Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[C:19]1(=O)[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1.C(N(CC)CC)C.O.[C:35]1([CH3:45])[CH:40]=[CH:39][C:38]([S:41]([OH:44])(=[O:43])=[O:42])=[CH:37][CH:36]=1>C(O)C>[C:35]1([CH3:45])[CH:36]=[CH:37][C:38]([S:41]([OH:44])(=[O:42])=[O:43])=[CH:39][CH:40]=1.[OH:25][C:22]1[CH:23]=[CH:24][C:19]([N:12]2[CH2:11][CH2:10][CH:9]([O:8][C:7]3[CH:15]=[CH:16][C:4]([O:3][C:2]([F:1])([F:17])[F:18])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)=[CH:20][CH:21]=1
Reactant: FC(F)(F)Oc1ccc(OC2CCNCC2)cc1
Reactant: O=C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: Oc1ccc(N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)cc1
Yield: 63.6 %

Procedure:
4.00 g of 4-(4-trifluoromethoxyphenoxy)piperidine, 2.575 g of 1,4-cyclohexanedione and 2.16 ml of triethylamine were heated in 60 ml of ethanol and reacted at 50° C. to 60° C. for 6 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure and ethyl acetate was added thereto to prepare an ethyl acetate solution, to which 4.37 g of p-toluenesulfonic acid monohydrate was added. After leaving at room temperature for 30 minutes, the precipitate was filtrated, washed with ethyl acetate and air-dried, and 5.116 g of 1-(4-hydroxyphenyl)-4-(4-trifluoromethoxyphenoxy)piperidine p-toluenesulfonate was obtained (yield 63.75%).
Reaction SMILES: C(OC([CH:8]1[NH:13][CH2:12][C:11]2[S:14][C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:16][C:10]=2[CH2:9]1)=O)(C)(C)C.C(C(O)=O)(F)(F)F>C(Cl)Cl>[N:16]1[C:10]2[CH2:9][CH2:8][NH:13][CH2:12][C:11]=2[S:14][C:15]=1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)Cc1nc2c(s1)CNC(C(=O)OC(C)(C)C)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cc1nc2c(s1)CNCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 50 ml of methylene chloride was dissolved 4.10 g (12.6 mmol) of ethyl 6-t-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-acetate, and under ice-cooling, 10 ml of CF3CO2H was added to the residue and the mixture was stirred at room temperature for 2 hours.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[S:6][C:5]=1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)(=[O:3])[CH3:2].[BH4-].[Na+].O>CO>[N:19]1[CH:20]=[CH:21][C:16]([C:5]2[S:6][C:7]([C:10]3[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=3)=[C:8]([CH3:9])[C:4]=2[CH:1]([OH:3])[CH3:2])=[CH:17][CH:18]=1
Reactant: CC(=O)c1c(-c2ccncc2)sc(-c2ccncc2)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1c(-c2ccncc2)sc(-c2ccncc2)c1C(C)O
Reaction time: 2 h

Procedure:
To a stirred solution of 3-acetyl-4-methyl-2,5-di(4-pyridyl)thiophene (200 mg, 0.68 mmol) in MeOH (5 mL) was added sodium borohydride (30 mg, 0.79 mmol) at 0° C., and the mixture was stirred for 2 hours. Water (5 mL) was added to the mixture. The whole was extracted with ethyl acetate (50 mL), the organic layer washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with CH2Cl2-MeOH (20:1) to provide the title product as a solid. Recrystallized from ethyl acetate gave the title product (130 mg, 75% yield).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:15]2[C:16](=[O:22])[NH:17][C:18]3=[CH:19][CH:20]=[CH:21][C:13](=[C:14]23)[O:12][CH2:11]1.C(O)(=O)C.C(#N)C>C(OCC)(=O)C>[Br:1][C:21]1[C:13]2[O:12][CH2:11][C:10]([CH3:9])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:15]3[C:16](=[O:22])[NH:17][C:18]([C:14]=23)=[CH:19][CH:20]=1
Reactant: CC1(c2ccccn2)COc2cccc3[nH]c(=O)n1c23
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CC(=O)O
Product: CC1(c2ccccn2)COc2c(Br)ccc3[nH]c(=O)n1c23
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-Bromosuccinimide (60 mg, 0.3 mmol) was added to a solution of 4-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (90 mg, 0.3 mmol), acetic acid (6 mL) and acetonitrile (6 mL) at 0° C. The reaction mixture was stirred for 1 h at 0° C., quenched with water, and was concentrated to give the crude product. The crude product was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The combined organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give a dark oil. The product was purified by FCC on silica gel eluting a hexane:ethyl acetate gradient containing 20% ethanol to give 7-bromo-4-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one as an off white solid (0.090 g. 80%). LCMS calculated for C15H13BrN3O2 (M+H)+: m/z=346.1, 348.1. found: 345.9, 347.9.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1Br.C([Li])CCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>CCOCC.CCCCCC.O1CCCC1>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[B:15]([OH:20])[OH:16]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CSc1ccccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: CSc1ccccc1B(O)O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 1-methylthio-2-bromobenzene (5 g) in dry ether (30 ml) was stirred at 0° C. and 1.63M n-butyllithium in hexane solution (16.6 ml) was added dropwise over a period of 15 minutes. The reaction mixture was stirred at 0° C. for 1.5 hours and then transferred to a cold (-78° C.) solution of triisopropyl borate (7.4 ml) in tetrahydrofuran (40 ml) over 40 minutes. After stirring for 1 hour at -78° C., the reaction mixture was allowed to warm to room temperature overnight. The suspension was poured into dilute 2M hydrochloric acid (40 ml) and the layers were separated. The aqueous phase was extracted with ether (2×80 ml) and the combined organic phases were washed with brine, dried with magnesium sulfate, evaporated and washed with petroleum ether (2×20 ml) to afford 2-methylthiophenyldihydroxyborane.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].C(#N)C.[F:9][C:10]([F:22])([F:21])[C:11]1[C:12]([S:17]([NH2:20])(=[O:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1>C(N(CC)CC)C>[F:21][C:10]([F:9])([F:22])[C:11]1[C:12]([S:17]([NH:20][C:2](=[O:3])[O:4][CH3:5])(=[O:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: NS(=O)(=O)c1ncccc1C(F)(F)F
Reactant: COC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)NS(=O)(=O)c1ncccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.2 %

Procedure:
Methyl chloroformate (3.31 g, 35 mmol) was added under cooling with ice to a dry acetonitrile (150 ml) solution containing 3-trifluoromethylpyridine-2-sulfonamide (7.91 g, 35 mmol) and triethylamine (16 ml), and the mixture was continuously stirred at room temperature for 3 hours. Then, the solvent was distilled off under reduced pressure, and the residue was dissolved in 300 ml of water. A small amount of insoluble substances were removed by filtration, and the filtrate was adjusted to pH of 1 to 2 with concentrated hydrochloric acid under cooling with ice. Precipitated crystals were collected by filtration and thoroughly washed with water, then washed with a solvent mixture of ethyl ether/n-hexane and dried to obtain 4.4 g of desired methyl N-(3-trifluoromethylpyridine-2-sulfonyl)carbamate. Melting point: 128°-129° C.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCCCCNC(=O)C3CCCC3)c2CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCCCCCc1c(Cl)ccc2c1CCNCC2)C1CCCC1
Yield: 55.5 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-[5-(cyclopentanecarbonyl-amino)-pentyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (311 mg, 0.67 mmoles) in dichloromethane (10 mL) and add trifluoroacetic acid (3 mL). Stir the reaction for 1 h. Concentrate in vacuo and purify the residue by preparative HPLC to give 7-chloro-6-[5-(cyclopentanecarbonyl-amino)-pentyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (135 mg) as an oil. Dissolve the oil in methanol (5 mL) and add (L)-tartaric acid (56 mg, 0.37 mmoles). Concentrate the mixture in vacuo and then add water (5 mL). The resulting solution is then freeze dried overnight to yield the title compound as a white solid (184 mg, 55%). MS (ES+) m/z=363.2 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([O:13]CC)=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl.[CH3:17][NH:18][O:19][CH3:20].C([Mg]Cl)(C)C.O>C1COCC1>[CH3:20][O:19][N:18]([CH3:17])[C:11]([CH:8]1[CH2:7][CH2:6][C:5]2([O:1][CH2:2][CH2:3][O:4]2)[CH2:10][CH2:9]1)=[O:13]
Reactant: CNOC
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)C1CCC2(CC1)OCCO2
Yield: 98.4 %

Procedure:
Ethyl 1,4-dioxaspiro[4,5]decane-8-carboxylate (6.28 g, 29.3 mmol) obtained in Step 1 was dissolved in THF, and N,O-dimethylhydroxylamine hydrochloride (4.30 g, 44.1 mmol) was added thereto, followed by stirring. In an atmosphere of argon at −30° C., a 2.0 mol/L solution of isopropylmagnesium chloride in THF (44.1 mL, 88.2 mmol) was added dropwise to the reaction mixture, followed by stirring at −5° C. for 1 hour. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate) to afford N-methoxy-N-methyl-1,4-dioxaspiro[4,5]decane-8-carboxamide (6.61 g, 99%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:12]=[CH:11][C:6]2[CH2:7][O:8][B:9]([OH:10])[C:5]=2[CH:4]=1.C(N(CC)CC)C.[Cl:20][C:21]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].Cl>ClCCl>[Cl:20][C:21]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:22]=1[C:23]([NH:2][C:3]1[CH:12]=[CH:11][C:6]2[CH2:7][O:8][B:9]([OH:10])[C:5]=2[CH:4]=1)=[O:24]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: Nc1ccc2c(c1)B(O)OC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)B(O)OC2)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
A 250 ml round bottom flask was charged with a mixture of 6-amino-1-hydroxy-2,1-benzoxaborolane hydrochloride (1 g, 5.4 mmol, 1 eq), triethylamine (2.3 ml, 16.2 mmol, 3 eq) and dichloromethane (100 ml). 2-Chloro-4-fluorobenzoyl chloride (1.14 g, 5.9 mmol, 1.1 eq) was added, and the reaction mixture was allowed to stir at room temperature overnight. Aqueous hydrochloric acid (1 M, 50 ml) was added to the mixture and the suspension was vigorously mixed. The resulting white precipitate was then collected by vacuum filtration and dried under vacuum. LCMS (m/e) 306 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.96 (s, 2H) 7.29-7.45 (m, 2H) 7.59 (dd, J=9.0, 2.3 Hz, 1H) 7.63-7.78 (m, 2H) 8.15 (d, J=1.8 Hz, 1H) 9.25 (s, 1H) 10.53 (s, 1H). Amount Obtained: 1.1 g, 67% yield.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH2:10][CH2:11][CH3:12])=[C:8]([F:13])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.O[NH3+:16].S(Cl)(Cl)=O.O>CN1CCCC1=O>[Cl:1][C:2]1[C:9]([CH2:10][CH2:11][CH3:12])=[C:8]([F:13])[CH:7]=[CH:6][C:3]=1[C:4]#[N:16]
Reactant: [NH3+]O
Reactant: CCCc1c(F)ccc(C=O)c1Cl
Agent: Cl
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CN1CCCC1=O
Product: CCCc1c(F)ccc(C#N)c1Cl
Temperature: 100 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of 2-chloro-4-fluoro-3-propylbenzaldehyde (877 mg) in 1-methyl-2-pyrrolidone (15 mL) was added hydroxyammonium hydrochloride (383 mg), and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was ice-cooled, thionyl chloride (1.00 mL) was added dropwise thereto, and the mixture was stirred at the same temperature for 10 min. Water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate=15:1→2:1) to give the title compound as a colorless oil (yield: 660 mg).
Reaction SMILES: [CH3:1][Si:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([CH2:19]O)[CH:16]=[N:15][CH:14]=2)=[N:8]1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[O:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1[O:43][CH:44]1[CH2:50][NH:49][CH2:48][CH2:47][NH:46][CH2:45]1>C(Cl)(Cl)Cl>[O:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1[O:43][CH:44]1[CH2:50][N:49]([CH2:19][C:17]2[N:18]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:22])([CH3:21])[CH3:1])[N:8]=3)[CH:14]=[N:15][CH:16]=2)[CH2:48][CH2:47][NH:46][CH2:45]1
Reactant: C1CCC(OC2CNCCNC2)OC1
Reactant: C[Si](C)(C)CCOCn1ccc(Nc2cncc(CO)n2)n1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: C[Si](C)(C)CCOCn1ccc(Nc2cncc(CN3CCNCC(OC4CCCCO4)C3)n2)n1
Reaction time: 1 h

Procedure:
To a mixture of 44.9 mg of (6-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyrazin-2-yl)methanol, 73 μl of N,N-diisopropylethylamine and 4 ml of chloroform was added 16 g of methanesulfonyl chloride at room temperature followed by stirring for 1 hour. The reaction mixture was dropped into a solution of 6-(tetrahydro-2H-pyran-2-yloxy)-1,4-diazepane obtained in Reference Example 5 in 2 ml of chloroform, and the reaction mixture was stirred at room temperature for 15 hours. The resulting reaction mixture was washed with water and brine. The resulting organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by a basic thin-layer chromatography (eluent: chloroform/methanol=30/1) to give the title compound.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[C:7]([O:34][CH2:35][CH2:36][CH:37]([NH2:46])CC2C=CC=CC=2C)[CH:6]=1.NCCCOC1C=C(OC)C=CC=1C(NC1C=C([N+]([O-])=O)C=CC=1C(NC1C=CC(OC)=CC=1)=O)=O.[CH3:83][C:84]1[CH:91]=[CH:90][CH:89]=[CH:88][C:85]=1[CH:86]=O>>[CH3:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[O:15])=[O:10])=[C:7]([O:34][CH2:35][CH2:36][CH2:37][NH:46][CH2:83][C:84]2[CH:91]=[CH:90][CH:89]=[CH:88][C:85]=2[CH3:86])[CH:6]=1
Reactant: Cc1ccccc1C=O
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OCCC(N)Cc2ccccc2C)cc1
Agent: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OCCCN)cc1
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OCCCNCc2ccccc2C)cc1

Procedure:
Using methods substantially equivalent to those described in Example 94-E except that sodium borohydride was the reducing agent, 2-[4-methoxy-2-(3-(2-methylbenzyl)-aminopropoxy)benzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide (50 mg, 0.084 mmol, 56%) was prepared from 2-[2-(3-aminopropoxy)-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide and 2-methylbenzaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](OS(C3C=CC(C)=CC=3)(=O)=O)=[N:13][C:12]=12.C(N(CC)CC)C.[CH:39]1([CH2:42][N:43]2[CH2:48][CH2:47][NH:46][CH2:45][C:44]2=[O:49])[CH2:41][CH2:40]1.Cl>CN(C)C=O.O>[CH:39]1([CH2:42][N:43]2[CH2:48][CH2:47][N:46]([C:14]3[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:11]4[N:10]=[N:9][C:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])=[C:12]4[N:13]=3)[CH2:45][C:44]2=[O:49])[CH2:40][CH2:41]1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc3c(-c4ccccc4F)nnn3c3ccccc23)cc1
Reactant: O=C1CNCCN1CC1CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CN(c2nc3c(-c4ccccc4F)nnn3c3ccccc23)CCN1CC1CC1
Yield: 21 %

Procedure:
A solution of 3-(2-fluorophenyl)-5-(4-methylbenzenesulfonyloxy)-[1,2,3]triazolo[1,5-α]quinazoline (0.10 g, 0.23 mmol), triethylamine (1 ml, 7.2 mmol) and 1-cyclopropylmethylpiperazin-2-one.HCl (0.22 g, 1.15 mmol) in dry N,N-dimethylformamide (2 ml) was stirred at 50° C. under nitrogen for 18 h. The mixture was cooled, then diluted with water (15 ml) and extracted with EtOAc (2×75 ml). The combined organic extracts were washed with brine, dried over MgSO4 and evaporated to give a brown oil. Purification by preparative thin layer chromatography eluting with CH2Cl2:MeOH (93:7) gave 1-cyclopropylmethyl-4-[3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-α]quinazolin-5-yl]piperazin-2-one (0.020 g, 21%) as a white solid. δH (400 MHz; CDCl3) 0.26-0.31 (2H, m), 0.52-0.58 (2H, m), 0.99-1.05 (1H, m), 3.37 (2H, d, J=7), 3.77 (2H, dd, J=5 and 5), 3.97 (2H, dd, J=5 and 5), 4.39 (2H, s), 7.20-7.31 (2H, m), 7.35-7.41 (1H, m), 7.66 (1H, dd, J=7 and 7), 7.94 (1H, dd, J=8 and 8), 8.02-8.11 (2H, m), 8.72 (1H, d, J=8); m/z (ES+) 417 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:16]2[C:15]3[N:11]([CH:12]=[CH:13][N:14]=3)[CH2:10][CH2:9][C:8]=2[NH:7][CH:6]=1)=[O:4].[BrH:17]>>[BrH:17].[N:14]1[CH:13]=[CH:12][N:11]2[C:15]=1[C:16]1[C:5]([C:3]([OH:4])=[O:2])=[CH:6][NH:7][C:8]=1[CH2:9][CH2:10]2
Reactant: COC(=O)c1c[nH]c2c1-c1nccn1CC2
Agent: Br
Product: O=C(O)c1c[nH]c2c1-c1nccn1CC2
Temperature: 25 °C

Procedure:
A solution of 5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acid methyl ester (516 mg) and 48% hydrobromic acid (5 mL) is heated at 60° for 60 hours. The mixture is cooled to room temperature and concentrated in vacuo. The residue is slurried with diethyl ether and the ether is decanted off. This is repeated until no more color is visible in the ether layer. The remaining solid is dried in vacuo to give 5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acid hydrobromide, 350 mg, brown solid: 1H NMR(DMSO-d6) 3.17 (2H, t), 4.40 (2H, t), 7.35 (1H, d), 7.57 (1H, d), 7.63 (1H, s), 12.34 (1H, s), 12.45 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11](OCC)(=[O:17])[C:12](OCC)=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[NH:9][C:12](=[O:13])[C:11](=[O:17])[NH:10]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cc(Cl)c(Cl)cc1N
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2[nH]c1=O
Temperature: 25 °C

Procedure:
A mixture of 4,5-dichlorophenylenediamine (54 g, 305 mmol) and diethyl oxalate (124 mL, 146.1 g, 920 mmol) was refluxed overnight, cooled to room temperature, and filtered. The residue was washed with ethanol and dried in vacuo to give the title product as a gray solid powder (67.5 g, 96%); mp>320° C.; IR (KBr, cm−1) 3188, 3156, 3057, 2918, 1724, 1693, 1613, 1497, 1452, 1340, 1338, 1250, 1131, 877, 811, 676, 669, 565; 1H NMR (DMSO) δ 12.00 (s, 2H), 7.18 (s, 2H); 13C NMR (DMSO) δ 154.8, 126.0, 124.4, 116.0; MS (ACPI), m/z 231.0 (M+); Anal. Calcd for C8H4N2O2Cl2: C, 41.59; H, 1.75; N, 12.12. Found: C, 41.60; H, 1.85; N, 12.05.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)(=[O:14])=[O:13].CI.[C:26]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]([CH3:26])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)(=[O:14])=[O:13]
Reactant: COC(=O)Cc1ccccc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)Cc1ccccc1N(C)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 8 h

Procedure:
2-(2-(3,4-Dichlorophenylsulfonamido)phenyl)acetic acid methyl ester (14.3 g, 38.21 mmol) and methyl iodide (8.2 ml, 132.25 mmol) were dissolved in acetone (300 ml); K2CO3 (7.3 g, 52.90 mmol) was added thereto, and stirring was carried out overnight at 40° C. in a closed flask. The suspension was cooled and then filtered, concentrated, filtered over silica gel (eluant DCM) and concentrated.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:8][C:9]([C:11]1[C:15]([CH3:16])=[CH:14][S:13][C:12]=1[NH:17][C:18](=[O:31])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH:20]=1)=[O:10])[CH3:7].[C:32](=O)([O-])[OH:33].[Na+]>CN(C)C=O>[CH2:6]([O:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14]([CH:32]=[O:33])[S:13][C:12]=1[NH:17][C:18](=[O:31])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH:20]=1)=[O:10])[CH3:7]
Reactant: O=C([O-])O
Reactant: CCOC(=O)c1c(C)csc1NC(=O)c1cccc(CN(CC)CC)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(NC(=O)c2cccc(CN(CC)CC)c2)sc(C=O)c1C
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
Separately, phosphorus oxychloride (200 μl) was added dropwise to N,N-dimethylformamide (73 mg) at 0° C., and the mixture was stirred at that temperature for 5 min. The reaction system was heated to 80° C., 2-(3-diethylaminomethyl-benzoylamino)-4-methyl-thiophene-3-carboxylic acid ethyl ester (187 mg) synthesized by the above process was then added thereto, and the mixture was stirred at that temperature for 3 hr. After the completion of the reaction, the reaction solution was neutralized with a saturated sodium hydrogencarbonate solution, and was then subjected to separatory extraction with chloroform, and the organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 2-(3-diethylaminomethyl-benzoylamino)-5-formyl-4-methylthiophene-3-carboxylic acid ethyl ester as a useful intermediate (110 mg, yield 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C:11](=O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.CN.[C:23]([BH3-])#[N:24].[Na+]>C1COCC1.CO.CC(OC)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH:11]([NH:24][CH3:23])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1Cc2ccccc2C(c2ccc(Cl)c(Cl)c2)C1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CNC1Cc2ccccc2C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 50 °C
Yield: 54 %

Procedure:
To a solution of ketone 5 (350 mg, 1.202 mmol) in THF (18 mL) and methanol (24 mL) was added methylamine hydrochloride (980 mg, 10 eq). After the solid dissolved, sodium cyanoborohydride (6.0 mL, 1 M in THF, 5 eq) was added in one portion. The mixture was heated in a 50° C. oil bath overnight before being quenched with aqueous sodium bicarbonate and extracted with MTBE. The combined organic layer was washed with brine and evaporated to give a brown-green oil. The oil was dissolved in MTBE and extracted into 10% aqueous hydrochloric acid. The aqueous layer was basicified with KOH and extracted with MTBE. The volatile components were removed in vacuo and the crude green oil was separated on silica gel to give the methylamine (0.20 g, 54%) as a pale-green oil.