Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)(=O)=O.[C:16]1([CH2:22][SH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH2:22]([S:23][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: SCc1ccccc1
Reactant: O=S(=O)(Oc1cncc(Cl)c1)C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Clc1cncc(SCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 104.6 %

Procedure:
To a solution of 5-chloropyridin-3-yl trifluoromethanesulfonate (1.73 g) in toluene (15 mL) were added phenylmethanethiol (861 mg), N,N-diisopropylethylamine (1.88 g), tris(dibenzylideneacetone)dipalladium(0) (121 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (153 mg), and the mixture was stirred under an argon atmosphere at 80° C. for 3 hr. The reaction mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane→hexane-ethyl acetate=19:1) to give the title compound as a yellow oil (yield 1.63 g, quantitative).
Reaction SMILES: Br[C@H:2]1[C:19]2[C@:14]([CH3:21])([CH:15]=[CH:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[C@@H:3]1OC(=O)C.[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C)C=O.O>[N:27]([C:18]1[C:17](=[O:20])[CH:16]=[CH:15][C@@:14]2([CH3:21])[C:19]=1[CH:2]=[CH:3][C@@H:4]1[C@@H:13]2[CH2:12][CH2:11][C@@:9]2([CH3:10])[C@H:5]1[CH2:6][CH2:7][C:8]2=[O:22])=[N+:28]=[N-:29]
Reactant: CC(=O)O[C@H]1[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)C=CC(=O)C=C2[C@@H]1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]12C=CC(=O)C(N=[N+]=[N-])=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 100 °C
Yield: 73 %

Procedure:
To a stirred solution of 0.5 g of 6β-bromo-7α-acetoxyandrosta-1,4-dien-3,17-dione in 30 ml of dimethylformamide and 1.2 ml of water are added 0.11 g of sodium azide. The reaction mixture is heated at 100° C. for 45 minutes, cooled, poured into 500 ml of iced water and extracted with ethyl acetate. The combined extracts are washed with water, dried over sodium sulphate, filtered and evaporated in vacuo to give a residue which is purified by column chromatography on silica gel. Elution with n-hexane:ethyl acetate 70:30 yields 0.28 g of the title compound, m.p. 123°-125° C. (dec.);
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[S:4][C:3]1=S.C1(C)C=CC(S(OC)(=O)=O)=CC=1.C1(OC)C=CC=CC=1.[CH2:35]([N:42]1[C:46](=[O:47])[CH2:45][S:44][C:43]1=[N:48][C:49]1[CH:50]=[C:51]([CH:54]=[CH:55][C:56]=1[NH:57][CH2:58][CH3:59])[C:52]#[N:53])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CC#N>[CH2:35]([N:42]1[C:46](=[O:47])[C:45](=[C:3]2[N:2]([CH3:1])[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:5]([CH3:13])[S:4]2)[S:44][C:43]1=[N:48][C:49]1[CH:50]=[C:51]([CH:54]=[CH:55][C:56]=1[NH:57][CH2:58][CH3:59])[C:52]#[N:53])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Cc1sc(=S)n(C)c1-c1ccccc1
Reactant: CCNc1ccc(C#N)cc1N=C1SCC(=O)N1Cc1ccccc1
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CC#N
Solvent: COc1ccccc1
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2SC(C)=C(c3ccccc3)N2C)C(=O)N1Cc1ccccc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 64.2 %

Procedure:
To an 8 mL vial was added 3,5-dimethyl-4-phenyl-3H-thiazole-2-thione (100 mg, 0.45 mmol), methyl p-toluenesulfonate (126 mg, 0.68 mmol) and anhydrous anisole (0.5 mL). The reaction was heated to 120° C. and stirred for 3 h. The cooled reaction mixture was diluted with anhydrous MeCN (3 mL) and then treated with 3-(3-benzyl-4-oxothiazolidin-2-ylideneamino)-4-(ethylamino)benzonitrile (50 mg, 0.14 mmol) and TEA (70 μL, 0.50 mmol). The reaction mixture was warmed to 80° C. and the resulting solution was allowed to stir for 16 h. The product mixture was concentrated under reduced pressure and chromatographed (silica gel, 1:1 EtOAc/Hex) to yield the title product (48.3 mg, 64%) as a yellow solid. 1H-NMR (CDCl3): δ 7.40 (5H, m), 7.33 (2H, m), 7.25 (3H, m), 7.23 (2H, m), 6.46 (1H, d), 5.18 (2H, s), 4.28 (1H, m), 3.46 (3H, s), 2.99 (2H, m), 2.28 (3H, s), 1.01 (3H, t); MS(ESI): 538 (MH+).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[PH2]([O-])=O.[Na+].O.O[CH2:23][CH:24]([CH2:26]O)O>S(=O)(=O)(O)O>[CH:23]1[C:6]2=[C:7]3[C:12]([C:13]([C:14]4[C:5]2=[CH:4][CH:3]=[CH:2][CH:1]=4)=[O:15])=[CH:11][CH:10]=[CH:9][C:8]3=[CH:26][CH:24]=1
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: O
Product: O=C1c2ccccc2-c2cccc3cccc1c23
Temperature: 120 °C
Reaction time: 3 h

Procedure:
208 g of anthraquinone are dissolved in 1,000 g of concentrated sulphuric acid at 80°-110°. 96 g of sodium hypophosphite, dissolved in 240 g of glycerol, are added to this solution in a manner such that a temperature of 100° C. can be maintained. The mixture is then heated to 120° C. and kept at this temperature for 3 hours. The melt is then poured into 3 l of water and the product which has precipitated is filtered off. It is washed with hot water until the runnings are almost colourless, the filter cake is then suspended in 1.5 l of water and the suspension is rendered weakly alkaline and boiled up. After renewed filtration of the product, washing with hot water and drying at 100° C., 200-225 g of 92-97% pure benzanthrone≈80-93% of theory result.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>CN(C)C=O>[O:25]1[CH2:26][CH2:27][N:22]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:23][CH2:24]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCOCC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed a solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv) in N,N-dimethylformamide (4 mL), morpholine (76.6 mg, 0.88 mmol, 2.00 equiv), DIEA (170.3 mg, 1.32 mmol, 3.00 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 136.4 mg (86%) of methyl 3-morpholino-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[Cl-].[NH4+]>[Fe].C(O)C.O>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: CN(C)CCn1ncc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN(C)CCn1ncc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
A mixture of dimethyl-[2-(5-nitro-indazol-1-yl)-ethyl]-amine (1 g, 4.3 mmol), iron powder (1.9 g, 34 mmol), and ammonium chloride (120 mg, 2.2 mmol) in a 4:1 ethanol/H2O solution (20 mL) was heated to reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was stirred in triethylamine/ethyl acetate (1/4, 10 mL) for 15 minutes and then filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure to provide the title compound (0.80 g, 92%). 1H NMR (300 MHz, DMSO-d6) ppm 2.15 (s, 6H), 2.64 (t, J=6.44, 2H), 4.34 (t, J=6.44, 2H), 4.77 (s, 2H), 6.72 (m, 1H), 6.79 (m, 1H), 7.35 (m, 1H), 7.67 (m, 1H); MS (DCI/NH3) m/z 205 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[OH:8])[CH2:2]1.BrC1C=NC=CC=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1O>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:8][C@@H:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C@H:3]1[O:4][CH2:5][CH2:6][NH:1][CH2:2]1
Reactant: Oc1ccccc1F
Reactant: OC(c1cccnc1)C1CNCCO1
Solvent: Brc1cccnc1
Product: Fc1ccccc1O[C@@H](c1cccnc1)[C@@H]1CNCCO1

Procedure:
(S)-2-[(S)-(2-Fluorophenoxy)-pyridin-3-yl-methyl]-morpholine was synthesized via morpholin-2-yl-pyridin-3-yl-methanol from 3-bromopyridine and 2-fluorophenol according to general procedure C and was isolated as a gummy oil (mixture of diastereoisomers). MS (APCI): 289 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH:16](O)COC(CCCCCCCCCCC)=O)=[O:13]>OCC(CO)O>[CH:15]([O:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[CH2:16]
Reactant: CCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCC
Solvent: OCC(O)CO
Product: C=COC(=O)CCCCCCCCCCC

Procedure:
1,3 DLa was easily purified and recovered by crystallization in dry methanol at room temperature (RT) or in hexane at −20° C. (purity >98%). When lauric acid (La) was used as an acyl-donor, solvent was added to dissolve the FFA. Though the method as described in J. Am. Oil Chem. Soc., 1992, 69:955-960, allowed faster reaction rate with high yield of 1,3-DLa (65%), the highest yield (78%) of 1,3-DLa obtained from esterification between glycerol and lauric acid vinyl ester (LaVE) at 0° C. in a solvent-free condition catalyzed by CAL-B after 24 h, as illustrated in FIG. 14. FIG. 14 summarizes data of various synthesis of 1,3-dilaurin. Method1=esterification of glycerol and lauric acid in n-hexane at 0° C. catalyzed by CAL-B; Method2=esterification of glycerol and lauric acid vinyl ester in a solvent-free condition at 0° C. catalyzed by CAL-B; Method3 (Schneider's method)=esterification of glycerol (immobilized on silica gel) and lauric acid vinyl ester in MTBE at room temperature catalyzed by Lipozyme RM IM™ (Eurzyme, Dublin, Ireland). (DG=1,3-dilaurin, MG=1-monolaurin). LaVE, as acyl donor, allowed higher yield and faster reaction with less amount of MG than La.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.C(O)(=O)C.[CH2:26]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][CH2:43][CH2:44][C:45](=O)[C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:38][CH2:37]1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([BH3-])#N.[Na+]>C(O)C>[CH2:26]([O:33][C:34]([N:36]1[CH2:37][CH2:38][CH:39]([CH2:42][CH2:43][CH2:44][C@@H:45]([NH:1][C@@H:2]2[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]3[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=3[S:4][CH2:3]2)[C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:40][CH2:41]1)=[O:35])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSc2ccccc21
Reactant: CCOC(=O)C(=O)CCCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H](CCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 9 %

Procedure:
In 30 ml of ethanol is dissolved 2.1 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5acetate, and 0.4 g of acetic acid, 2.5 g of ethyl 5-(1-benzyloxycarbonyl-4-piperidyl)-2-oxovalerate and 10 g of Molecular sieve 3A are added to the solution. The mixture is stirred at room temperature for 20 minutes, and a solution of 0.4 g of sodium cyanoborohydride in 50 ml of ethanol is added dropwise to the mixture at room temperature with stirring over the period of 3 hours. The reaction solution is allowed to stand at room temperature overnight, and concentrated under reduced pressure, and 300 ml of water and 300 ml of ethyl acetate are added to the residue, followed by shaking. The insoluble matter is removed by filtration, and the ethyl acetate layer is dried over anhydrous magnesium sulfate and ccncentrated under reduced pressure. Ethyl acetate (20 ml) and 2 g of oxalic acid are added to the residue, and the mixture is shaken thoroughly and admixed with 300 ml of petroleum ether, followed by allowing the mixture to stand. The solution portion is removed by decantation, and 100 ml of water and 200 ml of ethyl acetate are added to the precipitate portion, followed by adding excess sodium hydrogencarbonate to conduct neutralization. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give an oily material. This product is separated and purified by silica-gel column chromatography (hexane:ethyl acetate=2:1) to give from the first fraction 0.4 g of tert-butyl 3(R)-[4-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylbutyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oily material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:19])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[CH:6][CH:7]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>C(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:11]2[O:10][C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]2=[O:19])=[CH:21]1
Reactant: CCOC(=O)C1=C(Nc2cccc(Cl)c2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2cccc(Cl)c2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 42.5 %

Procedure:
To a solution of ethyl 2-[(3-chlorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.36 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.051 g, 0.35 mmol) in ethanol (3.0 mL), piperidine (0.0035 mL, 0.035 mmol) was added at ambient temperature. The mixture was refluxed for 6 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound (0.061 g, y. 23%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([C:8]1[C:9](O)=[C:10]([N+:15]([O-:17])=[O:16])[C:11](=[O:14])[NH:12][CH:13]=1)[CH3:7]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[Cl:3][C:9]1[C:8]([CH2:6][CH3:7])=[CH:13][NH:12][C:11](=[O:14])[C:10]=1[N+:15]([O-:17])=[O:16]
Reactant: CCc1c[nH]c(=O)c([N+](=O)[O-])c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Product: CCc1c[nH]c(=O)c([N+](=O)[O-])c1Cl
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
Phosphorus oxychloride (6.7 ml, 39.1 mmoles) was added to a solution of compound 5b (3.00 g, 16.3 mmoles) and benzyltriethylammonium chloride (14.90 g, 65.2 mmoles) in acetonitrile (60 ml). The mixture obtained was agitated at 40° C. for 30 minutes and heated under reflux for 1 hour. After evaporation of the solvent, 60 ml of water was added and the mixture agitated at ambient temperature for 3 hours. The yellow precipitate was collected, washed with cyclohexane (3×6 ml) and dried to give compound 6b (2.4 g, 74%) in the form of pale yellow crystals: NMR-1H (DMSO-d6) δ 13.19 (1H, s, NH-1), 7.73 (1H, s, H-6), 2.56 (2H, q, L=7.5 Hz, CH2CH3), 1.16 (3H, t, J=7.5 Hz, CH2CH3 ).
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]2[C:10](=[C:11]([O:22][CH3:23])[CH:12]=[CH:13][C:14]=2[O:20][CH3:21])[C:9]=1[O:24][CH3:25])[CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6].C1CCC(N=C=NC2CCCCC2)CC1.ClCCl.[C:44](O)(=[O:46])[CH3:45]>CN(C)C1C=CN=CC=1.CCCCCC>[C:44]([O:1][CH:2]([C:8]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]2[C:10](=[C:11]([O:22][CH3:23])[CH:12]=[CH:13][C:14]=2[O:20][CH3:21])[C:9]=1[O:24][CH3:25])[CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6])(=[O:46])[CH3:45]
Reactant: COc1ccc(OC)c2c(OC)c(C(O)CCC(C)C)cc(OC)c12
Reactant: CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1ccc(OC)c2c(OC)c(C(CCC(C)C)OC(C)=O)cc(OC)c12
Reaction time: 0.5 h
Yield: 90 %

Procedure:
In a 25 ml two-neck flask 1 mmole of 2-(1-hydroxy-4-methylpentyl)-1,4,5,8-tetramethoxynaphthalene, 226 mg (1.1 mmole) of DCC and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were introduced and then 3 ml of dry dichloromethane was added thereto. After adding 1 mmole of acetic acid at 0° C. under nitrogen gas, the reaction mixture was stirred for 30 minutes and then subsequently stirred at normal temperature for further 3 hours. To the reaction mixture was added 20 ml of n-hexane. The mixture was stirred for further 10 minutes and then filtered to remove the insoluble materials. The filtrate was dried over anhydrous magnesium sulfate to obtain a crude product. The crude product was purified by silica gel column chromatography (silica gel 2.5×20 cm) using the solvent condition which increases the amount of ethylacetate so that the n-hexane/ethylacetate ratio can vary from 20:1 to 5:1, to obtain the title compound as a pale yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=1.[Cl:14][C:15]1[CH:16]=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:18]=[C:19]([Cl:22])[C:20]=1F.Cl>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:18]=[C:19]([Cl:22])[C:20]=1[O:7][C:8]1[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=1
Reactant: Cc1cc(O)n[nH]1
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Temperature: 60 °C
Yield: 53.6 %

Procedure:
Potassium carbonate (2.8 g, 20.0 mmol) was added to a solution of 3-hydroxy-5-methylpyrazole (1.47 g, 15.0 mmol) and 3,5-dichloro-4-fluorobenzotrifluoride (3.5 g, 15.0 mmol) in DMF (30 ml), and the mixture was stirred under heating at 60° C. for 6 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (70 ml) and extracted with ethyl acetate (30 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10→1/7), to give a white solid of 3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole (2.5 g, yield: 54.0%). mp: 153-155° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.27 (s, 3H), 5.68 (s, 1H), 7.64 (s, 2H), 8.75-9.70 (br s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH2:34]([O:36][C:37]1[CH:43]=[C:42]([CH2:44][CH2:45][N:46]2[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]2)[CH:41]=[CH:40][C:38]=1[NH2:39])[CH3:35].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:39][C:38]3[CH:40]=[CH:41][C:42]([CH2:44][CH2:45][N:46]4[CH2:47][CH2:48][N:49]([CH3:52])[CH2:50][CH2:51]4)=[CH:43][C:37]=3[O:36][CH2:34][CH3:35])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: CCOc1cc(CCN2CCN(C)CC2)ccc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CCOc1cc(CCN2CCN(C)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 130 °C
Yield: 52.9 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.22 mmol), 2-(ethyloxy)-4-[2-(4-methyl-1-piperazinyl)ethyl]aniline (Example 146, step D) (46 mg, 0.17 mmol), and p-toluenesulfonic acid (99 mg, 0.52 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 130° C. for 72 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (67 mg, 0.09 mmol, 56%); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.21 (s, 1H), 9.34 (s, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 8.27 (s, 1H), 8.02 (s, 1H), 7.80 (s, 1H), 7.73 (s, 1H), 7.65 (s, 1H), 7.59 (s, 1H), 7.46 (s, 1H), 7.38 (s, 1H), 7.18 (s, 2H), 6.96 (s, 2H), 6.72 (s, 1H), 6.46 (s, 1H), 4.02-4.11 (m, 2H), 2.60-2.71 (m, 2H), 2.25-2.32 (m, 10H), 2.12 (s, 3H), 1.26 (s, 3H). MS (ESI): 689 [M+H]+.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C>C1COCC1>[CH2:1]([S:3]([NH:7][CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: NC1CCCOc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCS(=O)(=O)NC1CCCOc2ccccc21
Reaction time: 8 h
Yield: 70.6 %

Procedure:
0.86 g (6.7 mmol) of ethanesulfonyl chloride was added dropwise with ice cooling to a solution of 1.0 g (6.1 mmol) of 5-amino-2,3,4,5-tetrahydro-1-benzoxepine and 2.5 g (24 mmol) of triethylamine in 20 ml of THF. The mixture was allowed to come to room temperature and was stirred overnight, and the solvent was distilled off in vacuo. After stirring the residue with water, the deposited product was filtered off with suction. 1.1 g of 5-ethylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine were obtained, m.p. 109-111° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.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>[CH:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:7][N:6]=[CH:5]4)[CH:24]=2)[CH2:19][CH2:20]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc2c(N3CCNCC3)nncc2c1
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: [K+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCNCC3)nncc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A mixture of 6-bromo-1-(piperazin-1-yl)phthalazine (0.12g, 0.41 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.12g, 0.41 mmol), tetrakis(triphenylphosphine)palladium (24mg, 0.0205 mmol) and 2 M potassium carbonate (0.7 mL, 1.4 mmol) in 5 mL DME/EtOH (4:1) was stirred at 90° C. for 2 h. The mixture was directly purified via flash chromatography (silica gel) with a gradient of 2% 2 M ammonia in MeOH/DCM to 10% 2 M ammonia in MeOH/DCM to give the title compound (0.14g) as a yellow solid. Found MS (ES+): 388(M+H)+.