Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][N:13]([C:16]4[O:20][N:19]=[C:18]([CH:21]([CH3:23])[CH3:22])[N:17]=4)[CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH:35]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH:21]([C:18]1[N:17]=[C:16]([N:13]2[CH2:14][CH2:15][CH:10]([O:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([C:34]5[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH:35]=5)[CH:25]=[CH:24][C:5]=4[N:6]=3)[CH2:11][CH2:12]2)[O:20][N:19]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1noc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)n1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: C1COCCO1
Solvent: O
Product: CC(C)c1noc(N2CCC(Oc3nc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4s3)CC2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To a degassed solution of 5-(4-(6-bromobenzo[d]thiazol-2-yloxy)piperidin-1-yl)-3-isopropyl-1,2,4-oxadiazole (697 mg, 1.646 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (764 mg, 2.470 mmol), and potassium carbonate (683 mg, 4.94 mmol) in dioxane (12 mL) and water (4 mL) was added Pd(Ph3P)4 (114 mg, 0.099 mmol). The mixture was stirred at 100° C. under argon overnight. The mixture was cooled to rt, diluted with water (40 mL), and extracted with CH2Cl2 (3×40 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 50% EtOAc) to afford tert-butyl 4-(2-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (238 mg, 0.453 mmol, 28% yield) as a yellow foam. LCMS (m/z)=526 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([NH:18][CH:19]3[CH2:21][CH2:20]3)=[O:17])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[C:22]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([NH:18][CH:19]3[CH2:20][CH2:21]3)=[O:17])[N:10]=[N:9]2)=[CH:4][CH:3]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(N)cc1
Solvent: ClCCl
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution of 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.34 g) obtained in Example 1d) in dichloromethane (24 ml) was added benzoyl chloride (0.14 ml) under ice-cooling, and the mixture was stirred for 30 min and at room temperature for 3 hr. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the precipitated solid was washed with ethyl acetate to give the title compound as a white powder (0.36 g, 78%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([OH:8])=O)[CH3:2].Cl.CN(C)CCCN=C=NCC.[C:29]1([C:35]2[N:36]=[C:37]([NH2:40])[S:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([NH:40][C:37]1[S:38][CH:39]=[C:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:36]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)O
Reactant: Nc1nc(-c2ccccc2)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccccc1)C(=O)Nc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-Benzyl-malonic acid monoethyl ester (150 mg, 0.67 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.74 mmol) in DMF (4 mL) at 25° C. was added 4-phenyl-thiazol-2-ylamine (119 mg, 0.67 mmol), the resulting mixture was stirring at 25° C. for overnight and concentrated in vacuo, and the residue was dissolved in CH2Cl2 (20 mL) was washed with 5% NaHCO3, dried with MgSO4 and concentrated in vacuo. The residue was purified by HPLC. The product was obtained 170 mg (67%) as white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.[C:26]([O-])([O-])=[O:27].[K+].[K+]>CO>[CH3:26][O:27][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1nc(Nc2ccc(OC)c(Cl)c2)nc(NC2CCCCCC2)n1

Procedure:
To 6-chloro-N-(3-chloro-4-methoxyphenyl)-N′-cycloheptyl-[1,3,5]triazine-2,4-diamine (5 g) dissolved in methanol was added K2CO3 (3.2 g) and refluxed for about 6–8 h. TLC was monitored. After the completion of the reaction, the reaction mass was filtered through vacuum and the filtrate was evaporated to yield the title compound. (Wt. 4.7 g Y: 95%)
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([N:21]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCC(NC1CCCCC1)c1nn2cccc2c(=O)n1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(c1nn2cccc2c(=O)n1Cc1ccccc1)N(C(=O)c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.7 %

Procedure:
3-Benzyl-2-(1-cyclohexylamino-propyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 28, 26.3 mg, 0.072 mmol) in CHCl3 (1.5 mL) at 25° C. was treated with benzoylchloride (34.9 mg, 0.248 mmol) and triethylamine (16.8 mg, 0.166 mmol). The resulting mixture was stirred at 25° C. for 18 h, then concentrated under vacuum and purified by preparative HPLC using a YMC S10 ODS 20×100 mm column affording the desired compound (8.0 mg, 23.7%) as a colorless film: LC/MS 94% at 4.42 min (ESI+) 469 (M++H).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.C(O)CCC.[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)#[N:14]>CN(C)C=O>[CH2:7]([O:3][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([C:13]#[N:14])=[CH:16][CH:17]=1)[CH2:6][CH2:5][CH3:4]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CN(C)C=O
Product: CCCCOCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84 %

Procedure:
To a mixture of sodium hydride (270 mg, 11 mmol, 66% in oil) and tetrahydrofuran (20 mL) was added n-butanol (1.1 mL, 12 mmol) at 0° C., which was stirred for 45 minutes at room temperature. The reaction mixture was cooled to 0° C., and a mixture of 4-cyanobenzyl bromide (1.5 g, 7.4 mmol) and tetrahydrofuran (10 mL) was added dropwise at that temperature. The reaction mixture was stirred for 3 hours at room temperature, and N,N-dimethylformamide (10 mL) was added to the reaction mixture and stirred for further 4.5 hours at the same temperature. The reaction mixture was partitioned into water and diethyl ether. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:6) to obtain the title compound (1.2 g, 84%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:10]2)=[CH:6][CH:5]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:22]([C:11]1([C:16]([O:18][CH3:19])=[O:17])[C:12](=[O:15])[CH2:13][CH2:14][N:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:21][CH:20]=2)[CH2:10]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)C1CN(Cc2ccc(Cl)cc2)CCC1=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1(Cc2ccccc2)CN(Cc2ccc(Cl)cc2)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
In a three-necked flask, under a azote atmosphere, sodium hydride (0.115 g, 60% in mineral oil, 2.871 mmol) was added at 0° C. by small portions to a solution of methyl 1-(4-chlorobenzyl)-4-oxopiperidine-3-carboxylate obtained above (0.809 g, 2.871 mmol) in 1.80 mL of anhydrous DMF. The resulting mixture was stirred 30 min at room temperature and then a solution of benzyl bromide (0.341 mL, 2.871 mmol) in 2.20 mL of anhydrous DMF was added. The reaction was followed by HPLC and UPLC-MS. After 24 h at room temperature, it was diluted with ethyl acetate. The organic phase was washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo to give a yellow oil that was purified by flash chromatography (SiO2, petroleum ether:ethyl acetate 95:5 as eluent). Evaporation and drying in vacuo of the pure fractions gave pure methyl 3-benzyl-1-(4-chlorobenzyl)-4-oxopiperidine-3-carboxylate as a colorless oil. (0.623 g, 1.675 mmol, 58% yield). 372.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[Cl:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>>[Cl:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: COc1cccc(CN)c1
Product: COc1cccc(CNC(=O)c2ccc(CCl)cc2)c1
Yield: 83.9 %

Procedure:
Using 3-methoxybenzylamine (754 mg, 5.39 mmol) and 4-chloromethylbenzoyl chloride (1.17 g, 6.0 mmol), the procedure of Reference Example 13 was repeated to obtain 1.31 g (83.9%) of the title compound in the form of colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].C(O)CC.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:20]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([O:11][CH3:10])[CH:21]=2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC
Reactant: Cc1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2nc(Cl)ncc2C)cc1OC
Temperature: 110 °C
Yield: 56.4 %

Procedure:
To a solution of 2,4-dichloro-5-methylpyrimidine (244 mg, 1.5 mmol) and methyl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (210 mg, 1.0 mmol) in toluene (3 mL) were added n-propanol (1 mL), aqueous sodium bicarbonate (2 M, 1.5 μL) and tetrakis(triphenylphosphine)palladium[0](116 mg, 0.1 mmol). The reaction was heated at 110° C. for 40 h, then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted twice further with ethyl acetate and the combined organic fractions were washed with water, brine then dried (sodium sulfate), filtered and concentrated. Silica gel chromatography using 30-60% ethyl acetate/petroleum spirit as eluent provided methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-2-methoxybenzoate as a cream solid (165 mg, 56%); LC-ESI-MS (method B): rt 6.2 min.; m/z 293.3/295.3 [M+H]+.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C2C(=CC=CC=2)C=CC=1>CCCCCC.[Pd]>[C:9]([O:11][CH2:12][CH3:13])(=[O:10])/[CH:8]=[CH:7]\[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C#Cc1ccccc1
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: CCCCCC
Product: CCOC(=O)/C=C\c1ccccc1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
Ethyl phenylpropiolate (10.8 g, 0.062 mol) was dissolved in hexane (540 ml), followed by addition of quinoline (11.2 g) and palladium on calcium carbonate (Lindlar catalyst, 3.6 g). The resulting reaction mixture was stirred under hydrogen (1 atm) at room temperature, and the progress of the reaction was monitored closely by GC analysis. The reaction was stopped by displacement of the hydrogen atmosphere with nitrogen once the rate of absorption of hydrogen was observed to decrease abruptly. The resulting mixture was faltered through a pad of diatomaceous earth and the filtrate was dried over Na2SO4. Solvent was removed under reduced pressure. Then the residue was distilled under vacuum (2.5 mm Hg, at 98°-100° C.) to provide 10.08 g of cis-ethyl cinnamate, for a yield of nearly 95%. By GC analysis, this product mixture was found to contain 5.7% over-reduced alkane and 3.5% trans-ethyl cinnamate, but was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][N:6]=1)=[O:4].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:45][CH2:44][CH2:43][C@@:30]3([C:34](=[O:35])[N:33]([C@H:36]4[CH2:41][CH2:40][C@@H:39]([OH:42])[CH2:38][CH2:37]4)[CH2:32][CH2:31]3)[CH2:29]2)=[C:24]([F:46])[CH:23]=1>>[F:46][C:24]1[CH:23]=[C:22]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([N:2]([CH3:1])[CH3:20])=[O:4])=[N:6][CH:7]=2)[CH:27]=[CH:26][C:25]=1[N:28]1[CH2:45][CH2:44][CH2:43][C@@:30]2([C:34](=[O:35])[N:33]([C@H:36]3[CH2:37][CH2:38][C@@H:39]([OH:42])[CH2:40][CH2:41]3)[CH2:32][CH2:31]2)[CH2:29]1
Reactant: O=C1N([C@H]2CC[C@@H](O)CC2)CC[C@]12CCCN(c1ccc(Br)cc1F)C2
Reactant: CN(C)C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CN(C)C(=O)c1ccc(-c2ccc(N3CCC[C@]4(CCN([C@H]5CC[C@@H](O)CC5)C4=O)C3)c(F)c2)cn1

Procedure:
This compound was prepared by using procedures that were analogous to those described for the synthesis of Example 1, Step 8 starting from N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide and (5S)-7-(4-bromo-2-fluorophenyl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one. LC/MS m/e 495.3 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): 8.86 (1H, d, J=1.7 Hz), 8.15 (1H, dd, J=8.1, 2.3 Hz), 7.51-7.65 (3H, m), 7.12 (1H, t, J=8.9 Hz), 4.37 (1H, d, J=3.1 Hz), 3.78 (1H, m), 3.71 (1H, m), 3.22-3.38 (3H, m), 3.06 (1H, d, J=11.7 Hz), 3.00 (3H, s), 2.97 (3H, s), 2.64-2.74 (2H, m), 2.18-2.27 (1H, m), 1.60-1.91 (8H, m), 1.39-1.51 (3H, m), 1.22-1.30 (2H, m).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][C:6](=O)[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:3].[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.Cl.C(O)C.[BH4-].[Na+]>CO>[CH3:1][CH:2]([CH3:3])[CH2:4][CH2:5][CH:6]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)CCC(=O)CCC(C)C
Reactant: NCCCCCCCN1CCCCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC(C)CCC(CCC(C)C)NCCCCCCCN1CCCCC1

Procedure:
To a solution of 1.70 g of 2,8-dimethylnonan-5-one and 1.98 g of 1-(7-aminoheptyl)piperidine in 50 ml of methanol was added 6 N hydrochloric acid-ethanol to have a pH value of approx. 7 (pH test paper). To the resulting solution was added under cooling 1.26 g of sodium borohydride all at once. The resulting mixture was stirred under chilling with ice for one hour, and then stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was extracted with chloroform after addition of water and an aqueous sodium hydroxide solution. The chloroform portion was dried and evaporated under reduced pressure to remove the solvent, yielding an oily product. The oily product was purified by silica gel column chromatography (eluent: chloroform-methanol 80:1 to 40:1) to give the desired compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>CO>[NH:10]([C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1)[NH2:11]
Reactant: Cc1ccnc(Cl)n1
Reactant: NN
Solvent: CO
Solvent: O
Product: Cc1ccnc(NN)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
To a solution of 2-chloro-4-methylpyrimidine (6.06 g, 47.1 mmol) in MeOH (40 mL) was added hydrazine monohydrate (10 mL, 206 mmol). The solution was stirred for 16 h at room temperature and then purified by reverse phase HPLC to provide 4.43 g of the title compound. (76%) as a white solid. MH+125.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11]2)([O-:5])=[O:4].[CH3:20][O:21][CH2:22]Cl.O>CN(C)C=O>[CH3:20][O:21][CH2:22][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[N+:3]([O-:5])=[O:4])[CH:11]=[C:12]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: COCCl
Reactant: CCOC(=O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cccc([N+](=O)[O-])c2n1COC
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a suspension of sodium hydride (60%, in oil, 0.51 g) in N,N-dimethylformamide (15 ml) was slowly added ethyl 7-nitro-1H-indole-2-carboxylate (2.50 g) at 0° C., and the mixture was stirred for 30 min. Chloromethyl methyl ether (1.00 ml) was added to the reaction mixture over 20 min at 0° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (2.29 g, yield 77%) as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). melting point 62-63° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](C(C)=O)[CH3:8].C(I)C.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1>O>[CH2:7]([O:23][C:19]1[CH:18]=[C:17]([C:16]([F:24])([F:25])[F:15])[CH:22]=[CH:21][CH:20]=1)[CH3:8]
Reactant: CCC(C)=O
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Solvent: O
Product: CCOc1cccc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
Potassium carbonate (22.6 g) and then a mixture of methyl ethyl ketone (MEK) (150 mL) and ethyl iodide (47.8 g) were added to a mixture of MEK (310 mL) and 3-trifluoromethylphenol (a) (25.0 g) at room temperature, and the reaction mixture was heated and stirred for 2 hours. After returning the mixture to room temperature, water was added for liquid separation and the aqueous layer was extracted three times with diethyl ether. The organic layers were combined, washed with an 1 M aqueous sodium hydroxide solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 19.3 g of Compound (b).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>CC#N>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][C:18]3[S:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH:10]=2)[CH:6]=[CH:7]1
Reactant: Oc1ccc2cc[nH]c2c1
Reactant: Clc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: c1ccc2sc(Oc3ccc4cc[nH]c4c3)nc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.9 %

Procedure:
To a suspension of 6-hydroxyindole (5.0 g, 37.6 mmol) and Cs2CO3 (36.7 g, 112.8 mmol) in MeCN (75 mL) was added 2-chlorobenzthiazole (6.4 g, 4.7 mL, 37.6 mmol) and the resulting suspension was stirred (rt, 2 d). The reaction mixture was partitioned with brine and EtOAc (200 mL each) and the aqueous layer was extracted with EtOAc (200 mL). The organic layers were combined, washed with brine (300 mL), dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using EtOAc:hexane (0-40%) to afford the title compound as a tan solid (6.1 g, 61%). MS (ESI): mass calcd. for C15H10N2OS, 266.3; m/z found, 267.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.57 (s, 1H), 7.72 (dd, J=8.4, 0.6, 1H), 7.65-7.63 (m, 2H), 7.39-7.35 (m, 2H), 7.27-7.22 (m, 1H), 7.19-7.18 (m, 1H), 7.08 (dd, J=8.4, 2.1, 1H), 6.55-6.53 (m, 1H).
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][O:14][C:15]1[CH:41]=[CH:40][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH:37]=[CH:38][CH:39]=2)[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33](=[O:36])(=[O:35])[NH2:34])=[O:25])=[CH:17][CH:16]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH:37]=[CH:38][CH:39]=2)[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([NH:34][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:36])=[O:35])=[O:25])=[CH:40][CH:41]=1
Reactant: COc1ccc(COc2cccc(C(=O)Nc3ccccc3S(N)(=O)=O)c2)cc1
Reactant: CCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(OC)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
In a stream of nitrogen and at 0° C., 0.22 ml (1.10 mmol) of decanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 400 mg (1.00 mmol) of 3-(4-methoxybenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 6 and 237 mg (1.90 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 520 mg (yield: 94.6%) of the title compound.