceraldehyde and 2.44 g. of 4-dimethylaminopyridine in an ice-bath is added 4.16 g. of 4-(n-hexadecylamino)benzoyl chloride hydrochloride. After 4 hours at room temperature, chloroform and water are added. The chloroform extract is chromatographed quickly and evaporated in vacuo to yield 4-(n-hexadecylamino)benzoyl glyceraldehyde.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]2[C:19]3[CH:18]=[C:17]([F:20])[CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Se](=O)=[O:23]>O1CCOCC1>[C:1]([C:8]1[NH:9][C:10]2[C:19]3[CH:18]=[C:17]([F:20])[CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:21]=1)(=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc2ncc3nc(Cc4ccccc4)[nH]c3c2c1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=C(c1ccccc1)c1nc2cnc3ccc(F)cc3c2[nH]1
Temperature: 80 °C
Yield: 94.1 %

Procedure:
To a suspension of 830 mg of 2-benzyl-8-fluoro-1H-imidazo[4,5-c]-quinoline (VII-1) in 50 ml of dioxane heated to 80° C. was added 1.07 g of selenium dioxide. The reaction mixture was refluxed for 1.5 hours. The resulting precipitate was immediately removed by filtration and concentrated under reduced pressure, and the residue obtained was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with water and saturated brine, and dried. The ethyl acetate was removed and the residue was chromatographed on a column of silica gel for purification. After elution with chloroform-methanol (30:1 v/v), 820 mg (yield 94%) of the compound (I d-1) was obtained as crystals. This was recrystallized from ethanol-chloroform to give light yellow crystals melting at 255°~256° C.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH:7]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]([CH3:38])[CH3:37])[CH:31]=1)[CH2:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[N:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[N:10]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[Cl:21][C:16]1[CH:15]=[C:14]([C:12]2[N:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:10]=[C:9]([CH2:8][CH:7]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([N:36]([CH3:38])[CH3:37])[CH:31]=3)[C:6]([OH:39])=[O:5])[CH:13]=2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CN(C)c1cccc(C(Cc2cc(-c3ccc(Cl)c(Cl)c3)n(-c3ccc(Cl)cc3Cl)n2)C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cccc(C(Cc2cc(-c3ccc(Cl)c(Cl)c3)n(-c3ccc(Cl)cc3Cl)n2)C(=O)O)c1
Reaction time: 2 h
Yield: 109.2 %

Procedure:
3-[5-(3,4-Dichloro-phenyl)-1-(2,4-dichloro-phenyl)-1H-pyrazol-3-yl]-2-(3-dimethylamino-phenyl)-propionic acid tert-butyl ester (20 mg, 0.03 mmol) was dissolved in 1:1 trifluoroacetic acid/dichloromethane (1.0 mL) and stirred for 2 h. The reaction mixture was concentrated under reduced pressure, and the crude residue was dissolved in 1:1 acetonitrile/water (2.0 mL). The solution was lyopholized to afford the title compound (18 mg, >99%). HPLC: Rt=2.60 (Method B). MS (ESI): mass calculated for C26H21Cl4N3O2, 547.04; m/z found, 548/550[M+H]+. 1H NMR (500 MHz, DMSO-d6): 7.81 (d, J=1.9 Hz, 1H), 7.60-7.58 (m, 3H), 7.45 (d, J=2.2 Hz, 1H), 7.18 (t, J=7.9 Hz, 1H), 7.02 (dd, J=8.5, 2.2 Hz, 1H), 6.78 (m, 3H), 6.64 (s, 1H), 3.96 (dd, J=8.8, 6.6 Hz, 1H), 3.36 (dd, J=15.1, 9.0 Hz, 1H), 2.93 (dd, J=15.1, 6.6 Hz, 1H), 2.91 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14](=O)OCC)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[CH3:14][NH:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CCOC(=O)Nc1cc(OC)c(OC)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 3,4,5-trimethoxyphenylcarbamate (6.0 g) in tetrahydrofuran (150 ml) was added a 1M solution of lithium aluminum hydride in tetrahydrofuran (23.5 ml) dropwise. The mixture was stirred at room temperature for 1 hour, then refluxed for 1 hour. The product was cooled and an excess of 1M sodium hydroxide added dropwise. The precipitate was filtered off, and the filtrate partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate, and solvent removed under reduced pressure. The residue was redissolved in ethyl acetate and washed with 2M hydrochloric acid. The aqueous layer was washed with ethyl acetate, then basified with 1M sodium hydroxide, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and solvent removed under reduced pressure, to give N-methyl-3,4,5-trimethoxyaniline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](Br)[C:11]=1/[CH:12]=[CH:13]\[C:14]([NH:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])=[O:15])[C:5]([O:7][CH3:8])=[O:6]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[C:10]2[C:11]=1[CH:12]=[CH:13][C:14](=[O:15])[N:16]2[C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24]
Reactant: COC(=O)c1cc(Br)c(/C=C\C(=O)Nc2c(Cl)cccc2Cl)c(Br)c1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c2ccc(=O)n(-c3c(Cl)cccc3Cl)c2c1
Temperature: 80 °C

Procedure:
Methyl 3,5-dibromo-4-{(1Z)-3-[(2,6-dichlorophenyl)amino]-3-oxoprop-1-enyl}benzoate (1.25 g)(contaminated with 20% of the E isomer) was dissolved in dimethylformamide(36 mL) and the solution degassed with argon. Copper (I) iodide (340 mg) and dry potassium carbonate (468 mg) were added and the mixture heated to 80° C. for 30 min. The reaction mixture was poured into 5% ammonium hydroxide solution and extracted into ethyl acetate, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography eluting with 80% hexane: 20% ethyl acetate to give the title compound.