Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:13]2[N:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]([C:27]4[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=4)[CH:26]=3)=[O:21])=[CH:15][CH:14]=2)[CH2:12][CH2:11][C:6]2(OCC[O:7]2)[CH2:5][CH2:4]1)#[N:2].O.Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[C:1]([C:3]1([C:13]2[N:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]([C:27]4[CH:28]=[CH:29][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:32]=4)[CH:26]=3)=[O:21])=[CH:15][CH:14]=2)[CH2:12][CH2:11][C:6](=[O:7])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(C)c1ccc(-n2cc(C(=O)Nc3ccc(C4(C#N)CCC5(CC4)OCCO5)nc3)cn2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1ccc(-n2cc(C(=O)Nc3ccc(C4(C#N)CCC(=O)CC4)nc3)cn2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
A solution of N-[6-(8-cyano-1,4-dioxaspiro[4.5]dec-8-yl)pyridin-3-yl]-1-(4-isopropylphenyl)-1H-pyrazole-4-carboxamide (236 mg) in a mixture of acetic acid (5 ml), water (1 ml) and 1N hydrochloric acid aqueous solution (1 ml) was stirred at 100° C. for two hours. After completion of the reaction, a saturated aqueous solution of potassium carbonate was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified with column chromatography to give the titled compound (216 mg).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]([NH2:28])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[CH3:31][NH:28][C:18]1[CH:17]=[CH:16][C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH2:10][CH2:11]2)=[CH:20][C:19]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1Nc1ccccc1
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CNc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 10.1 %

Procedure:
A suspension of 5-(4-benzoylpiperazin-1-yl)-N1-phenylbenzene-1,2-diamine (0.2 g, 0.54 mmol), paraformaldehyde (0.025 g, 1.01 mmol), and 6 drops of acetic acid in 10 ml 1,2-dichloroethane was stirred at room temperature for 5 hours. Sodium triacetoxyborohydride (0.45 g, 2.2 mmol) was added and stirred overnight before quenching with 10 ml water. The mixture was extracted with ethyl acetate (3×20 ml) and dried over anhydrous sodium sulfate. ((4-(4-(Methylamino)-3-(phenylamino)phenyl)piperazin-1-yl)(phenyl)methanone (0.021 g, 10%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) 8 (ppm) 2.86 (s, 3H), 2.97 (s, br, 4H), 3.58 (s, br, 2H), 3.94 (s, br, 3H), 5.18 (s, 1H), 6.88 (m, 6H), 7.25 (m, 2H), 7.47 (m, 6H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:14][CH:13]3[O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]4[O:38][CH2:37][C:36](=[O:39])[N:35]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:34]=4[CH:45]=3)=[CH:8][CH:7]=2)[CH2:2]1.Cl[C:47]1[O:48][C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=1>C(Cl)(Cl)Cl>[O:48]1[C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=[C:47]1[N:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:19])[CH2:14][CH:13]3[O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]4[O:38][CH2:37][C:36](=[O:39])[N:35]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:34]=4[CH:45]=3)=[CH:8][CH:7]=2)[CH2:2]1
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC4CNC4)cc3)cc21
Reactant: Clc1nc2ccccc2o1
Solvent: ClC(Cl)Cl
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC4CN(c5nc6ccccc6o5)C4)cc3)cc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 0.382 g of benzyl 4-[4-(azetidin-3-yloxy)phenyl]-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benz[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate in 10 ml of chloroform is admixed at 0-5° C. with 0.156 ml of 2-chlorobenzoxazole. The reaction solution is stirred at room temperature over 20 hours and subsequently poured onto an ice-water mixture. The reaction mixture is extracted with ethyl acetate (2×50 ml) and the combined organic phases are washed with 50 ml of brine, dried over sodium sulphate, filtered and concentrated. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=020 (2:1 EtOAc-heptane); Rt=4.99.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]2[CH:14]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:16]=[C:6]2[C:5]1=[O:22]>O.C(O)C>[CH3:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]2[CH:14]=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=[C:6]2[C:5]1=[O:22]
Reactant: CCOC(=O)c1cc2c(=O)n(C)c3ccccc3n2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1c(=O)c2cc(C(=O)O)cn2c2ccccc21
Yield: 94.1 %

Procedure:
A solution of 0.9 g of sodium hydroxide in 50 ml of water was added to a suspension of 1.66 g of ethyl 5-methyl-4,5-dihydro-4-oxo-pyrrolo[1,2-a]quinoxaline-2-carboxylate in 30 ml of hot ethanol and the mixture was warmed on a water bath for one hour after which thin layer chromatography showed no ester present. The resulting solution was filtered hot and the filtrate was acidified to a pH of 1-2 with concentrated hydrochloric acid. The mixture was cooled and filtered and the recovered product was rinsed with water and dried over P2O5 under vacuum to obtain 1.40 g (95% yield) of 5-methyl-4,5-dihydro-4-oxo-pyrrolo[1,2-a]quinoxaline-2-carboxylic acid melting at 330°-333° C.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH2:12][CH2:13][N:14]([CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([Cl:17])[CH:19]=2)[CH2:15][CH:16]=1
Reactant: Clc1cccc(CBr)c1
Reactant: C1=C(c2nc3ccccc3s2)CCNC1
Agent: Cl
Product: Clc1cccc(CN2CC=C(c3nc4ccccc4s3)CC2)c1
Yield: 44 %

Procedure:
4-(Benzothiazol-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (200 mg, 0.8 mmol) was reacted with 3-chlorobenzyl bromide (0.1 ml, 0.8 mmol) as exemplified in Example 1. The crude product was purified by flash chromatography eluting with 15% ethyl acetate in petroleum ether to give the title compound as a pale yellow solid (120 mg, 45%); (Found: C, 65.57; H, 4.87; N, 7.59. C19H17ClNS. 0.5H2O requires C, 65.22; H, 5.19; N, 8.01%). δH (CDCl3), 2.77 (2H, m, NCH2 CH2), 2.84 (2H, m, NCH2CH2), 3.24 (2H, m, NCH2 CH2), 3.65 (2H, s, NCH2Ar), 6.68 (1H, m, NCH2CH), 7.25 (2H, s, ArH), 7.36 (4H, m, ArH), 7.82 (1H, d, J 8.0Hz, ArH), 7.98 (1H, d, J 8.1Hz, ArH). m/z (ES+) 341 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[CH:16]=[CH:17][CH:18]=1)[C:5]2=O.O.[NH2:31][NH2:32]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=4)[CH:16]=[CH:17][CH:18]=3)=[CH:7][NH:32][N:31]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: NN
Reactant: COc1ccc(-c2cccc(-c3coc4cc(O)c(Cl)cc4c3=O)c2)cc1OC
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cccc(-c3c[nH]nc3-c3cc(Cl)c(O)cc3O)c2)cc1OC

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-3-(3′,4′-dimethoxy-biphenyl-3-yl)-7-hydroxy-chromen-4-one (0.1 g, 0.24 mmol), hydrazine hydrate (2.5 ml), ethanol (10 ml). The quenched solution was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give an oil which was purified by column chromatography to give 4-Chloro-6-[4-(3′,4′-dimethoxy-biphenyl-3-yl)-1H-pyrazol-3-yl]-benzene-1,3-diol as an off white solid (0.05 g, 49.3.3%); Rf 0.3 cf SM 0.6 ethyl acetate/hexane (70/30).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:43]=[C:44]([N+:46]([O-])=O)[CH:45]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[C:29](/[C:32]2[CH:40]=[CH:39][C:35]3[O:36][CH2:37][O:38][C:34]=3[CH:33]=2)\[C:30]#[N:31])=[CH:24][C:23]=1[O:41][CH3:42])=[O:8])([O-])=O>CN(C=O)C.O.[Zn]>[NH2:46][C:44]1[CH:43]=[C:6]([CH:5]=[C:4]([NH2:1])[CH:45]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[C:29](/[C:32]2[CH:40]=[CH:39][C:35]3[O:36][CH2:37][O:38][C:34]=3[CH:33]=2)\[C:30]#[N:31])=[CH:24][C:23]=1[O:41][CH3:42])=[O:8]
Reactant: COc1cc(/C=C(\C#N)c2ccc3c(c2)OCO3)ccc1OCCCCCCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(/C=C(\C#N)c2ccc3c(c2)OCO3)ccc1OCCCCCCCCCCCOC(=O)c1cc(N)cc(N)c1
Yield: 61.4 %

Procedure:
5 g (7.6 mmol) of 11-{4-[(Z)-2-(1,3-benzodioxol-5-yl)-2-cyanoethenyl]-2-methoxyphenoxy}undecyl 3,5-dinitrobenzoate are dissolved in a mixture of 84 ml of DMF and 9 ml of water. 15.7 g (58 mmol) of ferric chloride hexahydrate are added. 6.31 g (97 mmol) of zinc powder are added portionwise within 30 min. The mixture is allowed to react for 2 hours. The reaction mixture is then partitioned between ethyl acetate and water and filtered. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Filtration of the residue on silica gel using toluene:ethyl acetate(1:3) as eluant and yielded 2.8 g (61%) of 11-{4-[(Z)-2-(1,3-benzodioxol-5-yl)-2-cyanoethenyl]-2-methoxyphenoxy}undecyl 3,5-diaminobenzoate as a white powder.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[CH3:6][O:7][NH:8][CH:9]([CH3:29])[CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:15]=[C:14]1[CH2:26][CH2:27][CH3:28]>O1CCCC1>[CH2:26]([C:14]1[N:13]([CH2:12][CH2:11][CH2:10][CH:9]([N:8]([O:7][CH3:6])[C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH3:29])[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:15]=1)[CH2:27][CH3:28]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(C)NOC
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: CCCc1nc2cnc3ccccc3c2n1CCCC(C)N(OC)C(=O)NCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
Ethyl isocyanate (0.49 mL, 4.59 mmol) was added to a solution of O-methyl-N-[1-methyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]hydroxylamine (0.600 g, 1.83 mmol) in tetrahydrofuran (THF) (25 mL) at 0° C. and stirred for 1 hour at ambient temperature. Analysis by LC-MS showed the reaction was incomplete and additional ethyl isocyanate (0.19 mL) was added to the reaction mixture. After 1 hour of stirring at ambient temperature, the reaction mixture was concentrated under reduced pressure to afford 0.700 g of 1-[4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-methylbutyl]-3-ethyl-1-methoxyurea.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4]([C:13]([OH:15])=O)=[C:3]1[CH3:16].C(Cl)(=O)C(Cl)=O.[CH:23]([NH2:26])([CH3:25])[CH3:24]>>[CH:23]([NH:26][C:13]([C:4]1[C:5]2[C:10](=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]=1[CH3:16])=[O:15])([CH3:25])[CH3:24]
Reactant: CC(C)N
Reactant: COc1ccc2c(C(=O)O)c(C)n(C)c2c1
Agent: O=C(Cl)C(=O)Cl
Product: COc1ccc2c(C(=O)NC(C)C)c(C)n(C)c2c1

Procedure:
This material was prepared from 1,2-dimethyl-6-methoxy-1H-indole-3-carboxylic acid 16c, oxalyl chloride and isopropylamine in a manner as previously described for example 16d. 1H NMR (300 MHz, CDCl3) δ 7.53 (1H, d, J=8.7 Hz), 6.85 (1H, dd, J=2.3, 8.7 Hz), 6.77 (1H, d, J=2.3 Hz), 4.35 (1H, m), 3.87 (3H, s), 3.63 (3H, s), 2.69 (3H, s), 1.30 (3H, s), 1.27 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 261. found 261.
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]1[N:7]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:19]=[C:20]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:21]=[C:22]([C:23]([O:25]C)=[O:24])[C:5]=2[N:4]=1.[Li+].[OH-]>C1COCC1>[F:33][CH:2]([F:1])[C:3]1[N:7]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:19]=[C:20]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:21]=[C:22]([C:23]([OH:25])=[O:24])[C:5]=2[N:4]=1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)F)n2Cc1cccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(N2CCOCC2)cc2c1nc(C(F)F)n2Cc1cccc2ccccc12
Yield: 66.4 %

Procedure:
A mixture methyl 2-(difluoromethyl)-6-morpholino-1-(naphthalen-1-ylmethyl)-1H-benzo[d]imidazole-4-carboxylate (700 mg, 1.55 mmol) and 2N LiOH (5 mL) in THF (10 mL) was stirred at 45° C. for 4 h. It was filtered, the filter cake was dissolved in water (10 mL) and formic acid was added to adjust pH to 3-4. Then a filtration was performed and the filter cake was collected, dried under vacuum to give the product (450 mg, 66%) as a white solid. 1H NMR (300 MHz, DMSO-d6,): δ ppm 3.07 (s, 4H), 3.68 (s, 4H, s), 6.20 (s, 2H), 6.30 (d, 1H, J=7.2 Hz), 7.20-7.72 (m, 6H), 7.85 (d, 1H, J=8.1 Hz), 8.01 (d, 1H, J=7.8 Hz), 8.24 (d, 1H, J=7.5 Hz); LC-MS: m/e=438 [M+1]+
Reaction SMILES: [CH3:1][NH2:2].C1COCC1.[I:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]=[C:16]=[O:17]>>[I:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([NH:2][CH3:1])=[O:17]
Reactant: O=C=Nc1ccccc1I
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccccc1I
Reaction time: 0.5 h

Procedure:
A solution of methylamine in THF (2 M, 19 mL, 39 mmol) was cooled to 0° C. and 2-iodophenylisocyanate (0.68 g, 12.6 mmol) was added dropwise over 5 minutes. The solution was stirred for 30 minutes, after which it was evaporated to dryness in vacuo to yield a white solid (2.05 g) 1H NMR (400 MHz, d6-DMSO): δ 7.81-7.77 (2H, m), 7.53 (1H, s), 7.30-7.26 (1H, m), 6.87 (1H, d, J=4.3 Hz), 6.77-6.73 (1H, m), 2.65 (3H, d, J=4.6 Hz).
Reaction SMILES: [CH2:1]([N:5]([CH:10]1[CH2:14][S:13](=[O:16])(=[O:15])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]1=2)[S:6]([CH3:9])(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].[N+:21]([O-])([O-:23])=[O:22].[Na+]>S(=O)(=O)(O)O>[CH2:1]([N:5]([CH:10]1[CH2:14][S:13](=[O:15])(=[O:16])[C:12]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:11]1=2)[S:6]([CH3:9])(=[O:7])=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C1CS(=O)(=O)c2ccccc21)S(C)(=O)=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCCN(C1CS(=O)(=O)c2cc([N+](=O)[O-])ccc21)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.2 %

Procedure:
At -10° C., 0.5 g (1.6 mmol) of N-butyl-N-(1,1-dioxo-2,3-dihydro-1H-benzo[b]thiophen-3-yl)methanesulfonamide (Example 5) was dissolved in 5 ml of concentrated sulfuric acid and admixed with 0.15 g (1.8 mmol) of sodium nitrate, and the mixture was stirred at RT for 20 h. The reaction mixture was poured into 50 ml of ice-water, stirred for 30 minutes, filtered off with suction, washed neutral with water and dried under reduced pressure. This procedure gave 0.5 g of N-butyl-N-(6-nitro-1,1-dioxo-2,3-dihydro-1H-benzo[b]thiophen-3-yl)-methanesulfonamide; m.p. 52-55° C.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[H-].[Na+].Cl[C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl) pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:4][CH:3]=1.[CH2:20]=O.Cl>C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][N:9]([CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[CH3:20])=[CH:18][CH:19]=1
Reactant: C=O
Reactant: Clc1ccc(OCCNCCCn2ccnc2)cc1
Agent: Cl
Solvent: O=CO
Product: CN(CCCn1ccnc1)CCOc1ccc(Cl)cc1
Temperature: 95 °C

Procedure:
N-[2-(4-Chlorophenoxy)ethyl]-3-(imidazol-1-yl) propylamine (1.50 g) was added dropwise to 98% formic acid (1.0 ml) at 0° C. Formaldehyde (0.96 ml of a 37% aqueous solution) was added and the mixture heated at 95° C. for 6 hours. On cooling, concentrated hydrochloric acid (0.6 ml) was added. The mixture was evaporated to dryness and the residue dissolved in water, basified with 5M sodium hydroxide solution and extracted with ethyl acetate to give N-[2-(4-chlorophenoxy)ethyl]-3-(imidazol-1-yl)-N-methylpropylamine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH:7]([C:17](O)=[O:18])[O:8][C:9]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:10]=3[CH2:11][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[NH2:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>C1C=CC=CC=1>[Cl:16][C:13]1[CH:14]=[CH:15][C:9]2[O:8][CH:7]([C:17]([NH:26][CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[O:18])[O:6][C:5]3[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][C:4]=3[CH2:11][C:10]=2[CH:12]=1
Reactant: O=C(O)C1Oc2ccc(Cl)cc2Cc2cc(Cl)ccc2O1
Reactant: NCc1cccnc1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(NCc1cccnc1)C1Oc2ccc(Cl)cc2Cc2cc(Cl)ccc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 15 g of 2,10-dichloro-12H-dibenzo[d,g][1,3]dioxocin-6-carboxylic acid was added 75 ml of thionyl chloride, and the heterogenous mixture was refluxed with occasional stirring until it became homogenous. The mixture was refluxed for an additional 2 hours after which the thionyl chloride was distilled off under reduced pressure affording a solid residue which was dissolved in 300 ml of dry benzene by warming on a steam bath. The benzene was distilled off under reduced pressure affording a white crystalline residue to which was added 500 ml of dry benzene. The mixture was stirred at room temperature until homogenous then 35 g of 3-aminomethylpyridine was added. After standing at room temperature for 2 hours the mixture was heated to reflux for an additional 3 hours, cooled to room temperature, poured into ice water and separated. Methanol was added to aid the solubility of the product in the organic layer. The organic layer was washed with water and distilled under reduced pressure resulting in a residue which was dried and recrystallized twice from methanol-acetone (1:1) to give the desired product, M.P. 225°-226°C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8](OC(OCC)CBr)[CH3:9].Br>C(O)C>[N:1]1[CH:8]=[CH:9][N:3]2[CH:4]=[CH:5][CH:6]=[N:7][C:2]=12
Reactant: Nc1ncccn1
Reactant: CCOC(CBr)OCC
Agent: Br
Solvent: CCO
Product: c1cnc2nccn2c1
Yield: 81.4 %

Procedure:
A solution of 2-aminopyrimidine (0.5 g, 5.26 mmol), bromoacetaldehyde diethyl acetal (2.07 g, 10.5 mmol) and 48% aqueous hydrobromic acid (0.5 ml) in ethanol (5 ml) was heated at reflux for 18 h. The reaction was cooled and pre-adsorbed directly onto silica gel. Purification by flash chromatography eluting with dichloromethane (containing 1% conc. ammonia) on a gradient of methanol (1-3%) gave a solid which was triturated with 5% diethyl ether in isohexane to afford imidazo[1,2-α]pyrimidine (0.51 g, 82%) as a tan solid: δH (400 MHz, CDCl3) 6.92 (1H, dd, J 7 and 4), 7.59 (1H, d, J 1), 7.84 (1H, d, J 1), 8.49 (1H, dd, J 7 and 2), 8.58 (1H, dd, J 7 and 2).
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[S:22]([CH3:25])(=[O:24])=[O:23]>CN(C)C=O.O>[F:21][C:19]1[CH:20]=[CH:15][C:16]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:17]([NH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:18]=1
Reactant: Nc1cccc2ccccc12
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(F)cc1Nc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.8 %

Procedure:
Naphthalen-1-amine (0.89 g, 4.7 mmol) and 60% NaH in oil (0.24 g, 6.1 mmol) were stirred in N,N-dimethylformamide (5 mL) for 15 min. at 0° C. and for 30 min. at room temperature. 2,4-Difluoro-1-(methylsulfonyl)benzene (0.67 g, 4.7 mmol), was added to the reaction as a solid. The reaction was allowed to stir at room temperature for 16 h. The reaction was poured in water and extracted with ether. After removal of solvent the crude was purified on silica chromatography in 10% ethyl acetate in hexanes to obtain 0.56 g of product (0.36 mg, 38% yield). 1H NMR (400 MHz, CDCl3): δ 8.30 (s, 1H), 7.89 (m, 3H), 7.54 (m, 5H), 6.79 (t, 1H), 6.48 (d, 1H), 3.22 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH:15]([CH3:17])[CH3:16])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:29])[CH:5]=[C:6](OC1C=CC(OC(C)C)=CC=1)[O:7]2.[OH:30][C:31]1[CH:36]=[CH:35][C:34]([SH:37])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[OH:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH:15]([CH3:16])[CH3:17])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:29])[CH:5]=[C:6]([S:37][C:34]1[CH:35]=[CH:36][C:31]([OH:30])=[CH:32][CH:33]=1)[O:7]2
Reactant: COc1c(OC(C)C)cc2oc(Oc3ccc(OC(C)C)cc3)cc(=O)c2c1O
Reactant: Oc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1c(OC(C)C)cc2oc(Sc3ccc(O)cc3)cc(=O)c2c1O
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 89.6 %

Procedure:
A mixture consisting of 9.49 g of 5-hydroxy-7-isopropoxy-2-(4-isopropoxyphenoxy)-6-methoxychromone obtained in Example 4, 4.49 g of 4-hydroxythiophenol, 4.91 g of potassium carbonate, and 200 ml of acetone was stirred over 1.2 hours at room temperature. The solution thus reacted was made weakly acidic by addition of dilute hydrochloric acid. The product was extracted twice with chloroform. The organic layer was washed with saturated salt water and was then dried over sodium sulfate anhydride. The solvent was distilled out under reduced pressure. The resulting crude product was recrystallized from hexane:ethyl acetate, so that 7.95 g of 5-hydroxy-2-(4-hydroxyphenylthio)-7-isopropoxy-6-methoxychromone with the following physicochemical properties was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:10]=[C:11]([O:20][CH3:21])[CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[C:14]2[CH3:19].[CH2:22]([S:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])=[O:25])[CH3:23]>ClCCl.O>[CH2:22]([S:24]([N:27]1[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]2[CH:10]=[C:11]([O:20][CH3:21])[CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[C:14]3[CH3:19])[CH2:31][CH2:32]1)(=[O:26])=[O:25])[CH3:23]
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: COc1cc(NCCCCCCCl)c2nccc(C)c2c1
Solvent: O
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCN(CCCCCCNc2cc(OC)cc3c(C)ccnc23)CC1
Yield: 68.2 %

Procedure:
A mixture of 1.5 g. (0.0049 mole) of N-(6-chlorohexyl)-6-methoxy-4-methyl-8-quinolinamine and 2.7 g (0.015 mole) of 1-(ethylsulfonyl)-piperazine was heated at 130° for 50 min, allowed to cool and taken up in dichloromethane and water. The organic layer was washed again, dried, and concentrated to dryness in vacuo. The residue was chromatographed over 70 g of silica gel first with ethyl acetate and then with 2% methanol in ethyl acetate. The eluant containing product, Rf(silica--ethyl acetate)=0.05, was concentrated to dryness in vacuo. Recrystallization of the residue from 2-propanol afforded 1.5 g (68%) of the title compound, mp 72°-74°.