Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](I)[CH3:2].[CH2:4]([O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([OH:22])[CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:4]([O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([O:22][CH2:1][CH3:2])[CH:13]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCI
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(OCc2ccccc2)ccc1C(=O)OC

Procedure:
Ethyl iodide (0.14 mL) was added to a mixture of methyl 4-benzyloxy-2-hydroxybenzoate (0.30 g) and potassium carbonate (0.32 g) in N,N-dimethylformamide (2.9 mL) at room temperature with stirring. The mixture was stirred at that temperature for 1.6 hrs and at 50° C. for 1.4 hrs. Water was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (0.29 g).
Reaction SMILES: [NH2:1][C:2]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][OH:4].[Na].Br[CH2:18][C:19]1[CH:20]=[C:21]([CH:34]=[C:35]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[C:22]([NH:24][C@@H:25]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[CH3:26])=[O:23]>CN(C=O)C.C1COCC1>[NH2:1][C:2]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][O:4][CH2:18][C:19]1[CH:20]=[C:21]([CH:34]=[C:35]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[C:22]([NH:24][C@@H:25]([C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1)[CH3:26])=[O:23]
Reactant: C[C@@H](NC(=O)c1cc(CBr)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Reactant: CCCCC(N)(CO)Cc1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCC(N)(COCc1cc(C(=O)N[C@H](C)c2ccc(F)cc2)cc(N(C)S(C)(=O)=O)c1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-amino-2-benzylhexane-1-ol intermediate II (0.100 mg, 0.48 mmol) in 1.1 mL DMF cooled to 0° C. was added sodium hexamethyldisylazide (0.48 mL, 0.48 mmol, 1 M in THF). The reaction mixture was stirred at 0° C. for 5 min and intermediate A 3-(bromomethyl)-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide (0.040 g, 0.090 mmol) in 1.8 mL DMF was added dropwise. The reaction mixture was stirred at 0° C. for 1.5 h, and quenched by adding water. The aqueous layer was washed with EtOAc (3×), and the combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (20 g silica, 0->8% 0.1% NH4OH in i-PrOH/hexanes) afforded 3-{[(2-amino-2-benzylhexyl)oxy]methyl}-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methyl sulfonyl)amino]benzamide. 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.69 (s, 1H), 7.53 (s, 1H), 7.37-7.34 (m, 2H), 7.29-7.20 (m, 3H), 7.17-7.15 (m, 2H), 7.04 (m, 2H), 6.56 (br s, 1H), 5.30 (m, 1H), 4.56 (s, 2H), 3.34 (s, 3H), 3.20 (m, 2H), 1.59 (d, J=6.9 Hz, 3H), 1.60-1.39 (br m, 6H), 0.90 (t, J=7.0 Hz, 3H).
Reaction SMILES: C([Li])CCC.[C:6]([C:8]1[CH:19]=[CH:18][C:11]([CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:10][CH:9]=1)#[CH:7].[C:20](=[O:22])=[O:21].Cl>CCCCCC.C1COCC1>[N:13]1([CH2:12][C:11]2[CH:18]=[CH:19][C:8]([C:6]#[C:7][C:20]([OH:22])=[O:21])=[CH:9][CH:10]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C#Cc1ccc(CN2CCCC2)cc1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)C#Cc1ccc(CN2CCCC2)cc1
Reaction time: 1 h

Procedure:
5.98 mL (14.85 mmol) of a 1.6M butyllithium solution in n-hexane is added dropwise to a solution of 2.3 g (12.41 mmol) of 1-(4-ethynylbenzyl)pyrrolidine in 50 mL of THF at −78° C. and stirred for 1 hour at this temperature. Then dry ice is added to the reaction mixture. Then the reaction mixture is allowed to come up to ambient temperature and stirred for 14 hours. The reaction mixture is combined with dilute hydrochloric acid and extracted with dichloromethane. The organic phase is separated off and dried over sodium sulfate. The sodium sulfate is separated off and the solvent is removed. Yield: 0.3 g (10.5% of theory); C14H15NO2 (M=229.28); calc.: molecular ion peak (M+H)+: 230; found: molecular ion peak (M+H)+: 230; Rf value: 0.15 (silica gel, dichloromethane/methanol/ammonia (9:1:0.1)).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][CH2:13][CH:14]([OH:16])[CH3:15].[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24](F)[CH:25]=1)[C:21]#[N:22].O>CN(C=O)C>[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:16][CH:14]([CH3:15])[CH2:13][O:12][CH3:11])[CH:25]=1)[C:21]#[N:22]
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: COCC(C)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC(C)Oc1cc(Br)cc(C#N)c1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
NaHMDS (148 mmol; 27.2 g) was charged to a 1000 ml round-bottomed flask (4 necks, thermometer, pressure-equalising dropping funnel, stopper, nitrogen inlet, magnetically stirred, oven dried, nitrogen purged), followed by DMF (300 ml). The mixture was stirred for 5 minutes then 1-methoxy-2-propanol (1.50 equiv; 148 mmol; 14.3 ml; 13.4 g) was added dropwise over a 10-minute period. The reaction temperature increased to 25° C. The mixture was cooled using a cold-water bath to 23° C., then 3-bromo-5-fluorobenzonitrile (1.00 equiv; 99.0 mmol; 20.0 g) in DMF (90 ml) was added over a 5 minutes period (cold water bath still present). The mixture warmed to 27° C. during addition, turning from yellow to brown. A line wash of DMF (10 ml) was added. The mixture was stirred at ambient temperature for 30 minutes, then quenched by addition of HCl solution (2M, aqueous, 200 ml), the dark brown reaction mixture turning pale yellow. The mixture was poured into water (400 ml) and extracted with EtOAc (3×400 ml). The combined organic extracts were washed with water (3×400 ml) and dried over MgSO4, filtered and the solvent removed in vacuo affording 3-bromo-5-(2-methoxy-1-methylethoxy)benzonitrile as an orange oil (25.38 g, 95%). 1H NMR (400 MHz, CDCl3) δ: 7.32 (s, 1H), 7.26 (s, 1H), 7.11 (s, 1H), 4.58-4.55 (m, 1H), 3.59-3.48 (m, 2H), 3.41 (s, 3H), 1.33-1.31 (d, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=1.Cl.Cl.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CN=1.[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52]>CO>[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52].[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:6]1[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=[C:2]1/[CH:1]=[CH:23]/[C:19]1[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1cccnc1
Reactant: Cc1nc2ccccc2n1-c1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccn1
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CO
Product: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1cccnc1

Procedure:
Free base of the titled compound was prepared from 2-methyl-1-(2-pyridyl)-1H-benzimidazole and pyridine-3-Carboxaldehyde according to the preparation of (E)-1-(2-pyridyl)-2-[2-(2-pyridyl)ethenyl]-1H-benzimidazole dihydrochloride (Example 44). The free base and oxalic acid were dissolved into MeOH. Concentration and recrystallization from ethyl MeOH/EtOH yielded the titled compound. MW: 388.39; mp: 193.3-194.1° C. (decomposed); 1H-NMR (DMSO) δ: 8.86-8.81 (1H, m), 8.80-8.76 (1H, m), 8.53 (1H, dd, J=4.8, 1.5 Hz), 8.19 (1H, dt, J=7.8, 1.9 Hz), 8.12-8.05 (1H, m), 7.93 (1H, d, J=16.0 Hz), 7.76 (2H, d, J=7.9 Hz), 7.68-7.61 (1H, m), 7.51-7.25 (4H, m), 7.33 (1H, d, J=16.0 Hz).
Reaction SMILES: [H-].[Na+].C[CH:4]([CH2:8][CH3:9])[CH2:5][CH:6]=[O:7]>CCCCCC.C(COC)OC>[CH3:4][CH:9]([CH2:5][CH3:6])[CH2:8][CH:4]=[CH:5][C:6]([O:7][CH2:9][CH3:8])=[O:7]
Reactant: CCC(C)CC=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: COCCOC
Product: CCOC(=O)C=CCC(C)CC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 122 %

Procedure:
Sodium hydride (60% dispersion, 2.4 g, 65 mmol) was washed with hexane and suspended in dimethoxyethane 60 mL. While cooling in ice water bath triethyl phosphonoacetate was slowly added, calcd. 5 minutes. The reaction was stirred for 15 minutes at 0° C. and a solution of 3-methyl-1-pentanal 11 (6.5 g, 65 mmol) in imethoxyethane 20 mL was added. After refluxing overnight, it was concentrated, water and hexane were added, the organic phase was separated, and the aqueous portion discarded. The solution was washed twice with brine and dried on magnesium sulfate. The solvent was evaporated to give 12 (6.75 g, 61%). 1H-NMR (CDCl3) δ6.89 (m, 1H, —CH2CH:CHCOOEt), 5.77 (d, 1H, —CH2CH:CHCOOEt), 4.16 (q, 2H, —COOCH2CH3), 2.15 and 1.98 (1H each and a multiplet, —CH2CH:CHCOOEt), 1.48 (m, 1H, C2H5(CH3)CHCH2), 1.30-1.10 (m), and 0.83.
Reaction SMILES: [H-].[Na+].CCCCCC.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16].[CH3:17][O:18][CH2:19]Br>CN(C)C=O>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][O:18][CH3:19]
Reactant: Oc1ccccc1Br
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COCOc1ccccc1Br
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
The oil was removed from 4.5 g (60% in oil, 112 mmol, Aldrich) of sodium hydride dispersion by three-20 mL washes with hexane then the residue was covered with 75 mL of dimethylformamide (Burdick and Jackson). The resulting mixture was heated to about 50° and 18.1 g (105 mmol, Aldrich) of 2-bromophenol was added dropwise over 15 minutes. Vigorous gas evolution was observed. The reaction was stirred for an additional 30 minutes then the resulting gray-brown solution was cooled to 0° and 9.6 mL (117 mmol, Aldrich) of bromomethyl methyl ether was added dropwise over 15 minutes. The reaction mixture was stirred for 1 hour at 0° then at room temperature for 16 hours. The resulting slurry was partitioned between 200 mL of 1M aqueous sodium hydroxide solution and 150 mL of 4:1 hexane/diethyl ether. The aqueous layer was separated and extracted with an additional 100 mL of 4:1 hexane/diethyl ether. The organic extracts were combined, washed with two-200 mL portions of water, dried (magnesium sulfate) and concentrated in vacuo to give 22.2 g (102 mmol, 97%) of title compound as a pale yellow liquid.
Reaction SMILES: [CH2:1]([C:3]1([CH2:23][CH3:24])[CH2:8][CH2:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:5][CH2:4]1)[CH3:2].[O:25]1[CH2:30][CH2:29][CH:28]([CH:31]=O)[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:23]([C:3]1([CH2:1][CH3:2])[CH2:8][CH2:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH2:18][CH2:19][N:20]([CH2:31][CH:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)[CH2:21][CH2:22]2)=[CH:5][CH2:4]1)[CH3:24]
Reactant: CCC1(CC)CC=C(c2ccc(OC)cc2N2CCNCC2)CC1
Reactant: O=CC1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC1(CC)CC=C(c2ccc(OC)cc2N2CCN(CC3CCOCC3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
To a solution of 1-[2-(4,4-diethylcyclohex-1-enyl)-5-methoxyphenyl]piperazine (90 mg, 0.27 mmol) prepared in Example (6f) in tetrahydrofuran (10 mL) were added tetrahydropyran-4-carbaldehyde (37 mg, 0.32 mmol), sodium triacetoxyborohydride (87 mg, 0.41 mmol) and acetic acid (32 mg, 0.57 mmol) in that order, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 50 mg of 1-[2-(4,4-diethylcyclohex-1-enyl)-5-methoxyphenyl]-4-(tetrahydropyran-4-ylmethyl)piperazine as a light yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19][CH2:18][C:7]=3[N:8](C(OC(C)(C)C)=O)[C:9]=2[CH:10]=1.[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][NH:40][C:39](=[O:43])[CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][N:40]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:19][CH2:18][C:7]=4[NH:8][C:9]=3[CH:10]=2)[C:39](=[O:43])[CH:38]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(c3ccc(Br)cc3n2C(=O)OC(C)(C)C)C1
Product: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc3c2C1
Yield: 12.1 %

Procedure:
Prepared from di-tert-butyl 7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2,5-dicarboxylate (1.24 g, 2.72 mmol) and 4-benzyloxypyridone (547 mg, 2.72 mmol) according to the procedure of Example 1 (step c). Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, 100:0 to 80:20 to 50:50 to 25:75 then 0:100) gave the title compound (155 mg, 10%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.40 (br s, 1H), 7.44-7.38 (m, 5H), 7.30 (d, J=7.5 Hz, 1H), 7.22 (d, J=8.2 Hz, 1H), 7.16 (s, 1H), 6.82 (dd, J=8.2, 1.4 Hz, 1H), 6.12-6.09 (m, 2H), 5.09 (s, 2H), 4.46 (br s, 2H), 3.70 (br m, 2H), 2.54 (br m, 2H), 1.50 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH:17]([OH:20])(C)[CH3:18].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:7]([O:20][CH2:17][CH3:18])=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)O
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, isopropanol and DBU in dioxane. EI-MS m/e (%): 299 (M{81Br}+, 43), 297 (M{79Br}+, 45), 257 ([M—C6H10]+, 98), 255 ([M—C6H10]+, 100), 206 (32), 94 (44), 43 (52).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:13]([O-])([O-])=O.[K+].[K+].CI>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1cccc(-c2ncn[nH]2)c1
Agent: [K+]
Solvent: CI
Product: Cn1ncnc1-c1cccc(Br)c1
Yield: 11.1 %

Procedure:
This reaction was carried out as described in Example 40, step c, using 5-(3-bromophenyl)-1H-[1,2,4]triazole (1.60 g, 7.2 mmol), K2CO3 (2.47 g, 17.8 mmol) and MeI (667 μl, 10.7 mmol). The residue was purified by column chromatography (silica gel, 80% Et2O/isohexane) to yield first 5-(3-bromophenyl)-1-methyl-1H-[1,2,4]triazole (190 mg, 11%), and then the solvent polarity was increased to 100% EtOAc to yield 3-(3-bromophenyl)-1-methyl-1H-[1,2,4]triazole (935 mg, 55%).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[C:10](=[O:20])[C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(OCC)(=O)C>[C:21]([O:8][C:9]1[C:10](=[O:20])[C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:23])[CH3:22]
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OC1=CC(=O)c2ccccc2C1=O
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
595 g (5.89 moles) of triethylamine are added dropwise in 30 minutes to a suspension of 500 g (2.87 moles) of 2-hydroxy-1,4-naphthoquinone (lawsone) in 2200 ml of ethyl acetate, cooled to +5° C., maintaining the temperature below +10° C. At the end of the dripping a dark red solution is obtained. The solution is kept at +5-10° C. for 30 minutes. 550 g (5.39 moles) of acetic anhydride are added dropwise in 30 minutes, maintaining the temperature between +5 and +10° C. At the end of the dripping, the mixture is left under agitation at +5° C. for 4 hours. The solid is filtered and washed with a mixture of 250 ml of ethyl acetate and 250 ml of hexane pre-cooled to +5° C. The damp product is dried at +40° C. at reduced pressure for 6 hours providing 496 g (yield 80%) of 2-acetoxy-1,4-naphthoquinone (acetyl-lawsone) as a yellow solid with melting point −131°-134° C.
Reaction SMILES: Br[C:2]#[C:3][CH:4]=[C:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:7][CH2:6]1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[K+].[K+].[NH:40]1[CH2:44][CH2:43][CH2:42][C:41]1=[O:45]>CCOC(C)=O.C1(C)C=CC=CC=1>[N+:17]([C:16]1[C:11]([N:8]2[CH2:9][CH2:10][C:5](=[CH:4][C:3]#[C:2][N:40]3[CH2:44][CH2:43][CH2:42][C:41]3=[O:45])[CH2:6][CH2:7]2)=[N:12][CH:13]=[CH:14][CH:15]=1)([O-:19])=[O:18]
Reactant: O=C1CCCN1
Reactant: O=[N+]([O-])c1cccnc1N1CCC(=CC#CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1CCCN1C#CC=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 1.8 %

Procedure:
A mixture of Compound 261a (111 mg, 0.345 mmol), cupric sulphate (11 mg, 0.69 mmol), 1,10-phenantroline (24.9 mg, 0.138 mmol), K2CO3 (95.4 mg, 0.69 mmol), 2-pyrrolidone (39.7 μl, 0.518 mmol) and 5 mL of toluene was stirred at 80° C. for 12 h. The reaction mixture was cooled to r.t., diluted with EtOAc, washed with water, dried over Na2SO4 and evaporated to dryness in vacuo. The crude residue was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with PE-EtOAc gradient from 98:2 to 0:10, giving the title product (2 mg)
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].CC1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N+:10]=1[O-].C(O)C.C(=O)(O)[O-].[Na+]>CS(C)=O>[C:13]([C:12]1[CH:15]=[CH:16][C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])=[N:10][CH:11]=1)#[N:14]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(C#N)c[n+]1[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Product: CC(=O)OCc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Acetic anhydride (3.2 g, 31.31 mmol) is heated to 115° C. under an argon atmosphere. The compound of Example 30A (700 mg, 5.22 mmol) is added and the solution is stirred at reflux for one hour. Ethanol (3 ml, 51.12 mmol) is added dropwise to the mixture and refluxing is continued for 10 minutes. The mixture is cooled to room temperature, poured into ice water and neutralised with saturated sodium bicarbonate solution. The aqueous phase is extracted with diethyl ether. The organic phase is washed with brine, dried with magnesium sulphate, filtered and concentrated in vacuo to afford a black oil. The oil is dissolved in dimethylsulfoxide (8 ml) and purified by preparative HPLC.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1.[Br:13][C:14]1[CH:15]=[C:16](F)[CH:17]=[CH:18][C:19]=1[Br:20]>>[Br:13][C:14]1[CH:15]=[C:16]([O:9][CH:6]2[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]3[O:12][CH:11]=[CH:10][C:5]2=3)[CH:17]=[CH:18][C:19]=1[Br:20]
Reactant: Fc1ccc(Br)c(Br)c1
Reactant: CN1CCC(O)c2ccoc2C1
Product: CN1CCC(Oc2ccc(Br)c(Br)c2)c2ccoc2C1

Procedure:
The same method as in Example 1 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 19) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dibromo-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6]2=[N:7][NH:8][CH:9]=[C:5]2[CH2:4][CH2:3]1.[CH2:11]=[O:12].C(N(CC)CC)C>CC(C)=O>[CH3:1][C:2]1([CH3:10])[C:6]2=[N:7][N:8]([CH2:11][OH:12])[CH:9]=[C:5]2[CH2:4][CH2:3]1
Reactant: CC1(C)CCc2c[nH]nc21
Reactant: C=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC1(C)CCc2cn(CO)nc21
Temperature: 130 °C
Reaction time: 5 h
Yield: 15.1 %

Procedure:
The mixture of 1.68 g of 6,6-dimethyl-2,4,5,6-tetrahydrocyclopenta [c] pyrazole, 0.41 g of paraformaldehyde and 0.2 g of triethylamine was stirred at 130° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. The filterate was concentrated under reduced pressure. Hexane was added to the residue, and then crystalline was formed. The crystalline was collected to obtain 0.31 g of {6,6-dimethyl-5,6-dihydrocyclopenta [c] pyrazole-2 (4H)-yl} methanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=O)[NH:6][CH:7]=1.P(Cl)(Cl)([Cl:14])=O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([Cl:14])=[N:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cc(Br)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)cnc1Cl
Yield: 89 %

Procedure:
A mixture of 5-bromo-3-nitropyridin-2(1H)-one (Step A, 2.5 g, 10.4 mmol), phosphoryl chloride (25 mL) and N,N-dimethylformamide (2.5 mL) was stirred under reflux for 3 h. After removal of solvent, the residue was dissolved in water (20 mL) and diethylether (20 mL) at 0° C. and the solution was separated. The organic layer was washed with saturated sodium hydrogen carbonate, dried over sodium sulfate and concentrated to afford the title compound (2.5 g, 89%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=1.[H-].[Na+].[CH3:11][O:12][CH2:13]Cl.O>CN(C)C=O>[CH3:11][O:12][CH2:13][N:3]1[C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=[C:2]1[Br:1]
Reactant: COCCl
Reactant: Clc1nc(Br)[nH]c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCn1c(Br)nc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
To a solution of 0.86 g of 2-bromo-4,5-dichloroimidazole in 5 ml of dimethylformamide was added 96 mg of sodium hydride at room temperature, and after standing for 30 minutes, 0.32 g of methoxymethyl chloride was added dropwise. The resulting mixture was stirred at room temperature for 1 hour, and after adding 40 ml of water, extracted with 30 ml of diethyl ether. Extraction with diethyl ether was repeated two more times, and the ether extract was dried over magnesium sulfate and concentrated to obtain an oily product. This product was purified by column chromatography on silica gel to obtain 0.40 g of 1-methoxymethyl-2-bromo-4,5-dichloroimidazole.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].CS(C)=O.[C:21]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)#[N:22]>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:28][CH2:27][C:26]4[CH:29]=[CH:30][C:23]([C:21]#[N:22])=[CH:24][CH:25]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Reactant: N#Cc1ccc(CN)cc1
Solvent: O
Solvent: CS(C)=O
Product: CCn1ncc2c(NCc3ccc(C#N)cc3)c3ccccc3nc21
Reaction time: 8 h
Yield: 19.9 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (1.0 g, 4.3 mmol), DMSO (3 ml) and 4-cyanobenzylamine (1.2 g, 9 mmol) was heated on a steam bath for 3 hours, then was allowed to sit at room temperature overnight. The reaction mixture was poured into water and an oil separated. The oil was extracted with hot 10% ethanol/ethyl acetate, washed with water, and the organic layer was dried and evaporated. The residue was crystallized from ether/ethyl acetate and then was purified by recrystallization from ethyl acetate/hexane, followed by column chromatography on silca gel eluting with ethyl acetate and finally crystallization of the residue thus obtained from ethyl acetate/hexane to afford 280 mg of 1-ethyl-N-(4-cyanophenylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, as yellow crystals, m.p. 233°-234° C.