Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[N:5]([C:13](=[O:15])[CH3:14])[C@@H:4]([CH3:16])[CH2:3]1.Cl[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:13]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=2)[C@H:2]([NH:1][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=2)[CH2:3][C@@H:4]1[CH3:16])(=[O:15])[CH3:14]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](N)C[C@@H]1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 200 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
To a mixture of 1-((2S,4R)-4-amino-6-bromo-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 1) (2.28 g, 8.05 mmol) and 6-chloronicotinonitrile (2.231 g, 16.10 mmol) was added NMP (20 mL) and the mixture treated with DIPEA (4.22 mL, 24.16 mmol). The mixture was split between 2 flasks and each flask was flushed with nitrogen, sealed and stirred under microwave irradiation at 200° C. for 2 h. The reaction mixtures were combined and partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (×4) and the combined organic layers were washed with water (×3), then brine and were dried (MgSO4) filtered and concentrated in vacuo. The brown solid residue was purified by chromatography (EtOAc in Hexanes gradient) to give 6-(((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (1.940 g, 5.04 mmol, 62.5% yield) as a pale yellow foam. LCMS (HpH, 2 min), Rt=1.02 min, MH+=386 (1 Br).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:12]2[CH:13]=[CH:14][C:15]([N+:17]([O-])=O)=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:20])=[O:5])[CH3:2].C(O)C.[H][H]>[C].[Pd].O1CCCC1>[NH2:17][C:15]1[CH:14]=[CH:13][C:12]2[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:8](=[O:20])[CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: [H][H]
Reactant: CCOC(=O)CN1C(=O)COc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CN1C(=O)COc2cc(N)ccc21
Yield: 74.7 %

Procedure:
A mixture of 4-ethoxycarbonylmethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (30 g), 10% palladium-carbon (3 g) and ethanol (150 ml) was charged in an autoclave, and catalytically reduced under conditions of 20 kg/cm2 of hydrogen pressure and at a temperature of 60° C. to 70° C. Tetrahydrofuran was added thereto, and the liquor was filtered, then the filtrate was distilled under reduced pressure. Recrystallization of the resulting solid from ethanol gave the desired 7-amino-4-ethoxycarbonylmethyl-2H-1,4-benzoxazin-3(4H)-one (20 g). mp. 136°-137° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:13]([N:14]2[N:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[O:16][C:15]2=[O:23])=[CH:12][C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=1.[CH2:24](Br)[C:25]#[CH:26].O>CN(C)C=O>[Cl:3][C:4]1[C:13]([N:14]2[N:18]=[C:17]([C:19]([CH3:20])([CH3:22])[CH3:21])[O:16][C:15]2=[O:23])=[CH:12][C:7]2[N:8]([CH2:26][CH:25]=[CH2:24])[C:9](=[O:11])[S:10][C:6]=2[CH:5]=1
Reactant: CC(C)(C)c1nn(-c2cc3[nH]c(=O)sc3cc2Cl)c(=O)o1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)sc2cc(Cl)c(-n3nc(C(C)(C)C)oc3=O)cc21
Reaction time: 0.5 h
Yield: 24.9 %

Procedure:
A dispersion of sodium hydride (50% oil; 0.16 g) in dry N,N-dimethylformamide (3 ml) was cooled to 0° C., and a solution of 3-[6-chloro-2(3H)-benzothiazolon-5-yl]-5-(1,1-dimethylethyl)-1,3,4-oxadiazol-2(3H)-one (1.00 g) in dry N,N-dimethylformamide (3 ml) was dropwise added thereto at the same temperature, followed by stirring at the same temperature for 30 minutes. Upon addition of propargyl bromide (0.44 g), the resultant mixture was heated to 50° C. and stirred for 5 hours. The reaction mixture was allowed to cool, combined with water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel thin layer chromatography with a mixture of ether and hexane (1:1) as an eluent to give 3-[6-chloro-3-(2-propenyl)-2(3H)-benzothiazolon-5-yl]-5-(1,1-dimethylethyl)-1,3,4-oxadiazol-2(3H)-one (0.28 g). nD25.5 1.5703.
Reaction SMILES: Cl.CC1(C)[O:7][CH:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([C:16]3[C:24]4[C:19](=[N:20][CH:21]=[C:22]([NH:25][C:26](=[O:42])[C:27]5[C:32]([F:33])=[CH:31][CH:30]=[C:29]([NH:34][S:35]([CH2:38][CH2:39][CH3:40])(=[O:37])=[O:36])[C:28]=5[F:41])[CH:23]=4)[NH:18][N:17]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:5][O:4]1>C1COCC1.CO>[OH:7][CH:6]([CH2:5][OH:4])[CH2:8][O:9][C:10]1[CH:11]=[C:12]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([NH:25][C:26](=[O:42])[C:27]4[C:32]([F:33])=[CH:31][CH:30]=[C:29]([NH:34][S:35]([CH2:38][CH2:39][CH3:40])(=[O:37])=[O:36])[C:28]=4[F:41])[CH:23]=3)[NH:18][N:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(-c4cccc(OCC5COC(C)(C)O5)c4)c3c2)c1F
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(-c4cccc(OCC(O)CO)c4)c3c2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.2 %

Procedure:
1N HCl (1.0 mL) was added to a solution of N-(3-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.050 g, 0.083 mmol) in THF/MeOH (2:1, 3 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was taken up in ethyl acetate (50 mL) and saturated NaHCO3 (50 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with ethyl acetate to give N-(3-(3-(2,3-dihydroxypropoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.008 g, 17%) as a solid. 1H NMR (400 MHz, CD3OD) δ 9.0 (s, 1H), 8.7 (s, 1H), 7.7 (m, 1H), 7.6-7.4 (m, 3H), 7.1 (m, 1H), 7.0 (m, 1H), 4.2 (m, 1H), 4.1-4.0 (m, 3H), 3.7 (m, 1H), 3.1 (m, 2H), 1.9 (m, 2H), 1.1 (t, J=7.6 Hz, 3H); m/z (APCI-neg) M−1=560.1.
Reaction SMILES: [Cl-].[CH:2]1([CH2:7][NH2+:8][CH2:9][CH2:10]Cl)[CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:12][C:13]1[CH:14]=[C:15]([N:20]=[C:21]=[S:22])[CH:16]=[CH:17][C:18]=1[Cl:19]>>[Cl:12][C:13]1[CH:14]=[C:15]([N:20]=[C:21]2[N:8]([CH2:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:9][CH2:10][S:22]2)[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: ClCC[NH2+]CC1CCCC1
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Product: Clc1ccc(N=C2SCCN2CC2CCCC2)cc1Cl

Procedure:
2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopentylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 3,4-dichlorophenyl isothiocyanate to give 2-(3,4-dichlorophenylimino)-3-(cyclopentylmethyl)-1,3-thiazolidine.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:21])[C:8]3[N:9]2[C:12]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[N:13][N:14]=3)=[CH:4][C:3]=1[C:22]([OH:24])=[O:23].S(=O)(=O)(O)O.[C:30](=O)([O-])O.[Na+]>CO>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:21])[C:8]3[N:9]2[C:12]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[N:13][N:14]=3)=[CH:4][C:3]=1[C:22]([O:24][CH3:30])=[O:23]
Reactant: O=C(O)c1cc2[nH]c(=O)c3nnc(C4CCOCC4)n3c2cc1Br
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2[nH]c(=O)c3nnc(C4CCOCC4)n3c2cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixed liquid of 360 mg of 8-bromo-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid and 10 mL of methanol was added 2 mL of concentrated sulfuric acid, followed by stirring overnight under a refluxing condition. After cooling to room temperature, the pH was adjusted to about 8 by the addition of a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with a mixed liquid of chloroform and isopropanol. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 320 mg of methyl 8-bromo-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylate as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[C:11](OCC)(=O)[CH:12]=[O:13]>C1(C)C=CC=CC=1.C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[F:8])[NH:9][C:12](=[O:13])[CH:11]=[N:10]2
Reactant: Nc1cc(F)c(F)cc1N
Reactant: CCOC(=O)C=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=c1cnc2cc(F)c(F)cc2[nH]1
Reaction time: 8 h

Procedure:
A mixture of 4,5-difluoro-1,2-benzenediamine (0.60 g) and 50% ethyl glyoxalate in toluene (0.87 ml) in ethanol (25 ml) was heated under reflux for 2 hours then cooled. After refrigeration overnight, the resulting solid was collected and washed with ice-cold ethanol and dried under vacuum to give a solid (0.57 g; 75%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([NH2:13])[CH:5]=1)#[N:2].Cl.Cl[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([NH:13][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:5]=1)#[N:2]
Reactant: N#CCc1cn(N)c2ccccc12
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: N#CCc1cn(Nc2ccncc2)c2ccccc12
Temperature: 90 °C
Yield: 126.4 %

Procedure:
3-Cyanomethyl-1H-indol-1-amine (12 g) and 4-chloropyridine hydrochloride (12 g) were combined in isopropanol (250 ml). After stirring at reflux (90° C.) for six hours, the mixture was poured into water (500 ml) and stirred five minutes. Thereafter the pH of the mixture was adjusted to 10 with sodium carbonate and the mixture was extracted with ethyl acetate (2x). The organic layer was washed with water (2x), brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give an oil (22 g). This oil was eluted on a silica gel column with ethyl acetate. Fractions containing product were combined and concentrated to an oil (16 g) which solidified upon standing. A portion of this solid was recrystallized from ethanol/ether (1:20) to give the title compound as a solid (2 g), m.p. 152°-153° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:10]\[CH:11]=O)=[CH:5][CH:4]=1.[C:18]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:20][CH3:21])=[O:19]>C(Cl)(Cl)(Cl)Cl>[CH3:21][O:20][C:18](=[O:19])/[CH:22]=[CH:11]/[CH:10]=[C:9](/[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCC/C(=C/C=O)c1ccc(OC)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCC/C(=C\C=C\C(=O)OC)c1ccc(OC)cc1
Yield: 52.7 %

Procedure:
As described in Example 99, (Z)-3-(4-methoxyphenyl)-2-octenal (5.5 g) was treated with (carbomethoxymethylene)triphenylphosphorane (8.7 g) in carbon tetrachloride (55 mL) for 4 days at room temperature. The mixture was isolated in the usual way and purified by HPLC (ether-hexane; 3:17) to afford 3.6 g of (2E,4E)-5-(4-methoxyphenyl)-2,4-decadienoic acid methyl ester as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CCCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCCCCOS(C)(=O)=O
Temperature: 0 °C
Yield: 85.3 %

Procedure:
A solution of non-polydispersed ethyl 6-hydroxyhexanoate (50.76 ml, 50.41 g, 227 mmol) in dry dichloromethane (75 ml) was chilled in a ice bath and placed under a nitrogen atmosphere. Triethylamine (34.43 ml, 24.99 g, 247 mmol) was added. A solution of methanesulfonyl chloride (19.15 ml, 28.3 g, 247 mmol) in dry dichloromethane (75 ml) was added dropwise from an addition funnel. The mixture was stirred for three and one half hours, slowly being allowed to come to room temperature as the ice bath melted. The mixture was filtered through silica gel, and the filtrate was washed successively with water, saturated NaHCO3, water and brine. The organics were dried over Na2SO4, filtered and concentrated in vacuo to a pale yellow oil. Final purification of the crude product was achieved by flash chromatography (silica gel, 1/1 hexanes/ethyl acetate) to give the non-polydispersed product (46.13 g, 85%) as a clear, colorless oil. FAB MS: m/e 239 (M+H), 193 (M−C2H5O).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1.CN1CCOCC1>CCO.[Pd]>[OH:1][C:2]1[C:7]([NH:8][C:16]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:17])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: O=[N+]([O-])c1cccnc1O
Agent: [Pd]
Solvent: CN1CCOCC1
Solvent: CCO
Product: O=C(Nc1cccnc1O)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
A sample of 10% Pd on C (0.40 g) was added to a solution of 2-hydroxy-3-nitropyridine (3.52 g, 25.0 mmol, 1 equiv) in EtOH. The reaction mixture was stirred at room temperature under H2 atmosphere (balloon) overnight and then was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was dissolved in CH3CN (100 mL), cooled to 0° C., and cyclopentanecarbonyl chloride (25 mmol, 3.04 mL, 1 equiv) and NMM (2.75 mL, 25 mmol, 1 equiv) were added sequentially. The resulting mixture was stirred at 0° C. for 20 min, then was partitioned between water (400 mL) and 10% CH3OH in CH2Cl2 (2×400 mL). The organic layers were dried over Na2SO4, concentrated, and the resulting residue recrystallized from CH2Cl2/hexanes to afford the title intermediate as a off-white solid (3.36 g, 65%); mp=242-243° C.; IR (cm−1) 3263, 1644, 1605, 1521, 1199; 1H NMR (DMSO-d6) δ 1.51-1.57 (m, 2H), 1.60-1.72 (m, 4H), 1.79-1.88 (m, 2H), 2.98-3.08 (m, 1H), 6.20 (t, 1H, J=6.9), 7.08 (d, 1H, J=6.6), 8.23 (d, 1H, J=7.5), 9.02 (s, br. 1H), 11.95 (s, br. 1H); Anal. C11H14N2O2: C, H, N.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]([Cl:11])[C:3]=1[NH2:4].[C:12](Cl)(Cl)=[S:13]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]([Cl:11])[C:3]=1[N:4]=[C:12]=[S:13]
Reactant: COc1ccc(Cl)c(N)c1Cl
Reactant: S=C(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)c(N=C=S)c1Cl

Procedure:
60.7 g of 2,6-dichloro-3-methoxy-aniline are dissolved in 65 ml of toluene and treated with 25 ml of thiophosgene in 50 ml of toluene. The solution obtained is heated to boiling under reflux overnight and subsequently evaporated in vacuo. There is obtained 2,6-dichloro-3-methoxyphenylisothiocyanate of boiling point 99° (0.13 Torr).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH:26]1[C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]2[C:35]([O:37][C:38](=O)[C:28]=2[CH:27]=1)=[O:36]>>[CH3:9][O:8][C:5]1[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]([N:1]2[C:35](=[O:36])[C:29]3[C:28](=[CH:27][CH:26]=[C:31]([C:32]([OH:34])=[O:33])[CH:30]=3)[C:38]2=[O:37])=[CH:7][CH:6]=1
Reactant: COc1ccc(N)cc1-c1nc2cc(-c3ccc(Cl)cc3)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: COc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccc(Cl)cc3)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-methoxyphenyl)-5-(4-chlorophenyl)benzoxazole (75 mg, 0.21 mmol) and 1,2,4-benzenetricarboxylic anhydride (41 mg, 0.21 mmol) the title compound was obtained (105 mg, 45%). 1H NMR (DMSO) δ 13.72(s, 1H), 8.42(dd, 1H), 8.32(s, 1H), 8.20(d, 1H), 8.09(m, 2H), 7.87(d, 1H), 7.78(d, 2H), 7.72(m, 2H), 7.54(d, 2H), 7.48(d, 1H), 4.04(s, 3H). MS 525.3 m/z (M+H)+.
Reaction SMILES: CC(C)CN[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15].[C:17](=[S:19])=[S:18].C(O)C>[OH-].[Na+]>[S:18]1[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=[C:17]1[SH:19]
Reactant: S=C=S
Reactant: CC(C)CNc1c(N)cnc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Sc1nc2cnc3ccccc3c2s1

Procedure:
N4-(2-methylpropyl)quinoline-3,4-diamine (5.4 g, 25 mmol) was combined with carbon disulfide (9 mL, 150 mmol) and ethanol (55 mL) and then heated at reflux on a steam bath for 2 hours. The resulting precipitate was isolated by filtration, washed with ethanol and then air dried to provide 4.4 g of crude product. A portion (1 g) was dissolved in hot dilute sodium hydroxide and then reprecipitated with acetic acid. The precipitate was isolated by filtration while still hot, washed with hexane and then air dried to provide thiazolo[4,5-c]quinoline-2-thiol as a solid, m.p. 282–284° C. Analysis: Calculated for C10H6N2S2: % C, 55.02; % H, 2.77; % N, 12.83: Found: % C, 54.96; % H, 2.69; % N, 12.74.
Reaction SMILES: [C:1]1([C:7]2[S:8](=[O:21])(=[O:20])[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][C:11](=O)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22](#[N:26])[CH2:23][C:24]#[N:25]>N1CCCCC1>[C:24]([C:23]([C:22]#[N:26])=[C:11]1[CH:12]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:8](=[O:21])(=[O:20])[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10]1)#[N:25]
Reactant: N#CCC#N
Reactant: O=C1C=C(c2ccccc2)S(=O)(=O)C(c2ccccc2)=C1
Solvent: C1CCNCC1
Product: N#CC(C#N)=C1C=C(c2ccccc2)S(=O)(=O)C(c2ccccc2)=C1
Temperature: 25 °C

Procedure:
A mixture of 8 gm (0.0464 mol) of 2,6-diphenyl-4H-thiopyran-4-one-1,1-dioxide of Example 1, 3.1 gm (0.047 mol) of malononitrile, 50 ml of alcohol and 20 drops of piperidine was refluxed for 1 hour. The reaction mixture was cooled to room temperature and the title compound was collected and recrystallized from 100 ml of toluene (mp 216°-217° C.).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12](=[O:19])[NH:11][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2.C([O-])(=O)C.[Na+].CO[CH:27]1[CH2:31][CH2:30][CH:29](OC)O1>C(O)(=O)C.CO>[N:2]1([CH:3]2[C:15]3[N:14]4[CH:16]=[CH:17][N:18]=[C:13]4[C:12](=[O:19])[NH:11][C:10]=3[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]2=3)[CH:27]=[CH:31][CH:30]=[CH:29]1
Reactant: COC1CCC(OC)O1
Reactant: NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=c1[nH]c2c(n3ccnc13)C(n1cccc1)c1ccccc1-2
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
To a suspension of 1.4 g of 10-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride in 25 ml of acetic acid are added 0.41 g of anhydrous sodium acetate and 0.66 g of 2,5-dimethoxytetrahydrofuran. The mixture is stirred at boiling for 1 hour 30 minutes and, after cooling to 20° C., the solid formed is isolated by filtration, washed twice with 30 ml in total of distilled water and air-dried. The product obtained (2.45 g) is chromatographed on 25 g of neutral silica gel (0.06-0.20 mm) contained in a column 2.4 cm in diameter, eluting with a dichloromethane/methanol mixture (90/10 by volume) and collecting an 18 ml fraction and a 540 ml fraction. After addition of decolorizing charcoal, the latter fraction is filtered and the filtrate is concentrated to dryness under reduced pressure (15 mmHg; 2 kPa) at 40° C. The product obtained is suspended for 10 minutes in 5 ml of methanol and then isolated by filtration, washed with 1 ml of methanol and dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 0.6 g of 10-(1-pyrrolyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is thus obtained, decomposing without melting above 260° C. (NMR spectrum: [200 MHz; (CD3)2SO-d6 ; δ in ppm]: 6.12 (t, J=2 Hz, 2H: --H 3 and --H 4 of the pyrrole); 6.61 (s, 1H: --CH-- 10); 6.91 (t, J=2 Hz, 2H: --H 2 and --H 5 of the pyrrole); 7.08 and 7.34 (2 broad s, 1H each: --H of the imidazole); from 7.30 to 7.55 and 7.93 [mt and d respectively (J=7.5 Hz), 3H and 1H: --H 6, --H 7, --H 8 and --H 9]; 12.60 (broad s, 1H: --CONH--)).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[Na+].[Na+].[CH:15]([C:17]1[CH:18]=[C:19]([O:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])=[O:16]>O1CCCC1.O>[CH:3]1([N:2]([CH3:1])[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][O:26][C:19]2[CH:20]=[CH:21][C:22]([N+:23]([O-:25])=[O:24])=[C:17]([CH:15]=[O:16])[CH:18]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CNC1CCCCC1
Reactant: O=Cc1cc(OCCCC(=O)Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)CCCOc1ccc([N+](=O)[O-])c(C=O)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a well-stirred solution of N-methyl-N-cyclohexylamine (29.5 ml) and sodium carbonate (28.8 g) in tetrahydrofuran (250 ml) and water (500 ml) cooled to 0° C. in an ice bath was added the tetrahydrofuran solution of the 4-(3-formyl-4-nitrophenyl)oxybutanoic acid chloride from Preparation 3 dropwise. When addition of the acid chloride was completed, the cooling bath was removed and the mixture allowed to stir at room temperature for 1 hour. Most of the tetrahydrofuran was removed by evaporation and the aqueous residue partitioned between ethyl acetate and saturated sodium carbonate (500 ml each). The combined organic layers were washed with additional saturated sodium carbonate (2×20 ml), water (1×100 ml), 1M HCl (2×200 ml) and with brine (2×200 ml) and dried with sodium sulfate. The ethyl acetate was evaporated to give a residue which was crystallized from ethyl acetate to give N-cyclohexyl-N-methyl-4-(3-formyl-4-nitrophenyl)oxybutanamide, (m.p. 98°-100° C.). Alternatively, the extraction residue was chromatographed on silica gel (10% ethyl acetate in dichloromethane as eluant.)
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.[CH3:29][C:30]1[N:31]=[C:32]([CH2:35]O)[S:33][CH:34]=1>C1(C)C=CC=CC=1>[N:15]([CH2:35][C:32]1[S:33][CH:34]=[C:30]([CH3:29])[N:31]=1)=[N+:16]=[N-:17]
Reactant: Cc1csc(CO)n1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1csc(CN=[N+]=[N-])n1
Reaction time: 8 h

Procedure:
Diphenylphosphoryl azide (DPPA) (1.2 eq) and 1,8-Diazabicyclo(5.4.0)undec-7-ene (DBU) (1.2 eq) were added to a stirred solution of (4-methylthiazol-2-yl)methanol (1 eq) in 7 ml anh. toluene under Ar. After stirring overnight, the solvent was removed in vacuo. Purification via flash chromatography yielded 2-(azidomethyl)-4-methylthiazole.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)[CH2:2][CH3:3].[C:14]1(B(O)O)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:22]2[C:23]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:19]=[CH:20][CH:21]=2)[CH:7]=1)[CH2:2][CH3:3]
Reactant: OB(O)c1cccc2ccccc12
Reactant: CCCNC(=O)c1cccc(Br)c1
Product: CCCNC(=O)c1cccc(-c2cccc3ccccc23)c1
Yield: 75 %

Procedure:
Using Preparation Method 2, N-n-propyl-3-bromobenzamide from Example 1A was reacted with 1-naphthylboronic acid. The resulting reaction mixture was purified using SiO2 with CH2Cl2/Petroleum ether 80:20 to CH2Cl2/AcOH 80:20 to give a thick yellow oil (75%). NMR 1H (ppm, CDCl3): 7.92-7.78 (m, 5H), 7.67-7.40 (m, 6H), 6.16 (br. s., 1H), 3.50-3.36 (m, 2H), 1.64 (sext., J3=7.33 Hz, 2H), 0.97 (t, J3=7.38 Hz, 3H).