Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][CH2:14][C:13]([C:27](O)=[O:28])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:30].Cl.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:44]=[C:45]([O:49][CH3:50])[C:46]=1[O:47][CH3:48])[CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC>CN(C)C=O>[ClH:30].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][CH2:14][C:13]([C:27]([N:41]1[CH2:40][CH2:39][N:38]([CH2:37][C:36]3[CH:44]=[C:45]([O:49][CH3:50])[C:46]([O:47][CH3:48])=[C:34]([O:33][CH3:32])[CH:35]=3)[CH2:43][CH2:42]1)=[O:28])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1=Cc2cc(OCc3ccccc3)c(OCc3ccccc3)cc2CC1
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(CN2CCN(C(=O)C3=Cc4cc(OCc5ccccc5)c(OCc5ccccc5)cc4CC3)CC2)cc(OC)c1OC
Yield: 69.1 %

Procedure:
Using 6,7-dibenzyloxy-1,2-dihydro-3-naphthoic acid (0.5 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (0.69 g), triethylamine (0.52 g), N,N-dimethylformamide (10 ml) and diethyl phosphorocyanidate (0.75 ml), as amidation as that described in Example 6 is carried out. The product is purified by silica gel column chromatography (hexane:acetone=1:1-1:2) and converted to the hydrochloride in a mixture of ethyl acetate and ethyl ether to yield 1-(6,7-dibenzyloxy-1,2-dihydro-3-naphthoyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (0.6 g) as colorless crystals, m.p. 186°-190° C.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]([CH3:21])([N:6]([CH3:20])[S:7]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)(=[O:9])=[O:8])[CH3:5].C1COCC1.CO.O[Li].O>O>[CH3:21][C:4]([N:6]([CH3:20])[S:7]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)(=[O:8])=[O:9])([CH3:5])[C:3]([OH:22])=[O:2]
Reactant: COC(=O)C(C)(C)N(C)S(=O)(=O)c1cccc2cccnc12
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C(C)(C)C(=O)O)S(=O)(=O)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
methyl-2-methyl-2-(N-methylquinoline-8-sulfonamido)propanoate (650 mg, 2.01 mmol) was charged, and dissolved through addition of THF (5 ml) and methanol (5 ml). LiOH.H2O dissolved in H2O (5 ml) was added thereto, followed by stirring for 12 hours at room temperature. After stirring for 12 hours, the resultant solution was vacuum-evaporated, adjusted with 2N—HCl to pH 5-6, and extracted with EA (×2). The organic layer was dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed so as to obtain 2-methyl-2-(N-methylquinoline-8-sulfonamido)propionic acid (610 mg, 1.97 mmol, 98%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=[O:19])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[C:10]([Cl:18])[CH:9]=1)([CH3:7])[CH3:6].CCN(CC)CC.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[S:36])=[CH:30][C:29]=1[O:37][CH3:38].O>C(Cl)Cl>[Cl:18][C:10]1[CH:9]=[C:8]([C:5]([CH3:7])([C:4](=[O:19])[CH2:3][NH:2][C:35]([NH:34][C:31]2[CH:32]=[CH:33][C:28]([F:27])=[C:29]([O:37][CH3:38])[CH:30]=2)=[S:36])[CH3:6])[CH:13]=[CH:12][C:11]=1[S:14]([NH2:17])(=[O:16])=[O:15]
Reactant: COc1cc(N=C=S)ccc1F
Reactant: CC(C)(C(=O)CN)c1ccc(S(N)(=O)=O)c(Cl)c1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=S)NCC(=O)C(C)(C)c2ccc(S(N)(=O)=O)c(Cl)c2)ccc1F
Reaction time: 2 h
Yield: 76.6 %

Procedure:
To a stirred mixture of 4-(4-amino-2-methyl-3-oxobutan-2-yl)-2-chlorobenzenesulfonamide hydrochloride (7.8 g, 23.7 mmol) in DCM (150 mL) was added Et3N (9.9 mL, 71.1 mmol, 3 eq) and 1-fluoro-4-isothiocyanato-2-methoxybenzene (4.35 g, 23.7 mmol). After stirring 2 h, DCM and water were added to the reaction mixture. The organic layer was separated, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography (Hex/EtOAc=1:1 to EtOAc/DCM=1:1) to give 2-chloro-4-(4-(3-(4-fluoro-3-methoxyphenyl)thioureido)-2-methyl-3-oxobutan-2-yl)benzenesulfonamide (8.6 g, 76%). 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.15 (m, 1H), 6.89 (d, J=7.6 Hz, 1H), 6.77 (m, 2H), 5.30 (s, 2H), 4.43 (d, J=4.4 Hz, 2H), 3.91 (s, 3H), 1.59 (s, 6H).
Reaction SMILES: C(C1C=CC(S([N:13]=[N+:14]=[N-])(=O)=O)=CC=1)(O)=O.[CH2:16]([O:23][C:24]([CH2:26][C:27](=[O:34])[CH2:28][CH:29]1[NH:32][C:31](=[O:33])[CH2:30]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(CC)CC>C(#N)C.CCOC(C)=O>[CH2:16]([O:23][C:24]([C:26](=[N+:13]=[N-:14])[C:27](=[O:34])[CH2:28][CH:29]1[NH:32][C:31](=[O:33])[CH2:30]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(CC(=O)OCc1ccccc1)CC1CC(=O)N1
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(C(=O)O)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: [N-]=[N+]=C(C(=O)CC1CC(=O)N1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.5 %

Procedure:
Freshly recrystallized p-carboxy benzene sulfonylazide (241 mg, 1.06 mmol) is added to a solution of 4-(3-benzyloxycarbonyl-2-oxopropyl)-azetidin-2-one (276 mg, 1.06 mmol) in anhydrous acetonitrile (6.6 ml). The resulting suspension is cooled in an ice-bath and stirred while Et3N (443 μl, 3.18 mmol) is added. The resulting yellow solution is stirred at room temperature. A precipitate forms quickly. After 90 mins, the mixture is diluted with EtOAc (50 ml) and filtered. The filtrate is washed with H2O (2×10 ml), 0.5 N NaOH (2×10 ml), H2O (4×10 ml) and brine, dried with MgSO4, filtered, and evaporated i.v. to an off-white solid (273 mg). This is triturated with Et2O to provide 4-(3-benzyloxycarbonyl-3-diazo-2-oxopropyl)-azetidin-2-one (227 mg) as a cream colored powder: ir (film from CHCl3) 3.0, 4.65, 5.66, 5.82, 6.05, 7.21, 7.70 and 8.23 cm- 1 ; nmr (CDCl3) δ 2.63 (ddd,1), 2.97 (dd, 1), 3.15 (ddd, 1), 3.40(dd, 1), 3.98 (m, 1), 5.27 (s, 2), 6.13 (m, 1), and 7.38 (s, 5); mass spectrum m/e 259, 245, 231, and 218.
Reaction SMILES: [CH3:1][NH2:2].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]3[C:14]4[S:21][C:20]([C:22]5[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=5)=[CH:19][C:15]=4[N:16]=[CH:17][N:18]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Cl>>[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]3[C:14]4[S:21][C:20]([C:22]5[CH:29]=[CH:28][C:25]([CH2:26][NH:2][CH3:1])=[CH:24][CH:23]=5)=[CH:19][C:15]=4[N:16]=[CH:17][N:18]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: CN
Agent: Cl
Product: CNCc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from methylamine and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. The product was converted to the mesylate salt analogous to example 17 being converted to the HCl salt. M.P. 140-147° C.; LC-MS: 386 (MH−); HPLC RT: 3.54 minutes.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[CH:12][C:11]([C:17]([OH:19])=O)=[CH:10][C:9]2=1)(=[O:3])[NH2:2].CN(C(ON1N=N[C:38]2[CH:39]=[CH:40][CH:41]=[N:42][C:37]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:52][N:53](C=O)[CH3:54]>CO>[Cl:27][C:22]1[CH:21]=[C:20]([C:6]2[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:16]3[NH:15][C:14]4[C:9]([C:8]=3[CH:7]=2)=[CH:10][C:11]([C:17]([N:42]2[CH2:37][CH2:38][CH:39]([N:53]([CH3:54])[CH3:52])[CH2:40][CH2:41]2)=[O:19])=[CH:12][CH:13]=4)[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: NC(=O)c1cc(-c2ccc(Cl)c(Cl)c2)cc2c1[nH]c1ccc(C(=O)O)cc12
Reactant: CN(C)C=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Product: CN(C)C1CCN(C(=O)c2ccc3[nH]c4c(C(N)=O)cc(-c5ccc(Cl)c(Cl)c5)cc4c3c2)CC1

Procedure:
A solution of 8-carbamoyl-6-(3,4-dichlorophenyl)-9H-carbazole-3-carboxylic acid (20 mg, 0.05 mmol), HATU (22 mg, 0.06 mmol) and N,N′-diisopropylamine (12 mg, 0.15 mmol) in DMF (0.2 ml) was agitated for 16 h at room temperature. The reaction mixture was diluted with methanol and then purified by reverse phase preparative HPLC to give 16 mg of 3-(3,4-dichlorophenyl)-6-(4-(dimethylamino)piperidine-1-carbonyl)-9H-carbazole-1-carboxamide. MS (ESI) m/z 510.2 (M+H). 1H NMR (DMSO-d6) δ ppm 11.66 (s, 1H), 8.91 (d, 1H, J=1.2), 8.42 (b, 1H), 8.38 (m, 2H), dd, 8.24 (d, 1H, J=2.3), 7.96 (dd, 1H, J=2.3, 8.4), 7.78 (d, 1H, J=8.3), 7.77 (d, 1H, J=8.3), 7.64 (b, 1H), 7.47 (dd, 1H, J=1.7, 8.4), 4.6-3.7 (b, 2H), 3.15-2.85 (b, 2H), 2.55-2.40 (b, 1H), 2.25 (bs, 6H), 1.9-1.7 (b, 2H), 1.47-1.35 (b, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:19])[CH2:14][CH2:15][C:16]=1[O:17][CH3:18])[CH3:2].[Cl-:20].[Li+]>O1CCOCC1.[Cu](Cl)Cl>[Cl:20][CH:14]1[C:13](=[O:19])[C:12]([C:4]2[C:5]([CH2:10][CH3:11])=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=2[CH2:1][CH3:2])=[C:16]([O:17][CH3:18])[CH2:15]1
Reactant: CCc1cc(C)cc(CC)c1C1=C(OC)CCC1=O
Reactant: [Cl-]
Agent: Cl[Cu]Cl
Agent: [Li+]
Solvent: C1COCCO1
Product: CCc1cc(C)cc(CC)c1C1=C(OC)CC(Cl)C1=O
Temperature: 25 °C

Procedure:
To a stirred solution of 2-(2,6-diethyl-4-methylphenyl)-3-methoxycyclopent-2-enone (0.715 g, 2.77 mmol) in 1,4-dioxane (45 ml), and under an atmosphere of nitrogen, are added copper (II) chloride (0.743 g, 5.53 mmol) and lithium chloride (0.176 g, 4.15 mmol). The reaction is heated at reflux for 7 hours and allowed to cool to room temperature overnight. The remaining solid is removed by filtration and washed with ethyl acetate (50 ml). The filtrate is washed with water (2×25 ml) and the aqueous washings re-extracted with ethyl acetate (1.5 ml). The combined organic phases are washed with brine (15 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure to give a brown oil. The crude product is purified by column chromatography on silica gel to give 5-chloro-2-(2,6-diethyl-4-methylphenyl)-3-methoxycyclopent-2-enone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH3:12])[C:7](=O)[CH2:6][CH2:5]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:25]([NH2:29])(=[O:28])[CH:26]=[CH2:27]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]3([CH3:12])[C:7](=[CH:6][CH2:5][C:4]=2[CH:3]=1)[NH:29][C:25](=[O:28])[CH2:26][CH2:27]3
Reactant: CC1C(=O)CCc2cc(F)ccc21
Reactant: C=CC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC12CCC(=O)NC1=CCc1cc(F)ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.4 %

Procedure:
To 6-fluoro-l-methyl-2-tetralone (7.06 g; 39.6 mmol) in a round bottomed flask was added p-toluenesulfonic acid (1.23 g; 6.5 mmol) and the mixture was stirred at room temperature under nitrogen for 15 minutes. Acrylamide (5.62 g; 79.2 mmol) was added and the reaction mixture was heated to 88°-90° C. under nitrogen for three days. The mixture was diluted with ethyl acetate and water and stirred at room temperature for 1 hour. The resulting layers were separated. The organic layer was washed three times with water, dried over MgSO4 and concentrated to a viscous oil. The crude product was crystallized from ethyl acetate to afford 1.59 g (17% yield) of the subtitle compound. Melting point 202° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]#[N:17])=[N:14][CH:15]=1.O.[NH2:19][NH2:20]>>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]1[NH:20][N:19]=[C:16]([C:13]2[N:14]=[CH:15][C:10]([NH2:9])=[CH:11][CH:12]=2)[NH:17][N:2]=1
Reactant: NN
Reactant: N#Cc1ccccn1
Reactant: N#Cc1ccc(N)cn1
Solvent: O
Product: Nc1ccc(C2=NNC(c3ccccn3)=NN2)nc1
Temperature: 90 °C
Yield: 31.3 %

Procedure:
A dry round-bottom flask was charged with 2-cyanopyridine (0.500 g, 4.8 mmol), 5-amino-2-cyanopyridine (0.572 g, 4.8 mmol), and 64% aqueous hydrazine hydrate (0.932 mL, 19.2 mmol). The flask was fitted with a reflux condenser, and the mixture was heated to 90° C. for 12 hr. The reaction mixture was cooled to room temperature. The resulting orange precipitate was isolated by filtration, washed with cold H2O, and dried under vacuum. The crude orange solid was concentrated in vacuo onto deactivated silica gel and chromatographed using a gradient (0-60%) of acetone in hexanes to give 377 mg (1.5 mmol, 31%) of 6-(6-pyridin-2-yl-1,4-dihydro-[1,2,4,5]tetrazin-3-yl)-pyridin-3-ylamine as an orange solid, mp 158-160° C.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][CH2:5][C:4]([C:8](=[O:32])[NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C(=O)C(C)(C)C)=[C:14]([O:25][C:26](=O)C(C)(C)C)[CH:13]=2)=[CH:3]1.[2H]C(Cl)(Cl)Cl.[2H]O[2H]>>[CH3:1][N:2]1[CH:7]=[CH:6][CH2:5][C:4]([C:8](=[O:32])[NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:25][CH3:26])[CH:13]=2)=[CH:3]1
Reactant: CN1C=CCC(C(=O)NCCc2ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c2)=C1
Agent: [2H]C(Cl)(Cl)Cl
Agent: [2H]O[2H]
Product: COc1cc(CCNC(=O)C2=CN(C)C=CC2)ccc1O

Procedure:
This compound was prepared following the same method as for the preparation of compound 5c. The crude solid obtained showed the same NMR (CDCl3 /D2O) pattern as compound 5a, except for a peak at δ 3.5 for the OCH3 protons. It was sufficiently pure for the determination of its retention time following the HPLC method of analysis detailed in Example 37 below. No trials were made for its further crystallization or elemental analysis.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([OH:12])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:23]([O:25][CH3:26])=[O:24]>ClCCl.CN(C=O)C.C(N(CC)CC)C>[N:1]1[CH:2]=[C:3]([C:10]([NH:19][C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=2[CH3:30])[C:23]([O:25][CH3:26])=[O:24])=[O:12])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: COC(=O)c1ccc(C)c(N)c1
Reactant: O=C(O)c1cnc2ccccn12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(NC(=O)c2cnc3ccccn23)c1
Temperature: 25 °C

Procedure:
To a suspension of imidazo[1,2-a]pyridine-3-carboxylic acid (1) (4.09 g, 25.3 mmol) in dichloromethane (100 mL) and DMF (0.25 mL) at 0° C. was added oxalyl chloride (4.15 mL, 48.0 mmol) dropwise over 10 minutes. The reaction was slowly warmed to room temperature and stirred until complete conversion was detected by LCMS. The reaction was subsequently reduced to dryness and suspended in dichloromethane (100 mL) and was added a solution of methyl 3-amino-4-methylbenzoate (2) (4.6 g, 27.9 mmol) in dichloromethane (100 mL) and triethylamine (7.1 mL). Contents were stirred at room temperature for 4 hours and diluted with dichloromethane (100 mL). The reaction was washed with water, saturated NaHCO3, brine, dried over magnesium sulfate, filtered and reduced to dryness. The crude solid was triturated with diethyl ether to remove excess aniline and dried to afford methyl 3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylbenzoate (3) as a white solid. MS m/z 310.1 (M+1)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[O:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].CN(C)C(N(C)C)=N.Cl>O1CCCC1.C(OCC)(=O)C>[C:7]1([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:19]2[C:20](=[O:22])[CH2:21][O:17][C:18]2=[O:23])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: BrCCCCOc1cccc2ccccc12
Reactant: O=C1COC(=O)N1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1COC(=O)N1CCCCOc1cccc2ccccc12
Yield: 60.2 %

Procedure:
A solution of 3.1 g (11.1 mmol) of 1-[(4-bromobutyl)oxy]naphthalene (Eur. J. Med. Chem. 1997, 32, 175-179) and 1.35 g (13.3 mmol) of 1,3-oxazolidine-2,4-dione (J. Med. Chem. 1991, 34, 1542-1543) in 30 ml of tetrahydrofuran is admixed dropwise with a solution of 2.55 g (22.2 mmol) of 1,1,3,3-tetramethylguanidine in 15 ml of tetrahydrofuran. The mixture is heated at reflux for 8 hours. 0.28 g (2.7 mmol) of 1,3-oxazolidine-2,4-dione and 0.32 g (2.7 mmol) of 1,1,3,3-tetramethylguanidine are added and the mixture is heated at reflux for 4 more hours. The reaction mixture is cooled using an ice bath, and 100 ml of ethyl acetate and then 50 ml of 1M aqueous hydrochloric acid are added. The system is decanted and the aqueous phase is extracted with 2×80 ml of ethyl acetate. The organic phases are subsequently washed with 80 ml of water and then with 80 ml of saturated aqueous sodium chloride solution. They are dried over sodium sulfate and then evaporated to dryness. The product is purified by chromatography on silica gel, eluting with an 80/20 mixture of cyclohexane and ethyl acetate, to give 2.0 g of product, which is used as it is in the following step.
Reaction SMILES: CN(C)C=O.[C:6]([C:10]1[CH:36]=[CH:35][C:13]([NH:14][C:15]2[CH:34]=[CH:33][C:18]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([OH:32])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:17][CH:16]=2)=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>C(OCC)(=O)C.O>[C:6]([C:10]1[CH:36]=[CH:35][C:13]([NH:14][C:15]2[CH:34]=[CH:33][C:18]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH2:45][CH2:46][N:47]5[CH2:52][CH2:51][O:50][CH2:49][CH2:48]5)=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:17][CH:16]=2)=[CH:12][CH:11]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)cc3)ccnc2cc1O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)cc3)ccnc2cc1OCCN1CCOCC1
Temperature: 77.5 °C
Reaction time: 6 h
Yield: 80.1 %

Procedure:
N,N-Dimethylformamide (2 ml) was added to 4-{4-[4-(tert-butyl)anilino]phenoxy}-6-methoxy-7-quinolinol (compound 21) (100 mg), potassium carbonate (167 mg), and 4-(2-chloroethyl)morpholine hydrochloride (70 mg), and the mixture was stirred at 75 to 80° C. for 6 hr. Water and ethyl acetate were added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and was dried over sodium sulfate, and the solvent was then removed by evaporation under the reduced pressure. The crude thus obtained was purified by thin-layer chromatography on silica gel using chloroform/methanol for development to give the title compound (102 mg, yield 81%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][N:6]([CH:12]([CH3:14])[CH3:13])[C:7]=1[C:8]([F:11])([F:10])[F:9].[C-:15]#[N:16].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1.O.CCOC(C)=O>[CH:12]([N:6]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:3]([CH2:2][C:15]#[N:16])[CH:4]=[N:5]1)([CH3:14])[CH3:13]
Reactant: CC(C)n1ncc(CCl)c1C(F)(F)F
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)n1ncc(CC#N)c1C(F)(F)F
Reaction time: 0.17 h
Yield: 104 %

Procedure:
Tetrabutyl ammonium bromide (7.95 gm, 24.7 mmol) was added to 4-(chloromethyl)-1-isopropyl-5-(trifluoromethyl)-1H-pyrazole (7 g, 31 mmol) in dioxane (75 mL) and water (75 mL) and the mixture was stirred for 10 minutes. Potassium cyanide (7.42 g, 114 mmol) was added and the mixture was stirred for 16 hours at room temperature. The mixture was diluted with EtOAc (100 mL) then the organic phase was washed with water (100 mL), brine (100 mL) and dried over sodium sulphate. The filtrate was evaporated in vacuo and purified by silica gel column chromatography eluting with hexane:EtOAc 90:10 to afford the title compound as a white solid (100%, 7.00 g).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH:26]=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:28]=[C:29]1[N:33]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:32](=[O:42])[CH2:31][S:30]1.N1CCCCC1>C(O)C>[O:28]=[C:29]1[N:33]([CH2:34][C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[C:32](=[O:42])[C:31](=[CH:26][C:24]2[N:25]=[C:21]([NH:20][C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:22][CH:23]=2)[S:30]1
Reactant: CC(C)(C)OC(=O)CN1C(=O)CSC1=O
Reactant: O=Cc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1C(=O)SC(=Cc2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C1=O

Procedure:
Following a procedure similar to that described in Example 17, the desired compound was prepared from 2 g of 2-tritylaminothiazole-4-carbaldehyde, 1.2 g of t-butyl 2,4-dioxothiazolidine-3-acetate, 0.88 g of piperidine and 20 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:14]=[CH:13][C:12]3[C:15]4[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][C:16]=4[C:17]([CH3:20])([CH3:19])[O:18][C:11]=3[C:7]=2[C:8](=[O:10])[CH:9]=1)([OH:3])=[O:2].C(CN)O>I.O>[C:1]([C:4]1[O:5][C:6]2[CH:14]=[CH:13][C:12]3[C:15]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:16]=4[C:17]([CH3:20])([CH3:19])[O:18][C:11]=3[C:7]=2[C:8](=[O:10])[CH:9]=1)([OH:3])=[O:2]
Reactant: COc1ccc2c(c1)C(C)(C)Oc1c-2ccc2oc(C(=O)O)cc(=O)c12
Agent: I
Solvent: NCCO
Solvent: O
Product: CC1(C)Oc2c(ccc3oc(C(=O)O)cc(=O)c23)-c2ccc(O)cc21

Procedure:
2.5 gm (0.007 mol) of 2-carboxy-4-oxo-6,6-dimethyl-8-methoxy-4H,6H-[2]-benzopyrano-[3,4-f]-[1]-benzopyran, prepared as described in Example 2, were refluxed for 4 hours in 50 ml of hydroiodic acid. Then, the reaction mixture was cooled and diluted with 200 ml of water. The precipitated yellow crystals were filtered off, washed with water, dried and recrystallized from methanol. 250 gm (10.5% of theory) of the compound named in the heading, m.p. 256°-258° C, were obtained. The ethanolamine salt, prepared in analogy with Example 1, had a melting point of 200°-202° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=2)[N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[CH:35]1([CH2:41][C:42](O)=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:35]1([CH2:41][C:42]([NH:1][C:2]2[CH:3]=[C:4]([C@@H:8]([N:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH2:31][CH3:32])[CH2:33][CH3:34])=[O:29])=[CH:24][CH:23]=3)[CH:5]=[CH:6][CH:7]=2)=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=C(O)CC1CCCCC1
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(N)c2)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(NC(=O)CC3CCCCC3)c2)N2CCNCC2)cc1
Reaction time: 22 h
Yield: 91332 %

Procedure:
To a room temperature solution of INTERMEDIATE 5a (250 mg; 0.54 mmol) in DMF (5 mL) was added cyclohexyl acetic acid (92 mg; 0.65 mmol), DIPEA (0.38 mL; 2.16 mmol) and HATU (0.31 g; 0.81 mmol). The reaction mixture was stirred for 22 hours then was concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with sodium hydroxide (2N) then with HCl (1M). The organic phase was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL) and TFA (1.5 mL) was added. The reaction mixture was stirred for 4 hours then was washed with saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Column chromatography eluting with 5% methanol in dichloromethane gave COMPOUND 77 (242 g; 92% for two steps). Purity (HPLC-215 nm): >99%; Optical purity (Chiral HPLC-215 nm): >99%. 1H NMR (400 MHz, CD3OD) δ 0.87-0.93 (m, 2H), 0.98 (t, J=7.13 Hz, 3H), 1.08-1.14 (m, 3H), 1.20-1.23 (m, 2H), 1.52-1.71 (br s, 6H), 1.72-1.77 (m, 1H), 2.12 (d, J=7.03 Hz, 2H), 3.09-3.14 (m, 2H), 3.18-3.23 (m, 6H), 3.26-3.33 (br s, 3H), 3.48-3.52 (m, 1H), 5.08 (s, 1H), 7.20 (d, J=4.49 Hz, 2H), 7.24-7.31 (m, 3H), 7.57 (d, J=7.81 Hz, 2H), 7.83 (s, 1H). Found: C, 58.11; H, 8.99; N, 7.46. C30H42N4O2×0.4HCl×6.5H2O has C, 57.90; H, 8.97; N, 9.00%. [α]D17=+4.6 deg [c 0.46, MeOH].