Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)N.C(O)(=O)C.Cl>O>[C:1]1([C:7]2[NH:16][C:18]3[C:26]([C:9]=2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc2[nH]c(-c3ccccc3)c(-c3ccccc3)c2c1
Reaction time: 0.25 h

Procedure:
1.96 g (10 mmol) of deoxybenzoin and 1.52 g of 4-hydrazinobenzoic acid were ground in a mortar and then fused in an open flask at 160° C. for 15 minutes (min). The cooled melt was admixed with 100 ml of acetic acid and 30 ml of concentrated hydrochloric acid and heated under reflux for 3 hours (h). The cooled solution was admixed with water, resulting in the precipitation of the product 2,3-diphenyl-1H-indole-5-carboxylic acid. The product was filtered off with suction and the residue was washed with water and dried. For purification, the crude product was stirred with warm toluene, filtered off with suction and dried again. This gave 2,3-diphenyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:50]([Cl:51])=[CH:49][C:5]2[NH:6][C:7]([CH2:9][CH2:10][CH:11]3[CH2:14][CH:13]([N:15]([CH2:17][C@@H:18]4[C@H:22]5[O:23]C(C)(C)[O:25][C@H:21]5[C@H:20]([N:28]5[C:32]6[N:33]=[CH:34][N:35]=[C:36]([NH:37]CC7C=CC(OC)=CC=7OC)[C:31]=6[CH:30]=[CH:29]5)[CH2:19]4)[CH3:16])[CH2:12]3)=[N:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+]>FC(F)(F)C(O)=O.O>[NH2:37][C:36]1[C:31]2[CH:30]=[CH:29][N:28]([C@@H:20]3[CH2:19][C@H:18]([CH2:17][N:15]([CH:13]4[CH2:12][CH:11]([CH2:10][CH2:9][C:7]5[NH:8][C:4]6[CH:3]=[C:2]([Cl:1])[C:50]([Cl:51])=[CH:49][C:5]=6[N:6]=5)[CH2:14]4)[CH3:16])[C@@H:22]([OH:23])[C@H:21]3[OH:25])[C:32]=2[N:33]=[CH:34][N:35]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCc4nc5cc(Cl)c(Cl)cc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(Cl)c(Cl)cc3[nH]2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
7-((3aS,4R,6R,6aR)-6-(((3-(2-(5,6-Dichloro-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (377 mg, 0.513 mmol) was dissolved in a mixture of Trifluoroacetic Acid (7.1 ml) and Water (0.8 ml) which had been pre-cooled at 0° C. in an ice bath. The solution was stirred at 0° C. for 30 minutes, then warmed to and stirring was continued for 3 h at RT. The suspension was concentrated and the residue was taken up in 15 ml MeOH and concentrated. This procedure was repeated twice and the residue placed on high vacuum. The material was taken up in 10 ml MeOH (gave a slurry) and was treated with 500 mg K2CO3 and 0.2 ml of water. The mixture was allowed to stir for 1.5 hr, during which time the pH of the solution was −9. The mixture was filtered through a fine frit, the solids were washed with 20 ml MeOH and the filtrate was concentrated to yield an off white solid. The material was left on high vacuum overnight and purified by flash chromatography (SiO2, eluting with 10-12% 7N NH3 in CH3OH/CH2Cl2) to give the desired product (227 mg). 1H NMR (400 MHz, MeOD) δH ppm 8.06 (s, 1H), 7.63 (m, 2H), 7.21 (dd, J=3.63, 2.38 Hz, 1H), 6.59 (d, J=3.52 Hz, 1H), 4.32 (m, 1H), 3.88 (m, 1H), 3.01 (m, 0.5H), 2.84 (m, 2H), 2.70 (m, 0.5H), 2.51 (m, 1H), 2.40 (m, 2H), 2.26 (m, 2H), 2.17 (d, J=7.05 Hz, 3H), 2.11 (m, 2H), 2.02 (m, 1H), 1.90 (m, 3H), 1.62 (m, 1H), 1.49 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[N:4][C:5](F)=[CH:6][CH:7]=1.[CH3:18][O-:19].[Na+]>CO.[Cl-].[Na+].O>[F:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[N:4][C:5]([O:19][CH3:18])=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: Fc1cccc(CNc2nc(F)ccc2F)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(F)c(NCc2cccc(F)c2)n1
Temperature: 150 °C
Yield: 62.2 %

Procedure:
3,6-difluoro-N-(3-fluorobenzyl)pyridine-2-amine (0.5209 g, 2.19 mmol), was dissolved in anhydrous MeOH (6.6 mL) and placed under argon. This mixture then was treated with sodium methoxide (0.500 mL, 0.473 g, 2.19 mmol, 25% in MeOH) by slow addition. The resulting mixture was then heated in the microwave at 150° C. for four 30 min. The reaction mixture was then poured into brine (25 mL). This mixture was extracted with EtOAc (3×25 mL), the combined extracts were washed with brine (1×25 mL) and dried (Na2SO4). After filtration the solvent removed in vacuo. The resulting residue was subjected to silica gel column chromatography. Elution using 100 hexanes to 25 EtOAc/75 hexanes afforded 0.3408 g (62%) of 3-fluoro-N-(3-fluorobenzyl)-6-methoxypyridin-2-amine. LCMS (m/z): 251.1 (MH+), retention time=1.07 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])=[CH:4][CH:3]=1.[OH:19]O.CSC>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])=[O:19])=[CH:6][CH:7]=1
Reactant: OO
Reactant: O=C(CSc1ccc(O)cc1)Nc1ccccc1
Solvent: CSC
Solvent: CC(=O)O
Product: O=C(CS(=O)c1ccc(O)cc1)Nc1ccccc1
Yield: 93 %

Procedure:
6.0 g (23.2 mmol) of 2-(4-hydroxyphenylthio)acetoanilide and 50 mL of acetic acid were added under a room temperature into a 100 mL flask with four inlets and attached with a stirrer and a thermometer. To the resultant solution, 2.8 g (24.7 mmol) of 30k aqueous solution of hydrogen peroxide was added, and the resultant solution was stirred for 12 hours at a room temperature. Following to the completion of the reaction, 0.5 g of dimethyl sulfide was added into the solution, and then, the solution was extracted with MIBK. The MIBK layer was washed several times with water, and followed by washing with sodium hydrogencarbonate. The MIBK in the solution was distilled out under reduced pressure, and the resultant residue was subjected to recrystallization with MIBK to obtain 5.9 g of 2-(4-hydroxyphenylsulfinyl)acetoanilide. The yield was 93% and the melting point of the compound was in a range of 208 to 210° C.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:24]1[C:32]2[C:27](=[N:28][CH:29]=[N:30][C:31]=2[NH2:33])[N:26]([C@H:34]2[CH2:39][CH2:38][C@@H:37]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)[CH2:36][CH2:35]2)[N:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[NH:7]([C:8]1[CH:9]=[CH:10][C:11]([C:24]2[C:32]3[C:27](=[N:28][CH:29]=[N:30][C:31]=3[NH2:33])[N:26]([CH:34]3[CH2:35][CH2:36][CH:37]([N:40]4[CH2:41][CH2:42][N:43]([CH3:46])[CH2:44][CH2:45]4)[CH2:38][CH2:39]3)[N:25]=2)=[CH:12][CH:13]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2ccc(Nc3ccccc3)cc2)OC1(C)C
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: CN1CCN(C2CCC(n3nc(-c4ccc(Nc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Yield: 76.3 %

Procedure:
A mixture of N-phenyl—N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (Intermediate AE) (0.33 g, 0.0011 mol), cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AC) (0.43 g, 0.00097 mol), tetrakis(triphenylphosphine)palladium (0.0067 g, 0.000058 mol) and sodium carbonate (0.26 g, 0.0024 mol) was heated in a mixture of ethylene glycol dimethyl ether (16 mL) and water (8 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (50 mL), the organic layer separated and the aqueous layer further extracted with ethyl acetate twice. The combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure to give a tan solid which was purified by flash column chromatography on silica using dichloromethane/triethylamine/methanol (92:7:1) as a mobile phase to give 3-(4-anilinophenyl)-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid (0.400 g, 0.00074 mol). It was dissolved at reflux in ethanol (17 mL) and a preheated solution of maleic acid (0.342 g, 0.003 mol) in ethanol (8 mL) was added. The mixture was refluxed for 10 min, cooled to ambient temperature and the precipitate collected by filtration, washed with ethyl acetate and dried to give cis-3-(4-anilinophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine trimaleate (0.44 g, 0.00053 mol) 1H NMR (DMSO-d6, 400 MHz) 8.45 (s, 1H), 8.23 (s, 1H) 7.52 (d, 2H), 7.28 (m, 2H), 7.20 (m, 4H), 6.89 (t, 1H), 6.19 (s, 6H), 4.83 (m, 1H), 3.1 (br, 9H), 2.72 (s, 3H), 2.28 (m, 2H), 2.07 (m, 2H), 1.74 (m, 4H); RP-HPLC (Delta Pak C18, 5μm, 300 A, 15 cm; 5%-85% acetonitrile—0.1M ammonium acetate over 20 min, 1 mL/min) Rt 13.12 min. MH+483.
Reaction SMILES: CS([Cl:5])(=O)=O.[CH3:6][N:7]([CH2:16][CH:17](O)[CH3:18])[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15].C(N(CC)CC)C>ClCCCl>[CH3:6][N:7]([CH2:16][CH:17]([Cl:5])[CH3:18])[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(C)c1N(C)CC(C)O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cccc(C)c1N(C)CC(C)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
3.1 ml (4.6 g, 40 mmoles) of methanesulfonyl chloride are added dropwise, at a temperature not exceeding 20° C., to a solution of 7.0 g (36.2 mmoles) of 1-[N-methyl-N-(2,6-dimethylphenyl)-amino]-2-propanol and 5.45 ml (4.0 g, 40 mmoles) of triethyl amine in 50 ml of 1,2-dichloroethane, and the resulting mixture is stirred at room temperature for 3 hours. The mixture is washed then thrice with 30 ml of water, each, dried over anhydrous magnesium sulfate, the solvent is evaporated, and the oily residue is distilled under reduced pressure. 6.9 g (90.2%) of 1-[N-methyl-N-(2,6-dimethylphenyl)-amino]-2-chloro-propane are obtained; b.p.: 116°-118° C./133 Pa.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[SH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:13](OC(=O)C)(=O)[CH3:14]>C(O)(=O)C>[CH3:13][C:14]1[S:12][C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cnc2ccccc2c1S
Solvent: CC(=O)O
Product: Cc1nc2cnc3ccccc3c2s1

Procedure:
A suspension of 3-aminoquinoline-4-thiol (about 12 g) in a mixture of acetic anhydride (150 mL) and acetic acid (300 mL) was heated at reflux overnight. The reaction mixture was filtered to remove a fine solid. The filtrate was evaporated under vacuum. The residue was diluted with ethanol then refluxed for 30 minutes. The solution was concentrated under vacuum and the residue diluted with water. The aqueous residue was made basic with sodium hydroxide and then extracted with diethyl ether. The ether extracts were combined, dried over magnesium sulfate and filtered. The filtrate was evaporated to provide 12.8 g of crude product. A sample (800 mg) was recrystallized from hexane to provide 2-methylthiazolo[4,5-c]quinoline as yellow needles, m.p. 95.5-97.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:6](=[O:7])[CH:5]=[C:4]([C:8]2[N:9]=[CH:10][S:11][CH:12]=2)[O:3]1.C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:21][C:5]1[C:6](=[O:7])[C:2]([CH3:13])([CH3:1])[O:3][C:4]=1[C:8]1[N:9]=[CH:10][S:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)OC(c2cscn2)=CC1=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(c2cscn2)=C(Br)C1=O
Reaction time: 1 h
Yield: 31.7 %

Procedure:
To a stirred solution of 2,2-dimethyl-5-(thiazol-4-yl)furan-3(2H)-one (90 mg, 0.46 mmol) in CHCl3 (1.8 mL) was added NBS (0.12 g, 0.69 mmol) portionwise at RT and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with DCM (10 mL), washed with water (5 mL), brine (10 mL), dried over Na2SO4, filtered and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-bromo-2,2-dimethyl-5-(thiazol-4-yl)furan-3(2H)-one (40 mg, 71%) as an off white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])=[C:4]([F:17])[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][CH:26]2[CH2:28][CH2:27]2)[C:22]([C:29]([F:32])([F:31])[F:30])=[CH:21][N:20]=1.Cl>CCCCO>[CH:26]1([NH:25][C:23]2[C:22]([C:29]([F:31])([F:32])[F:30])=[CH:21][N:20]=[C:19]([NH:1][C:2]3[C:7]([OH:8])=[CH:6][C:5]([C:9]([N:11]4[CH2:12][CH2:13][O:14][CH2:15][CH2:16]4)=[O:10])=[C:4]([F:17])[CH:3]=3)[N:24]=2)[CH2:27][CH2:28]1
Reactant: FC(F)(F)c1cnc(Cl)nc1NC1CC1
Reactant: Nc1cc(F)c(C(=O)N2CCOCC2)cc1O
Agent: Cl
Solvent: CCCCO
Product: O=C(c1cc(O)c(Nc2ncc(C(F)(F)F)c(NC3CC3)n2)cc1F)N1CCOCC1
Temperature: 100 °C
Reaction time: 10 h
Yield: 34.1 %

Procedure:
A mixture of (4-amino-2-fluoro-5-hydroxyphenyl)(morpholino)methanone (200 mg, 0.83 mmol), 2-chloro-N-cyclopropyl-5-(trifluoromethyl)pyrimidin-4-amine (198 mg, 0.83 mmol), concentrated HCl (0.1 mL), and n-BuOH (10 mL) was stirred at 100° C. for 10 h. The mixture was concentrated under reduced pressure and the residue was purified by rp-HPLC to afford the title compound as white solid (125 mg, 34%); 1H NMR (500 MHz, DMSO) δ 8.55-8.49 (m, 1H), 8.26 (s, 1H), 8.18-8.08 (m, 1H), 7.45 (br s, 1H), 6.77 (d, J=7.0 Hz, 1H), 3.62-3.53 (m, 4H), 3.48-3.46 (m, 2H), 3.30-3.11 (m, 2H), 2.84-2.82 (m, 1H), 0.84-0.78 (m, 2H), 0.75-0.68 (m, 2H); LCMS: m/z=442.3 [M+H]+.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[CH:23]=[C:22]([F:24])[C:21]([CH3:25])=[CH:20][C:18]=1[NH2:19]>>[Cl:16][C:17]1[CH:23]=[C:22]([F:24])[C:21]([CH3:25])=[CH:20][C:18]=1[NH:19][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Reactant: Cc1cc(N)c(Cl)cc1F
Product: CCOC(=O)c1cnc2ccnn2c1Nc1cc(C)c(F)cc1Cl
Yield: 84 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (4.35 g, 21.0 mmol) and 2-chloro-4-fluoro-5-methylaniline (3.02 g, 18.9 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (5.54 g, 76%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[F:33][C:34]([F:66])([F:65])[C:35]1[CH:36]=[C:37]([CH:62]=[CH:63][CH:64]=1)[CH2:38][NH:39][C:40](=[O:61])[C:41]1[CH:46]=[CH:45][N:44]=[C:43]([C:47]2[CH:52]=[C:51]([N:53]([CH2:57][CH2:58][CH3:59])[CH2:54][CH2:55][CH3:56])[CH:50]=[CH:49][C:48]=2[NH2:60])[CH:42]=1>ClCCl.CN(C)C1C=CN=CC=1>[F:65][C:34]([F:33])([F:66])[C:35]1[CH:36]=[C:37]([CH:62]=[CH:63][CH:64]=1)[CH2:38][NH:39][C:40]([C:41]1[CH:46]=[CH:45][N:44]=[C:43]([C:47]2[CH:52]=[C:51]([N:53]([CH2:54][CH2:55][CH3:56])[CH2:57][CH2:58][CH3:59])[CH:50]=[CH:49][C:48]=2[NH:60][C:14]([C:13]2[CH:12]=[C:11]([CH:19]=[CH:18][CH:17]=2)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:20])=[O:16])[CH:42]=1)=[O:61]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Reactant: CCCN(CCC)c1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCN(CCC)c1ccc(NC(=O)c2cccc(CSCCC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 10-mL vial, was placed a solution of 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid (355.2 mg, 1.20 mmol, 2.00 equiv) in dichloromethane (5 mL), EDC.HCl (228 mg, 1.19 mmol, 2.00 equiv), 4-dimethylaminopyridine (146.4 mg, 2.00 mmol), and N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-(dipropylamino)phenyl)isonicotinamide (300 mg, 0.64 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at 25° C. in an oil bath. The resulting solution was diluted with 50 mL of dichloromethane and washed with 3×50 mL of aqueous NH4Cl. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5-1:3). The product was obtained as 320 mg (67%) of a yellow to green oil.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH:33]1([CH2:36]O)[CH2:35][CH2:34]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH:33]1([CH2:36][O:32][C:29]2[CH:28]=[CH:27][C:26]([C:24]3[NH:25][C:21]([CH:13]([C:10]4[CH:11]=[CH:12][C:7]([S:4]([CH:1]5[CH2:3][CH2:2]5)(=[O:6])=[O:5])=[CH:8][CH:9]=4)[CH2:14][CH:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:22][CH:23]=3)=[N:31][CH:30]=2)[CH2:35][CH2:34]1
Reactant: OCC1CC1
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(O)cn3)[nH]2)cc1)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(OCC4CC4)cn3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.5 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-ol (0.260 g) in tetrahydrofuran (10 mL) were added cyclopropylmethanol (83 mg), tributylphosphine (0.29 mL) and 1,1′-(azodicarbonyl)dipiperidine (290 mg), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in toluene (10 mL), and hexane (10 mL) was added. The obtained suspension was filtered to remove the precipitate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80-70:30, volume ratio) to give the title compound (0.240 g, yield 83%) as a colorless amorphous solid. MS: 507 (MH+).
Reaction SMILES: O1CCCC1.Cl.[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:9]=1.[CH3:28][C:29]([CH3:34])=[CH:30][C:31](Cl)=[O:32]>C(N(CC)CC)C>[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][N:25]([C:31](=[O:32])[CH:30]=[C:29]([CH3:34])[CH3:28])[CH2:24][CH2:23]2)[N:9]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: CC(C)=CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc2nc(N3CCN(C(=O)C=C(C)C)CC3)nc(N)c2cc1OC
Reaction time: 0.33 h
Yield: 56.5 %

Procedure:
To 20 ml of tetrahydrofuran were added 2.4 g of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline hydrochloride and 2.6 g of triethylamine, after which the mixture was stirred for 20 minutes. There was then added 0.7 g of 3,3-dimethylacryloyl chloride, after which the mixture was stirred at room temperature for 15 hours. The resulting crystals were collected by filtration, washed with water and recrystallized from dimethylformamide to give 1.24 g of the desired product in the form of colourless powdery crystals melting at 278°-280° C. (with decomposition).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][N:11]=2)=[CH:6][CH:5]=1.Br[CH2:25][CH2:26][CH2:27][C@H:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>O>[CH3:35][C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:26][CH2:25][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: CCCCCCCCc1ccc(-c2ccc(O)cc2)nc1
Reactant: CCCCCC[C@@H](C)CCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCc1ccc(-c2ccc(OCCC[C@H](C)CCCCCC)cc2)nc1
Yield: 47.1 %

Procedure:
20 ml of a 30% aqueous solution of sodium hydroxide was added dropwise to a mixture of 2 g (0.007 mol) of 2-(p-hydroxyphenyl)-5-octylpyridine and 1.65 g (0.007 mol) of (R)-1-bromo-(4-methyl)decane with stirring. The resulting solution was heated to a temperature between about 90° and 100° C. for 3 hours. 150 ml of water was added to the reaction solution and the organic layer was extracted with chloroform. After washing the extract three times with water, chloroform was removed by distillation. The residue was chromatographed over 2.5×100 (cm) of silica gel and developed with hexane and benzene. The effluent was repeatedly recrystallized from a mixture of methanol and acetone to yield 1.44 g (0.0033 mol) of (R)2-[p-(4-methyldecyloxy)phenyl]-5-octylpyridine.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1.C(N(CC)CC)C.C(N=C=NCCCN(C)C)C.[Cl:34][C:35]1[CH:36]=[C:37]([O:46][CH2:47][CH:48]=[C:49]([Cl:51])[Cl:50])[CH:38]=[C:39]([Cl:45])[C:40]=1[O:41][CH2:42][CH2:43][NH2:44]>ClCCl>[Cl:34][C:35]1[CH:36]=[C:37]([O:46][CH2:47][CH:48]=[C:49]([Cl:51])[Cl:50])[CH:38]=[C:39]([Cl:45])[C:40]=1[O:41][CH2:42][CH2:43][NH:44][C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:14])=[CH:13][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)cc1
Reactant: NCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C=Cc1ccc(C(F)(F)F)cc1)NCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Yield: 62.6 %

Procedure:
To a solution of 0.15 g of 4-trifluoromethylcinnamic acid and 0.07 g of triethylamine dissolved in 5 ml of dichloromethane was added 0.14 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC) hydrochloride, while stirring under ice cooling. After stirring for 30 minutes, a solution of 0.20 g of 3,5-dichloro-4-(2-aminoethoxy)-1-(3,3-dichloro-2-propenyloxy)benzene dissolved in 5 ml of dichloromethane was added dropwise. After stirring at room temperature for 12 hours, the reaction mixture was concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.20 g of 3,5-dichloro-4-(2-(4-trifluoromethylcinnamamido)ethoxy)-1-(3,3-dichloro-2-propenyloxy)benzene (63% yield), m.p., 109.4° C.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:15][CH2:14][C@@H:13]([O:16][C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[CH2:12][NH:11][C:10]1=[O:25])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@H:9]1[CH2:15][CH2:14][C@@H:13]([O:16][C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[CH2:12][NH:11][C:10]1=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OC(=O)C2CCCCC2)CNC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@@H](OC(=O)C2CCCCC2)CNC1=O
Reaction time: 1 h

Procedure:
To a solution of (3S, 6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-(cyclohexanecarbonyl) oxy-2H-azepin-2-one (10 g, 28.2 mmol) in 40 mL of CH2Cl2 is added TFA (25 mL) at room temp., and the reaction solution is stirred at room temp. for 1 hr, then concd via rotary evaporation (bath temp<20° C.). The residue is diluted with CH2Cl2 (100 mL), and washed with NH4OH (10 mL) and then water (2×20 mL) and dried (Na2SO4). The reaction mixture is adsorbed on silica and chromatographed (5% methanol-CH2Cl2) to give 6.0 (85.0%) of (3S, 6R)-3-aminohexahydro-6-(cyclohexanecarbonyl)oxy-2H-azepin-2-one as a white solid: 1H NMR (CDCl3): δ 6.91 (s, 1H), 4.91 (s, 1H), 4.39 (s, 2H), 3.87 (d, J=9.8 Hz, 1H), 3.48 (t, J=6.02 Hz, 1H), 3.43 (dd, J=15.45Hz and 4.90 Hz, 1H), 2.30 (tt, J=10.92 Hz and 3.39 Hz, 1H), 2.13 (m, 1H), 1.91 (m, 4H), 1.73 (m, 2H), 1.65 (m, 1H), 1.40 (q, J=11.68 Hz, 4H), 1.24 (m, 2H).