Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH2:13][CH2:14][NH:15][C:16](N1C=CN=C1)=[O:17])([CH3:3])[CH3:2].N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[C:16](=[O:17])[NH:15][CH2:14][CH2:13][C:5]=12)([CH3:2])[CH3:3]
Reactant: CC(C)c1c(CCNC(=O)n2ccnc2)[nH]c2ccccc12
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)c1c2n(c3ccccc13)C(=O)NCC2
Yield: 33.8 %

Procedure:
A mixture of N-[2-(3-isopropylindol-2-yl)ethyl]-1-imidazolecarboxamide (2.0 g), 1,8-diazabicyclo[5.4.0]-undec-7-ene (1 g) and toluene (100 ml) was reflux for 1 hour. After cooling, the mixture was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (5% methanol-chloroform) to give 3,4-dihydro-5-isopropylpyrimido[1,6-a]indol-1(2H)-one (0.52 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1)[CH3:2].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[Cl:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C(=O)C.O1CCCC1>[Cl:46][C:45]1[CH:44]=[CH:43][C:26]([O:27][C:28]2[CH:29]=[CH:30][C:31]3[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]4[CH2:42][CH2:41]4)=[O:39])[N:36]=3)[N:33]=2)=[CH:25][C:24]=1[NH:23][C:8]([C:6]1[N:5]([CH3:11])[N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=1)=[O:10]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Cl
Reactant: CCc1cc(C(=O)O)n(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CCc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2Cl)n(C)n1
Yield: 64.2 %

Procedure:
Using 3-ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (188 mg, 1.22 mmol), tetrahydrofuran (4.5 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (107 μL, 1.22 mmol), N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (300 mg, 0.87 mmol) and N,N-dimethylacetamide (6.0 mL), and in the same manner as in Example 238, the title compound (268 mg, 64%) was obtained as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.OC1C2N=NNC=2C=CC=1.Cl.C([O:28][C:29](=[O:49])[CH:30]([NH:42][C:43]([O:45][CH2:46][CH:47]=[CH2:48])=[O:44])[CH2:31][C:32]1[O:36][N:35]=[C:34]([CH:37]2[CH2:41][CH2:40][CH2:39][NH:38]2)[CH:33]=1)C.C(N(CC)CC)C>CN(C)C=O.O>[CH2:46]([O:45][C:43]([NH:42][CH:30]([CH2:31][C:32]1[O:36][N:35]=[C:34]([CH:37]2[CH2:41][CH2:40][CH2:39][N:38]2[C:11](=[O:13])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH:33]=1)[C:29]([OH:49])=[O:28])=[O:44])[CH:47]=[CH2:48]
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2)no1)C(=O)OCC
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)Cc2ccc([N+](=O)[O-])cc2)no1)C(=O)O
Reaction time: 0.5 h
Yield: 17.3 %

Procedure:
A dimethyl formamide (82 mL) solution of 4-nitrophenylacetic acid (1.61 g, 8.87 mmol) in dimethyl formamide (82 mL) was stirred with 4-hydroxybenzotriazole monohydrate (1.40 g, 10.4 mmol) for 10 minutes. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimde hydrochloride (1.86 g, 9.72 mmol) was added and the mixture was stirred until all 1-(3-dimethylaminopropyl)-3-ethylcarbodiimde hydrochloride had dissolved. To this solution, 2-allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-propionic acid ethyl ester hydrochloride from Example 1C (3.16 g, 8.25 mmol) was added and the mixture stirred 30 minutes followed by addition of triethyl amine (1.26 mL, 9.04 mmol). After the reaction had stirred at room temperature over night it was poured into water and extracted with ethyl acetate three times. The combined extracts were washed with a saturated solution of sodium bicarbonate, water (2×) and brine. The organic portion was dried over magnesium sulfate and concentrated. The resulting residue was chromatographed on a Biotage Flash 40S column eluting with ethyl acetate/hexanes (5:1) to yield the title compound as a yellow oil (674 mg, 15%). MS (Cl) m/z 501.3 (M+1). Additionally, starting material 2-allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-propionic acid ethyl ester was recovered (2.15 g, 75%). MS (Cl) m/z 338.1 (M+1)
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH:11]([C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:15]=1[NH2:16])([CH3:13])[CH3:12]>ClCCl>[CH:1]([NH:16][C:15]1[C:17]([CH:21]([CH3:22])[CH3:23])=[CH:18][CH:19]=[CH:20][C:14]=1[CH:11]([CH3:13])[CH3:12])=[O:3]
Reactant: O=CO
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(C)c1cccc(C(C)C)c1NC=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of formic acid (14.361 g, 0.312 mol) and acetic anhydride (12.659 g, 0.124 mol) was stirred at room temperature for 1 h under an argon atmosphere. This mixture was added to a solution of 2,6-diisopropylaniline (17.729 g, 0.1 mol) in dry dichloromethane (60 ml) at such a rate that the temperature of the reaction mixture was kept between 5 and 10° C. The reaction was stirred at room temperature for 16 h and then refluxed for 4 h. The solvent was evaporated under reduced pressure, the residue was dissolved in CHCl3 (200 mL) and washed with a saturated aqueous NaHCO3 solution (3×200 mL), and water (200 mL). The organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure. The remaining yellow solid was recrystallized from diethyl ether (500 mL) to afford N-formyl-2,6-diisopropylaniline 8e3 as a white solid (13.96 g, 68%). 1H NMR (CDCl3, 300 MHz): δ=8.47-8.01 (m, 1H, CHO), 7.36-7.18 (m, 3H), 6.79 (broad s, 1H, NH), 3.06-3.26 (m, 2H), 1.21 (d, J=7 Hz, 12H). 2 (a) Arduengo, A. J.; Goerlich, J. R.; Marshall, W. J. Liebigs Ann./Recueil 1997, 365-374. (b) J. Liebscher, Methoden der Organischen Chemie (Houben-Weyl) 4th ed. (Ed.: E. Schaumann), Georg Thieme Verlag, New York, 1994 Band E 8b, Heratrene III/Part 2, p. 48. (c) Hromatka, O. U.S. Pat. No. 2,160,867, 1939.3 Kamer, P. C. J.; Nolte, R. J. M.; Drenth, W. J. Am. Chem. Soc. 1988, 110, 6818-6825.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[N:8]=[C:7]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(Cl)(Cl)([Cl:21])=O.C(=O)(O)[O-].[Na+]>>[Cl:21][C:9]1[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc(-c2ccccc2)c2cccc(Cl)c2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1nc(-c2ccccc2)c2cccc(Cl)c2n1
Temperature: 95 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To 1.24 g of 8-chloro-4-phenyl-2(1H)-quinazolinone (compound No. IV-4) was added 6.65 g of phosphorus oxychloride, followed by stirring at 95° C. for 1 hour. The resulting reaction solution was poured into 200 ml of ice water and sodium bicarbonate was added thereto, thereby adjusting the pH 9. Then, precipitated crystals were collected by filtration and recrystallized from ethanol to obtain 1.07 g of the titled compound. Mp.154.4.° C. 1H NMR (CDCl3): 7.52-7.65 (4H, m), 7.76-7.80 (2H, m), 8.02-8.08 (2H, m).
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([CH:8]([NH:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18])[CH3:9])[CH3:7])[CH:2]=[CH2:3].N1C=CC=CC=1.[Cl:25][CH2:26][C:27](Cl)=[O:28].O>C(OCC)(=O)C>[CH2:1]([O:4][N:5]=[C:6]([CH:8]([N:10]([C:11]1[C:12]([CH3:18])=[CH:13][CH:14]=[CH:15][C:16]=1[CH3:17])[C:27](=[O:28])[CH2:26][Cl:25])[CH3:9])[CH3:7])[CH:2]=[CH2:3]
Reactant: O=C(Cl)CCl
Reactant: C=CCON=C(C)C(C)Nc1c(C)cccc1C
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=CCON=C(C)C(C)N(C(=O)CCl)c1c(C)cccc1C
Reaction time: 0.25 h
Yield: 83.1 %

Procedure:
To a solution of 3-(2,6 -dimethylphenylamino)-2-butanone O-allyl oxime (4.5 g) in 75 ml ethyl acetate and 1.6 g pyridine was added dropwise 2.3 g chloroacetyl chloride. The mixture was stirred for 15 minutes, and poured into 1 liter of water. The organic phase was collected, diluted with 100 ml ether, washed with water, dried (MgSO4), treated with silica gel and stripped of solvent to yield 4.9 g yellow oil. The oil was chromatographed on silica gel (125 g) with elution by 3:1 CH2Cl2 :hexane followed by 5% acetone:CH2Cl2, to yield 2.5 g of the title product. This compound is tabulated as Compound No. 20 in Table I.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][C:12](OC)=[O:13])[C:6]=1[N+:16]([O-])=O.[H][H]>O1CCCC1.CO.[Pd]>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[NH:16][C:12](=[O:13])[CH2:11]2
Reactant: [H][H]
Reactant: COC(=O)Cc1cccc(CC(=O)OC)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)Cc1cccc2c1NC(=O)C2

Procedure:
A solution of 2-nitro-1,3-benzenediacetic acid dimethyl ester (5.98 g, 0.022 mole) in tetrahydrofuran and methanol (2:1, 100 ml) is treated with hydrogen gas in the presence of 20% Pd/C for 18 hours. The mixture is filtered and concentrated at reduced pressure to yield 2,3-dihydro-2-oxo-1H-indole-7-acetic acid methyl ester. Final purification is accomplished using flash chromatography on silica (elution with 1:19 methanol:dichloromethane) and results in pure 2,3-dihydro-2-oxo-1H-indole-7-acetic acid methyl ester, mp 156°-157° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[CH3:15][CH:16]([CH3:22])[CH2:17][CH2:18][C:19](Cl)=[O:20].C(N(CC)CC)C>O1CCCC1>[CH3:15][CH:16]([CH3:22])[CH2:17][CH2:18][C:19]([NH:14][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[C:9]=2[CH:1]=1)=[O:20]
Reactant: NC1CCc2oc3ccccc3c2C1
Reactant: CC(C)CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)CCC(=O)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 37.8 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol), 4-methylvaleryl chloride (1.5 g, 5.3 mmol), and triethylamine (2.1 mL, 15 mmol) in tetrahydrofuran (23 mL) provided 4-methyl-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-pentanamide (0.54 g). Mp 145.5-146.0° C.; Anal. Calcd. for C18H23NO2: C, 75.76; H, 8.12; N, 4.91; Found: C, 75.46; H, 8.14; N, 4.92.
Reaction SMILES: CC([O-])(C)C.[K+].Cl.[NH2:8][OH:9].[CH3:10][C:11]1([CH3:28])[O:15][CH:14]([CH2:16][O:17][C:18]2[C:25]([CH3:26])=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=2[CH3:27])[CH2:13][O:12]1>CO>[CH3:10][C:11]1([CH3:28])[O:15][CH:14]([CH2:16][O:17][C:18]2[C:25]([CH3:26])=[CH:24][C:21]([C:22]([NH:8][OH:9])=[NH:23])=[CH:20][C:19]=2[CH3:27])[CH2:13][O:12]1
Reactant: NO
Reactant: Cc1cc(C#N)cc(C)c1OCC1COC(C)(C)O1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Yield: 59.7 %

Procedure:
To a solution of potassium tert-butylate (6.18 g, 55.1 mmol) in MeOH (125 mL), hydroxylamine hydrochloride (5.74 g, 82.7 mmol) was added. To this solution, a solution of rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,5-dimethyl-benzonitrile (7.20 g, 27.6 mmol) in MeOH (40 mL) was added. The mixture was refluxed for 72 h before the solvent was removed in vacuo. The residue was purified by prep. HPLC (XBridge Prep C18, 30×75 mm, 5 μm, 2-95% acetonitrile in water containing 0.5% sat. aq. NH3) to give the title compound as a pale yellow solid (4.85 g). LC-MS: tR=0.67 min, [M+1]+=295.06; 1H NMR (CDCl3): δ1.43 (s, 3H), 1.48 (s, 3H), 2.29 (s, 6H), 3.76-3.81 (m, 1H), 3.83-3.88 (m, 1H), 3.93-3.99 (m, 1H), 4.17-4.23 (m, 1H), 4.47-4.54 (m, 1H), 5.02 (br s, 1H), 7.28 (s, 2H).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[C:8]([NH:13][C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[O:15])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[CH3:28]I.CO>C1COCC1.C(Cl)Cl>[CH:3]1[C:12]2[C:7](=[C:8]([N:13]([CH3:28])[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=3)=[O:15])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CI
Reactant: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2cnccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CN(C(=O)NCc1ccc(C(F)(F)F)cc1)c1cccc2cnccc12

Procedure:
Sodium hydride (60% dispersion in oil, 7 mg, 0.17 mmol) was added to a suspension N-isoquinolin-5-yl-N′-[4-(trifluoromethyl)benzyl]urea (Example 14; 48 mg, 0.14 mmol) in THF (3 mL) at room temperature and the reaction was stirred until effervescence ceased (20 minutes). Methyl iodide (11 μL, 0.17 mmol) was added and the reaction stirred at room temperature for 3 hours. TLC analysis (10% MeOH in CH2Cl2) indicated only one major product. The reaction was evaporated in vacuo and the product isolated by preparative TLC (4% MeOH in CH2Cl2) to give the title compound. m/z (ES+) 360 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([C:23]([Cl:25])=[O:24])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][NH2:39])[CH:33]=1>ClCCl>[ClH:25].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][NH:39][C:23]([CH:11]2[CH2:10][CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:12]2[S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[O:24])[CH:33]=1
Reactant: NCc1cccnc1
Reactant: Cc1ccc(S(=O)(=O)N2C(C(=O)Cl)CCC2c2ccc(F)cc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2C(C(=O)NCc3cccnc3)CCC2c2ccc(F)cc2)cc1
Product: Cl
Yield: 78.2 %

Procedure:
To a stirred and cooled (0° C.) solution of (2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic chloride (764 mg, 2 mmol) in dichloromethane (30 ml) was added pyridine (0.16 ml, 2 mmol) and 3-picolylamine (0.18 ml, 1.8 mmol). The reaction mixture was stirred at room temperature for 22 h. Aqueous work-up, formation of the hydrochloride (3N MeOH/HCl) and crystallization (diethyl ether) yielded the title compound (0.69 g, yield 70%) as a white solid, m.p. 186° C. and MS: m/e=454.5 (M+H+).
Reaction SMILES: O1[CH2:6][CH2:5][CH2:4][O:3][O:2]1.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O[BH-](O[C:30](=[O:32])[CH3:31])OC(=O)C)(=O)C.[Na+].O>ClCCl>[C:9]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:7][CH:18]1[CH2:6][CH2:5][C:4]2([O:3][O:2][CH:31]([C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:8]=3)=[CH2:15])[CH2:30][O:32]2)[CH2:16][CH2:17]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C1COOOC1
Reactant: Nc1ccccc1-c1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=C(c1ccccc1)C1COC2(CCC(Nc3ccccc3-c3ccccc3)CC2)OO1
Temperature: 25 °C
Yield: 21.8 %

Procedure:
To mixture of trioxane 3a (0.50 g, 1.82 mmol) and 2-aminobiphenyl (0.38 g, 2.27 mmol) in dichloromethane (20 ml) acetic acid was added (1 ml) and reaction mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.58 g, 2.73 mmol) was added slowly and it was stirred for 3 h at room temperature. The reaction mixture was then poured into water and extracted with CH2Cl2 (2×20 ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under vacuum and crude product was chromatographed over silica gel using benzene-hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4ab as oil (upper Rf, 0.17 g, 21.8% yield) and 4ac (lower Rf, 0.25 g, 32.6% yield), m.p. 74–76° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.23 g of 1-[2-(4-chlorophenyl)-ethyl]piperazine are dissolved in 100 ml of methylene chloride and there are added thereto 9 ml of triethylamine and then, dropwise and with external cooling, 11.08 g of 3-methoxybenzoyl chloride in 100 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature and is then extracted by shaking once with 50 ml of 2N sodium hydroxide solution and twice with 100 ml of water each time. After being dried over sodium sulphate, the mixture is concentrated to dryness by evaporation in vacuo. The oily 1-[2-(4-chlorophenyl)-ethyl]-4-(3-methoxybenzoyl)piperazine is dissolved in isopropanol, and alcoholic hydrochloric acid is added thereto. After the addition of ether, the crystals are filtered. 1-[2-(4-chlorophenyl)-ethyl]-4-(3-methoxybenzoyl)-piperazine hydrochloride having a melting point of 230°-232° is obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH3:2].[N:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=3)=[O:25])=[CH:23][C:18]=2[NH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[N:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C:34]([N:12]4[CH2:11][CH2:10][N:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[CH2:1][CH3:2])[CH2:14][CH2:13]4)=[O:35])=[CH:29][CH:28]=3)=[O:25])=[CH:23][C:18]=2[NH:17][CH:16]=1
Reactant: O=C(O)Cc1ccc(NC(=O)c2ccc3nc[nH]c3c2)cc1
Reactant: CCc1ccccc1N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccccc1N1CCN(C(=O)Cc2ccc(NC(=O)c3ccc4nc[nH]c4c3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-(2-ethylphenyl)piperazine (0.19 g; 1.0 mmol), 4-(5-benzimidazolylcarbonylamino)phenylacetic acid (0.329 g; 1.10 mmol), HOBT (0.14 g; 1.0 mmol), and EDC (0.230 g; 1.20 mmol) in DMF (30 mL) was added DIEA (0.23 mL; 1.3 mmol). The reaction was stirred at ambient temperature for 18 h and the solvent was evaporated under reduced pressure. The residue was partitioned between CH2Cl2 and saturated aqueous NaHCO3. The organic phase was separated and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried (MgSO4), filtered, and the solvent was evaporated under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 93:7:0.35 CH2Cl2 :MeOH:NH4OH as eluant. Evaporation of the product-containing fractions under reduced pressure gave the title compound as an amorphous solid.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]>>[N+:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[S:1][CH:2]=[CH:3][C:4](=[O:14])[C:5]1=2)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Product: O=c1ccsc2c3ccccc3n(-c3ccccc3[N+](=O)[O-])c12
Temperature: 95 °C
Reaction time: 40 h

Procedure:
By the same method as described in Example 7, 8.9 g of thiopyrano [3,2-b]-indol-4-(5H)-one is alkylated with o-fluoronitrobenzene, except the reaction is stirred for 40 hours at 95°C. The yield of product is 9.2 g, mp 207°-208°C after recrystallization from ether-hexane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([O:17][CH2:18]C)=[CH:15][CH:14]=[C:13]([N+:20]([O-:22])=[O:21])[C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(OC)=CC=[C:35]([N+:41]([O-:43])=[O:42])C=1C=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([N+:20]([O-:22])=[O:21])[C:10]=1[CH:11]=[CH:35][N+:41]([O-:43])=[O:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc([N+](=O)[O-])c(C=O)c1OCc1ccccc1
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1OCc1ccccc1
Product: COc1ccc([N+](=O)[O-])c(C=C[N+](=O)[O-])c1OCc1ccccc1
Yield: 83 %

Procedure:
This compound is obtained according to the operating method described in Example 1b, in which the 2-benzyloxy-3-ethoxy-6-nitrobenzaldehyde is replaced with 2-benzyloxy-3-methoxy-6-nitrobenzaldehyde. A pale yellow powder (yield=83%, m.p.=118°-119° C.) is obtained.
Reaction SMILES: [S:1]1[C:9]2[CH:8]([OH:10])[CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[Cl:11][C:12]1[CH:13]=[C:14](F)[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:11][C:12]1[CH:13]=[C:14]([O:10][CH:8]2[CH2:7][NH:6][CH2:5][C:4]3[CH:3]=[CH:2][S:1][C:9]2=3)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: OC1CNCc2ccsc21
Product: Clc1ccc(OC2CNCc3ccsc32)cc1Cl

Procedure:
The same method as in Example 1 was conducted using 4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 13) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([CH2:10]O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.P(Br)(Br)[Br:13]>C(OCC)C>[Br:13][CH2:10][C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[CH:2][S:1][C:5]=2[CH:6]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc2ncsc2c1
Solvent: CCOCC
Product: BrCc1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
Dissolve benzothiazol-6-yl-methanol (0.4 g, 2.55 mmol) in diethyl ether (10 mL) and add slowly a solution of phosphorus tribromide (0.7 g, 2.55 mmol) in diethyl ether (5 mL). Stir the reaction mixture for 2 h at ambient temperature, wash with brine, dry the organic phase over anhydrous Na2SO4, evaporate the solvent and purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1 and 4:1) to obtain the title compound as a white solid (0.5 g, 86%). MS (ES+) m/z: 229 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]=[C:9]([C:21]([O:23][CH3:24])=[O:22])[C:8]=2[C:25]([O:27][CH3:28])=[O:26])=[CH:3][CH:2]=1.Cl[C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1.Br.C(O)(=[O:43])C>C1(C)C=CC=CC=1>[O:43]=[C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]1[C:2]1[CH:3]=[C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]=[C:9]([C:21]([O:23][CH3:24])=[O:22])[C:8]=2[C:25]([O:27][CH3:28])=[O:26])[CH:5]=[CH:6][N:1]=1
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccncc2)c1C(=O)OC
Reactant: Clc1ccc2ccccc2n1
Reactant: CC(=O)O
Agent: Br
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccnc(-n3c(=O)ccc4ccccc43)c2)c1C(=O)OC

Procedure:
To a suspension of 1-(4-pyridyl)-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalen, N-oxide (1.99 g) in toluene (10 ml) is added 2-chloroquinoline (3.27 g). To the mixture is added five drops of a 30 % solution of hydrogen bromide in acetic acid, and the mixture is refluxed for 15 hours. After the mixture is concentrated under reduced pressure to remove the solvent, water and methylene chloride are added to the residue. The pH value e of the mixture is adjusted to pH 8 with an aqueous sodium hydrogen carbonate solution. The mixture is extracted with methylene chloride, and the extract is washed, dried and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:acetone=4:1) to give 1-[2-(2-oxo-1,2-dihydroquinolin-1-yl)-4-pyridyl]-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene (2.60 g).