Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH3:12]>CO>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=[CH:11][C:2]=1[NH2:12]
Reactant: N
Reactant: Clc1cnc2ccccc2n1
Solvent: CO
Product: Nc1cnc2ccccc2n1
Temperature: 80 °C
Reaction time: 12 h
Yield: 5 %

Procedure:
To 2-chloroquinoxaline (1.0 g, 6 mmol) was added ammonia in methanol (8 mL of a 2M solution). The reaction was sealed in a vial, heated to 80° C., and stirred for 12 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was taken up in methylene chloride and filtered. Hexane was added until a precipitate formed which was filtered and found to be the desired product (5% yield).
Reaction SMILES: [C:1]1([CH:9]=O)[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.S(=O)(=O)(O)O.O.[CH3:17][C:18]1[N:23]=[C:22]([NH2:24])[N:21]=[C:20]([NH2:25])[N:19]=1>CO>[NH2:25][C:20]1[N:21]=[C:22]([NH2:24])[N:23]=[C:18]([CH:17]=[CH:9][C:1]2[CH:2]=[CH:3][C:4]([CH:7]=[O:8])=[CH:5][CH:6]=2)[N:19]=1
Reactant: O=Cc1ccc(C=O)cc1
Reactant: Cc1nc(N)nc(N)n1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: Nc1nc(N)nc(C=Cc2ccc(C=O)cc2)n1
Temperature: 80 °C
Yield: 41 %

Procedure:
To 107.2 g (800 mmol) of benzene-1,4-dicarboxaldehyde suspended in 450 mL methanol was added with stirring 294.0 g of 31% aqueous sulfuric acid (50 mL of concentrated sulfuric acid was added slowly to 200 mL of water while stirring). The solid dissolved and a yellow solution was obtained. The solution was heated to 80° C. with an oil bath, and 25.0 g (200 mmol) 6-methyl-[1,3,5]triazine-2,4-diamine powder was added. The solution was stirred at 80° C. for 8 h then cooled to room temperature. Next, 1.2 g of yellow byproduct (1,4-bis[4-[2-(4,6-diamino-[1,3,5]triazin-2-yl)-vinyl]]-benzene) was removed by filtration, and the filtrate was treated with 2000 mL water. The resulting solid was collected by filtration and washed with saturated aqueous NaHCO3 and water until neutral. The excess benzene-1,4-dicarboxaldehyde was removed by sonicating and washing with acetone three times. Yield: 20.0 g of light yellow product. Yield=41%. 1HNMR (500 MHz, DMSO): δ9.992 (s, 1H), 7.894 (d, J=8.0 Hz, 2H), 7.847 (d, J=7.5 Hz, 2H), 7.806 (d, J=15.5 Hz, 1H), 6.928 (d, J=15.5 Hz, 1H), 6.806 (br, 4H). 13CNMR (500 MHz, DMSO): δ 193.914, 193.417, 170.671, 167.847, 141.836, 136.833, 131.461, 130.688, 128.883.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[CH:19]=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:22]=2>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[CH:19]=[N:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[C:23]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:22]=4)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCc1cnc2cc(-c3ccccc3)ccc2c1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: c1ccc(-c2ccc3cc(COc4ccc(CCCn5ccnc5)cc4)cnc3c2)cc1
Yield: 59 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 3-chloromethyl-7-phenylquinoline to give 3-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-7-phenylquinoline. The yield was 59%. Recrystallization from ethanol gave colorless prisms, mp 135-136° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]1[OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10]1=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2C[C@H]1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1Cc2ccccc2CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon to (+)-trans-3-tert-butoxycarbonylamino-1,2,3,4-tetrahydro-2-naphthalenol (70 mg) in methylene chloride (1 ml) was added Dess Martin periodinane (172 mg). The mixture was stirred for 1 hour at room temperature under argon and filtered through a silica gel column [10 g, elution with ethyl acetate: cyclohexane mixtures, 1:9 (150 ml) and 2:8 (50 ml)]. Evaporation of solvent gave a solid which was recrystallized from pentane to yield the title compound as white needles, m.p. 76° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12]([O-])(=O)[CH3:13].[Na+]>[Cu].CC1C=CC=CC=1>[I:1][C:2]1[CH:10]=[C:6]([C:7]([NH:9][C:6]2[CH:10]=[CH:2][CH:3]=[CH:4][C:12]=2[CH3:13])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc(I)ccc1O
Reactant: CC(=O)[O-]
Agent: [Cu]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccccc1NC(=O)c1cc(I)ccc1O

Procedure:
37.1 g. of 5-iodo salicylamide, 43.6 g. of 2-methyl benzene, 10 g. of anhydrous sodium acetate, 1 g. of copper bronze are mixed together and heated under reflux for 4 hours. The molten mass obtained is dissolved in alcohol. Said solution is filtered and concentrated by evaporation. 5-iodo-2'-methyl salicylanilide is obtained thereby. Said compound is then dissolved in about 5 times its amount by weight of a mixture of glacial acetic acid and ethyl acetate (1:1). A solution of 40.8 g. of bromine in 30 cc. of glacial acetic acid is added to said solution to obtain 5-iodo-2'-methyl-4'-bromo salicylanilide. Resulting compound (compound No. 5) forms colorless needle-shaped crystals having properties shown in Table 5 by recrystallizing from ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>ClCCl>[OH:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1cc(O)ccc1O
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1O
Reaction time: 0.5 h

Procedure:
Combine methyl 2,5-dihydroxybenzoate (8.45 g, 50.2 mmol), imidazole (4.1 g, 60.3 mmol), and t-butyldimethylsilyl chloride (9.09 g, 60.3 mmol) in dichloromethane (100 mL). After 30 minutes, dilute the reaction mixture with dichloromethane (100 mL) and extract with water. Dry the organic layer over MgSO4, filter and evaporate in vacuo to give methyl 2-hydroxy-5-(t-butyldimethylsilyloxy)benzoate.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[CH:7]=[CH:6][N+:5]([O-])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][N:5]=1)[C:1]([OH:10])=[O:9]
Reactant: O=C(O)c1cc[n+]([O-])cc1
Reactant: O=P(Cl)(Cl)Cl
Product: O=C(O)c1ccnc(Cl)c1
Temperature: 0 °C
Yield: 65.4 %

Procedure:
A mixture of isonicotinic acid N-oxide (28.0 g, 0.2 mol) and phosphorus oxychloride (120.0 g, 0.8 mol) was heated at reflux for 7 h. The reaction mixture was cooled and carefully poured into 600 mL of ice water. The precipitate was collected by filtration to give 20.6 g (65% yield) of product as a pale yellow solid, mp: 248-249 C (lit: 250-252 C).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][NH:12][C:11](=[O:23])[C:10]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5][CH:4]=1.Cl[CH2:30][CH:31]1[CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:30][CH:31]3[CH2:33][CH2:32]3)[C:11](=[O:23])[C:10]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)n[nH]c1=O
Reactant: ClCC1CC1
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)nn(CC2CC2)c1=O
Yield: 89.1 %

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-ethoxycarbonyl-2H-pyridazin-3-one and (chloromethyl)cyclopropane as starting materials, the procedures of Example 19 were repeated likewise, whereby the title compound was obtained in a yield of 89.1%.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[C:27]([Br:28])=[CH:26][CH:25]=[C:24]([N:29]([CH3:31])[CH3:30])[N:23]=4)[CH2:20][CH2:21][C@@H:14]23)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[I:34]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[C:27]([Br:28])=[CH:26][C:25]([I:34])=[C:24]([N:29]([CH3:30])[CH3:31])[N:23]=4)[CH2:20][CH2:21][C@@H:14]23)[CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:8]=1
Reactant: II
Reactant: CN(C)c1ccc(Br)c([C@@H]2CC[C@H]3[C@@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)OC(=O)N23)n1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: CN(C)c1nc([C@@H]2CC[C@H]3[C@@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)OC(=O)N23)c(Br)cc1I
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a slurry of (1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[3-bromo-6-(dimethylamino)pyridin-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one (200 mg, 0.372 mmol) in MeOH (7.25 mL) under nitrogen at room temperature was added silver sulfate (116 mg, 0.372 mmol), followed by iodine (94 mg, 0.372 mmol). The resulting mixture was stirred for 1 hour. The reaction was partitioned with ethyl acetate and aqueous sodium hydroxide (1.0 M). The organic was then washed with aqueous saturated sodium thiosulfate and the combined aqueous layers were extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to yield (1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[3-bromo-6-(dimethylamino)-5-iodopyridin-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one (180 mg, 0.271 mmol). MS ESI calc'd. for C21H18BrF6N3O2 [M+H]+ 666.0, found 666.1.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:14](=[O:15])[N:13]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[N:12]=[N:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C>[Pd].C(OCC)(=O)C>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([N:13]2[C:14](=[O:15])[N:10]([CH2:9][CH2:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[N:11]=[N:12]2)=[CH:21][CH:20]=1
Reactant: O=c1n(CCCC2CCCCC2)nnn1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(-n2nnn(CCCC3CCCCC3)c2=O)cc1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
A solution of 1-(3-cyclohexyl-propyl)-4-(4-nitro-phenyl)-1,4-dihydro-tetrazol-5-one (69.6 g, 210 mmol) in a mixture of absolute ethanol (220 mL) and ethyl acetate (300 mL) was added to a 2 L Parr hydrogenation vessel containing Degussa 10% Pd/C (3.48 g). The Parr vessel was shaken at room temperature under a hydrogen atmosphere maintained at 20 psi for 4.5 hours. The mixture was filtered through Celite and concentrated in vacuo to a light yellow oil which spontaneously crystallized to afford a light brown crystalline solid (63.5 g, 98%). Mp 64-69° C.; 1H NMR (CDCl3, 300 MHz) δ 7.64 (d, 8.8 Hz, 2 H), 6.78 (d, 9.2 Hz, 2 H), 3.98 (t, 7.0 Hz, 2 H), 1.88 (m, 2 H), 1.72-1.63 (m, 5 H), 1.29-1.11 (m, 6 H), 0.94-0.84 (m, 2 H); MS (EI) m/z 302.2 (MH+); Anal. calcd for C16H23N5O: C, 63.76; H, 7.69; N, 23.24. Found: C, 64.00; H, 7.78; N, 22.87; Rf =0.67 (B).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:5])[CH3:4].[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[N:17]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:16]([CH2:28][CH2:29][C:30](O)=O)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1>>[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]2[N:17]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:19])=[O:20])[CH:16]([CH2:28][CH2:29][C:30]3[O:1][N:2]=[C:3]([CH3:4])[N:5]=3)[CH2:15][CH2:14]2)=[CH:11][CH:12]=1
Reactant: CC(=N)NO
Reactant: Cc1ccc(S(=O)(=O)N2C(CCC(=O)O)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(CCc3nc(C)no3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, white solid, m.p. 91° C. and MS: m/e=430.5 (M+) was prepared in accordance with the general method of example 13 from N-hydroxy-acetamidine and (2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid, which was prepared in accordance with the general method of example 6a from (2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid methyl ester.
Reaction SMILES: N(C(C)C)C(C)C.C([Li])CCC.[C:13]1([C:19]2[N:23]3[C:24]4[C:29]([CH:30]=[CH:31][C:22]3=[N:21][N:20]=2)=[CH:28][C:27]([S:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)=[CH:26][CH:25]=4)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:38]1([C:41]([CH:43]2[CH2:45][CH2:44]2)=[O:42])[CH2:40][CH2:39]1>C1COCC1>[CH:38]1([C:41]([CH:43]2[CH2:45][CH2:44]2)([C:35]2[S:34][C:33]([S:32][C:27]3[CH:28]=[C:29]4[C:24](=[CH:25][CH:26]=3)[N:23]3[C:19]([C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=5)=[N:20][N:21]=[C:22]3[CH:31]=[CH:30]4)=[N:37][CH:36]=2)[OH:42])[CH2:40][CH2:39]1
Reactant: c1ccc(-c2nnc3ccc4cc(Sc5nccs5)ccc4n23)cc1
Reactant: O=C(C1CC1)C1CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OC(c1cnc(Sc2ccc3c(ccc4nnc(-c5ccccc5)n43)c2)s1)(C1CC1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
iPr2NH (0.12 g, 0.84 mmol) was dissolved in THF (2 mL) and cooled to −78° C. n-Butyllithium (2.5M, 0.37 mL, 0.84 mmol) was added dropwise, followed by 10f (150 mg, 0.42 mmol) in THF (5 mL). Dicyclopropylmethanone (53 mg, 0.46 mmol) in THF (0.25 mL) was added, and the reaction was stirred overnight at room temperature. The reaction was quenched with 5% aqueous NH4Cl (10 mL). The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by preparative HPLC to give the desired product, 10g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@@H:6]([C:19]1[CH:27]=[CH:26][C:22]2[CH2:23][CH2:24][O:25][C:21]=2[CH:20]=1)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15](=O)[CH3:16])[C:8]1=[O:18])[CH3:2].[NH2:29][C:30]1[C:35]([CH:36]=O)=[CH:34][CH:33]=[CH:32][N:31]=1.N1CCC[C@H]1C(O)=O>C(O)C>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C@@H:6]([C:19]1[CH:27]=[CH:26][C:22]2[CH2:23][CH2:24][O:25][C:21]=2[CH:20]=1)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:36][C:35]3[C:30](=[N:31][CH:32]=[CH:33][CH:34]=3)[N:29]=2)[C:8]1=[O:18])[CH3:2]
Reactant: Nc1ncccc1C=O
Reactant: CCOC(=O)C[C@@H](c1ccc2c(c1)OCC2)N1CCC(CCCC(C)=O)C1=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C[C@@H](c1ccc2c(c1)OCC2)N1CCC(CCCc2ccc3cccnc3n2)C1=O

Procedure:
A mixture of 4-2 (540 mg, 1.4 mmol), 2-amino-3-formylpyridine (170 mg, 1.4 mmol; for prep. see JOC 1983, 48, 3401) and proline (161 mg, 1.4 mmol) in absolute ethanol (20 mL) was heated at reflux for 12 h. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 50% ethyl acetate/chloroform 70:25:5 chloroform/ethyl acetate/MeOH) to give 4-3 as a yellow oil.
Reaction SMILES: [Na].C(O[C:5](=O)[CH:6]([CH3:12])[C:7]([O:9]CC)=[O:8])C.[Br:14][C:15]1[CH:16]=[C:17]([C:20]([Br:23])=[CH:21][CH:22]=1)CBr.[OH-].[K+]>C(O)C.O>[Br:14][C:15]1[CH:16]=[CH:17][C:20]([Br:23])=[CH:21][C:22]=1[CH2:5][CH:6]([CH3:12])[C:7]([OH:9])=[O:8]
Reactant: BrCc1cc(Br)ccc1Br
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(Cc1cc(Br)ccc1Br)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a 1000 ml three-necked round-bottom flask equipped with a reflux condenser, dropping funnel with pressure-equalizing, and magnetic stirring bar, 6.10 g (0.27 mol) of sodium metal was dissolved in 150 ml of dry ethanol. To the resulting solution, 45.5 g (0.26 mol) of diethylmethylmalonate in 50 ml of dry ethanol was added dropwise within 10 minutes. This mixture was stirred for 15 minutes; then 84.3 g (0.26 mol) of 3,6-dibromobenzylbromide was added, while vigorously stirring, at a rate that allowed the reaction mixture to maintain a gentle reflux. Additionally, this mixture was refluxed for 4 hours, and then cooled to room temperature. A solution of 52.1 g of KOH in 140 ml of water was added. This mixture was refluxed for 3 hours to saponificate the ester formed. Ethanol and water were distilled off. To the residue, 200 ml of water, and then, 12 M HCl (to pH 1) were added. The substituted methylmalonic acid precipitated and was separated, washed with 3×100 ml of cold water, and dried overnight on watch glass. Crude 3-(2,5-dibromophenyl)-2-methylpropanoic acid was obtained after decarboxylation of this substituted methylmalonic acid by heating it in a round bottom flask for 2 hours at 160° C. Crude 3-(2,5-dibromophenyl)-2-methylpropanoic acid was used without further purification. A mixture of this acid, 70 ml of SOCl2, and 100 ml of CH2Cl2 was stirred for 3 hours at reflux. Thionyl chloride and CH2Cl2 were distilled off. The residue was dried in vacuum, and then dissolved in 95 ml of CH2Cl2. To a suspension of 47.0 g (0.35 mol) of AlCl3 in 470 ml of CH2Cl2, the above-obtained solution of 3-(2,5-dibromophenyl)-2-methylpropionyl chloride was added dropwise, while vigorously stirring, for 1 hour at −20° C. This mixture was refluxed for 3 hours, cooled to ambient temperature, and then poured on 500 cm3 of ice. The organic layer was separated. The aqueous layer was extracted with 3×200 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and evaporated to dryness. The crude 4,7-dibromo-2-methyl-1-indanone was purified by flash chromatography on Silica Gel 60 (40-63 μm, d 50 mm, h 250 mm; eluent: hexanes/methyl-tert-butyl ether (1:1, vol.)). Yield 54.1 g (70%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11](Cl)=[O:12])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>N1C=CC=CC=1>[CH:18]1([NH:24][C:11](=[O:12])[CH:10]=[CH:9][C:8]2[CH:14]=[CH:15][C:5]([O:4][C:1](=[O:3])[CH3:2])=[C:6]([O:16][CH3:17])[CH:7]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NC1CCCCC1
Reactant: COc1cc(C=CC(=O)Cl)ccc1OC(C)=O
Solvent: c1ccncc1
Product: COc1cc(C=CC(=O)NC2CCCCC2)ccc1OC(C)=O

Procedure:
Using 3 g of 4-acetoxy-3-methoxycinnamoyl chloride, 1.4 ml of cyclohexylamine, and 100 ml of pyridine, a reaction similar to that conducted in Example 53 was carried out. As a result, 2.64 g of N-cyclohexyl-4-acetoxy-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([CH3:33])[CH:27]=4)[CH:23]=[C:22]([C:34]([F:37])([F:36])[F:35])[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:24]2[CH:23]=[C:22]([C:34]([F:36])([F:37])[F:35])[N:21]=[C:20]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=4)[CH:19]=3)[N:25]=2)=[CH:27][C:28]=1[CH3:33]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(-c4ccc(S(=O)(=O)NC(C)(C)C)s4)c3)n2)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(-c4ccc(S(N)(=O)=O)s4)c3)n2)ccc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.1 %

Procedure:
To a cooled and stirred solution of 5-{4-[4-(4-chloro-3-methyl-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.14 g) in dichloromethane (4 ml) was added TFA (4 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.048 g, 26%). MS (ISP) 511.1 [(M+H)+]; mp 280° C.
Reaction SMILES: I[C:2]1[C:10]([N+]([O-])=O)=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])/[C:5](=[O:14])[NH:6]2.[OH:23][CH2:24][CH:25]=[CH:26]B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.O.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>[OH:23][CH2:24][CH:25]=[CH:26][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[CH:15][C:16]1[NH:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:5](=[O:14])[NH:6]2
Reactant: OCC=CB(O)O
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc[nH]c1C=C1C(=O)Nc2cccc(C=CCO)c21
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.14 mmol) (Starting Material 2 supra) in dimethoxyethane (5 mL) was added 3-hydroxy-1-propenyl-boronic acid (from Example 66 above) (42 mg, 0.418 mmol), tetrakis(triphenylphosphine)palladium(0) (39 mg, 0.034 mmol) (Aldrich) and 2M Na2CO3 solution in H2O (0.34 mL). The reaction mixture was stirred at 85° C. overnight in a pressure tube. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (Hex:EtOAc=5:1) to provide 1,3-dihydro-4-(3-hydroxy-propenyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-indol-2-one as a yellow solid. (Yield 22 mg, 53%).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[CH3:23].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:19]2[CH:20]=[CH:21][C:22]([CH3:23])=[C:17]([CH3:16])[CH:18]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: Cc1ccc(B(O)O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)cc1C

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.5 g, 2.02 mmol), 3,4-dimethylphenylboronic acid (0.333 g, 2.22 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.557 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 48 h to give 4-chloro-2-(3,4-dimethylphenyl)-5,7-difluoro-3-methylquinoline as a white solid. Mass Spectrum (ESI) m/e=318.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19](CC3C=CC=CC=3)[CH2:18][CH2:17]2)[CH:3]=1.C(Cl)(Cl)Cl>C(O)C.[Pd]>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)[CH:3]=1
Reactant: COc1cc2nc(N3CCN(Cc4ccccc4)CC3)cc(N)c2cc1OC
Agent: [Pd]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1cc2nc(N3CCNCC3)cc(N)c2cc1OC
Yield: 51.2 %

Procedure:
4-Amino-6,7-dimethoxy-2-(4-benzylpiperazin-1-yl)quinoline (6.2 g) in ethanol (300 ml) with 5% Pd/C catalyst was stirred at 50° under an atmosphere of hydrogen (50 p.s.i.) for 20 hours. The mixture was cooled, chloroform (100 ml) added and the solution filtered through "Solkafloc". The solid was washed with chloroform-methanol (1:1, 4×100 ml) and the combined filtrates evaporated in vacuo. The residue was partitioned between chloroform-sodium carbonate solution (10%), the organic layer removed, the aqueous phase saturated with salt and further extracted with chloroform. The combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo to yield 4-amino-6,7-dimethoxy-2-(piperazin-1-yl)quinoline (2.42 g). Spectroscopy showed this product to be the same as that of Example 32.