Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])O.[Na+].Cl[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[CH3:17][O:18][C:19](=[O:26])[C@@H:20]1[CH2:24][CH:23]([CH3:25])[CH2:22][NH:21]1>C1(C)C=CC=CC=1>[CH3:17][O:18][C:19](=[O:26])[C@@H:20]1[CH2:24][CH:23]([CH3:25])[CH2:22][N:21]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: COC(=O)[C@@H]1CC(C)CN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CC(C)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
20 ml of an aqueous solution containing 1.89 g (22.5 mmol) of sodium hydrogencarbonate and 1.54 ml (10.8 mmol) of benzyl chloroformate were added to a solution of 0.93 g (6.5 mmol) of (2S)-4-methylproline methyl ester [obtained as described in Preparative Example 8(ii)′ above] in 20 ml of toluene, and the resulting mixture was stirred at room temperature over night. At the end of this time, the reaction mixture was extracted with ethyl acetate. The organic extract was washed with water and concentrated under reduced pressure to afford 1.78 g (yield: 99%) of (2S)-1-benzyloxycarbonyl-4-methylproline methyl ester as a pale yellow oil. Subsequently, all of the compound thus obtained was reduced using lithium borohydride, in a similar manner to that described in Preparative Example 5(i)′ above, to afford 1.07 g (yield: 66%) of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:24])[N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23])[CH2:16][CH2:17][C:12]=3[C:11]([C:25]([F:28])([F:27])[F:26])=[N:10]2)=[CH:5][CH:4]=1.[CH3:29][NH:30][CH2:31][CH2:32]N.C(N(CC)CC)C>CO.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:24])[N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]4[N:30]([CH3:29])[CH2:31][CH2:32][N:23]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:25]([F:26])([F:27])[F:28])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCCC#N)CC3)cc1
Reactant: CNCCN
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCCC2=NCCN2C)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
5-[1-(4-Methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-pentanenitrile (0.200 g, 0.510 mmol) was dissolved in 1:1 MeOH/CHCl3 (25 mL). Hydrogen chloride gas was bubbled through the solution for 15 min. The reaction was tightly capped and sealed, stirred overnight at rt, and then concentrated to dryness. The crude intermediate was dissolved in methanol (15 mL). N-Methylethylenediamine (0.04 mL, 0.510 mmol) and triethylamine (0.36 mL, 2.55 mmol) were added. The reaction was tightly capped and sealed and stirred overnight at rt. The reaction was concentrated and purified by reverse phase HPLC and freeze-dried to yield the title compound (0.184 g, 80%): 1H NMR (CHCl3) δ 7.43 (d, j=9.1 Hz, 2H), 6.95 (d, j=9.1 Hz, 2H), 3.95–3.83 (m, 2H), 3.85 (s, 3H), 3.71 (t, j=6.8 Hz, 2H), 3.58–3.50(m, 4H), 3.03 (t, j=7.9 Hz, 2H), 3.00(s, 2H), 2.68 (s, 4H), 1.73 (bs, 4H) ppm; Mass Spec 450.0(M+H)+.
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][C:4]1[C:9]([CH2:10]2)=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:5]=1[O:14][CH3:15].[F:16][C:17]([F:31])([F:30])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1.C(O)C>C1(C)C(C)=CC=CC=1>[CH3:15][O:14][C:5]1[CH:6]=[CH:7][C:8]([O:12][CH3:13])=[C:9]2[C:4]=1[CH2:3][C@@H:2]([N:27]1[CH2:26][CH2:25][N:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:30])([F:31])[F:16])[CH:19]=3)[CH2:29][CH2:28]1)[C@H:11]([OH:1])[CH2:10]2
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: COc1ccc(OC)c2c1CC1OC1C2
Solvent: Cc1ccccc1C
Solvent: CCO
Product: COc1ccc(OC)c2c1C[C@@H](O)[C@H](N1CCN(c3cccc(C(F)(F)F)c3)CC1)C2
Yield: 36.7 %

Procedure:
A solution of 10.3 g of 2,3-epoxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene, 11.5 g of N-(α, α, α-trifluoro-m-tolyl)piperazine, and 2 ml of absolute ethanol in 100 ml of xylene is refluxed for 7 days. The reaction mixture is concentrated in vacuo, and the residue is triturated with ether to give 11.9 g of crude product. Recrystallization from ethyl acetate gives 8.0 g of the title compound, melting point 184°-187° C.
Reaction SMILES: [N:1]1([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:31])C(=O)C1.O>CN(C=O)C>[Br:31][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]([CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]1)[CH2:2][CH2:3][CH2:4]2
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCc3ccccc32)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCCc3cc(Br)ccc32)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A solution of tert-butyl 4-(3,4-dihydroquinolin-1(2H)-yl)piperidine-1-carboxylate (0.85 g, 2.69 mmol) in 15 mL of DMF was cooled to 0° C. then treated dropwise with NBS (478 mg, 2.69 mmol) in 12 mL DMF. The reaction was stirred at 0° C. for 1 hour then treated with 100 mL H2O. The suspension was extracted with 2×75 mL of ethyl acetate. The combined organic layer was rinsed with brine (2×50 mL), dried over Na2SO4, filtered and concentrated to give a light brown oil. This residue was subjected to silica gel chromatography using the Biotage purification system (25+M column, 0-20% ethyl acetate/hexanes over 10 column volumes) to give a viscous oil which solidified to give a white solid (852 mg, 80.4%). 1H-NMR (CDCl3) δ 7.10 (dd, J=2.4 Hz, 8.7 Hz, 1H), 7.05-7.04 (m, 1H), 6.51 (d, J=9.0 Hz, 1H), 4.33-4.19 (m, 2H), 3.71-3.64 (m, 1H), 3.14 (t, J=6.0 Hz, 2H), 2.82-2.74 (m, 2H), 2.69 (t, J=6.3 Hz, 2H), 1.91-1.77 (m, 2H), 1.61-1.57 (m, 4H), 1.47 (s, 9H). MS (ESI): 395.1 and 377.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1COCC1.[Cl:14][C:15]1[CH:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=1.O>CS(C)=O>[Cl:14][C:15]1[CH:20]=[C:19]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Nc1ccc(O)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 4-aminophenol (740 mg, 6.8 mmol) in anhydrous DMSO (8 ml) was flushed with nitrogen and treated with 1M KOBut/THF solution (10 ml, 10 mmol). The mixture was stirred at room temperature under nitrogen for 10 minutes. 2,4-dichloropyridine (1.0 g, 6.8 mmol) was added and the mixture was heated at 60° C. for 30 minutes, cooled to room temperature and poured into 100 ml of water. The resulting precipitates were filtered, washed with water and dried to give 4-((2-chloropyridin-4-yl)oxy)aniline as light brown solid. The material was used for the following reactions without further purification. Yield: 1.15 g, 77%.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].C1(N)C(F)=C(F)C(F)=[C:17]([NH2:24])C=1F.Cl.Cl.CO[C:31]1[C:35](OC)=[N:34][S:33](=[O:39])(=[O:38])[N:32]=1>CO>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:31]2[C:35]([NH:24][CH3:17])=[N:34][S:33](=[O:39])(=[O:38])[N:32]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Agent: Cl
Solvent: CO
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1csc(NC(=N)N)n1
Reaction time: 0.25 h

Procedure:
A solution of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine (from the dihydrochloride, 4.27 g; 14.0 mmoles) in 30 ml of methanol was added to a well stirred suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.50 g; 14.0 mmoles) in 250 ml of methanol at 10°. After 15 minutes at 10°, the solution was cooled to 1° in a cooling bath and anhydrous methylamine was bubbled into the solution for 10 minutes. The reaction mixture was evaporated under reduced pressure and the residue placed on 60 g of silica gel and chromatographed using a gradient elution of methylene chloride-methanol. The appropriate fraction containing 4.53 g of product was placed on 80 g of aluminum oxide and rechromatographed using a gradient elution of ethyl acetate-methanol. The appropriate fractions were combined and evaporated to give a foam which crystallized from methanol to yield (2.38 g) of the title compound, mp 196°-198° (dec).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:29])[CH2:16][NH:17][C@H:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([OH:28])=[CH:23][CH:24]=3)[CH2:19]2)=[CH:11][C:10]=1[CH2:30][CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:43][C:44]([N:46]([CH3:48])[CH3:47])=[O:45].C(NCC)C>C(Cl)Cl.[Cl-].[Na+].O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:29])[CH2:16][NH:17][C@H:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:43][C:44]([N:46]([CH3:48])[CH3:47])=[O:45])=[CH:23][CH:24]=3)[CH2:19]2)=[CH:11][C:10]=1[CH2:30][CH2:31][O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)CBr
Reactant: Oc1ccc2c(c1)C[C@@H](NC[C@H](O)c1ccc(OCc3ccccc3)c(CCOCc3ccccc3)c1)CC2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCNCC
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)COc1ccc2c(c1)C[C@@H](NC[C@H](O)c1ccc(OCc3ccccc3)c(CCOCc3ccccc3)c1)CC2
Temperature: 25 °C
Yield: 78.4 %

Procedure:
(-)-(1R)-1-[4-Benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylamino)ethanol (450 mg) was dissolved in 4 ml of methylene chloride, 860 μl of 5 N aqueous sodium hydroxide solution and 143 mg of 2-bromo-N,N-dimethylacetamide were added to the solution with stirring at room temperature in that order, and the mixture was subjected to 3 hours of reaction at room temperature. Then, 143 mg of 2-brorno-N,N-dimethylacetamide was additionally added to the reaction solution, and the mixture was subjected to 1 hour of reaction at room temperature. Then, 267 μl of diethylamine was added and the mixture was stirred for 30 minutes. Brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by aminopropylated silica gel medium pressure liquid column chromatography (eluent: ethyl acetate) to give 410 mg of (-)-2-[(2S)-2-[[(2R)-2-[4-benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-hydroxyethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy)-N,N-dimethylacetamide in an oily form.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([OH:19])=[C:14]([CH3:20])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9]/[C:10](/[C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([OH:19])=[C:14]([CH3:20])[CH:13]=2)=[N:29]\[OH:30])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(CC(=O)c1cc(C)c(O)c(C)c1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1cc(C)c(O)c(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 3-(4-bromo-phenyl)-1-(4-hydroxy-3,5-dimethyl-phenyl)-3-o-tolyl-propan-1-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing less than 10% of the corresponding Z isomer as an off-white solid, MS (ESI+): m/z=436.2 [M−H]−.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[CH:18]=2)[NH:13][CH:12]=1)=O.O.NN.[OH-].[K+].O>C(O)COCCO>[F:1][C:2]1[C:3]([CH2:9][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)[CH:18]=3)[NH:13][CH:12]=2)=[CH:4][CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C(c1cccc(O)c1F)c1c[nH]c2ncc(-c3cccs3)cc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: Oc1cccc(Cc2c[nH]c3ncc(-c4cccs4)cc23)c1F

Procedure:
To (2-fluoro-3-hydroxy-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (P-0521, 50.0 mg, 0.15 mmol) in diethylene glycol (5.0 mL) were added hydrazine hydrate (1.0 mL, 0.020 mol) and potassium hydroxide (200.0 mg, 3.56 mmol). The reaction mixture was heated in a CEM Discovery microwave instrument at 180° C. for 20 minutes, poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The desired compound was isolated by silica gel column chromatography eluting with 5% methanol in methylene chloride to give a white solid (P-0052, 10 mg, 20%). MS(ESI) [M+H+]−=325.2.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-])([CH3:3])[CH3:2].[C:11]([Si](C)(C)C)#[N:12].C(N(CC)C(Cl)=O)C.C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=1)#[N:12]
Reactant: CC(C)c1cccc[n+]1[O-]
Reactant: C[Si](C)(C)C#N
Agent: CCN(CC)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: CC(C)c1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.8 %

Procedure:
A mixture of 2-isopropylpyridine-N-oxide (104, 1.33 g, 9.7 mmol), cyanotrimethyl-silane (TMS-CN) (1.42 mL, 1.06 g, 11.0 mmol) in 1,2-dichloroethane (40 mL) was stirred at room temperature for 5 min. Then, diethylcarbamoylchloride (Et2NCOCl, 1.23 mL, 9.7 mmol) was added and the mixture was stirred at room temperature under inert atmosphere. After 2 days, a aqueous solution of potassium carbonate (10%) was added and the stirring was continued for 10 min. The organic layer was separated, and the water layer was extracted twice with 1,2-dichloroethane. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (Hexanes/AcOEt, 3:1) to give 1.06 g (74%) of the title compound: m/z=147 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@@H:21]([OH:29])[CH2:22][C@@H:23]([OH:28])[CH2:24][C:25]([O-:27])=[O:26])[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@@H:10]([OH:30])[CH2:9]1)=[O:6])[CH3:4].[Na+].[OH-].[Na+].C(#N)C>C(O)C.O>[CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@@H:21]([OH:29])[CH2:22][C@@H:23]([OH:28])[CH2:24][C:25]([OH:27])=[O:26])[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@@H:10]([OH:30])[CH2:9]1)=[O:6])[CH3:4]
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)[O-])[C@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC#N
Product: CC[C@H](C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)O)[C@H]21
Temperature: 50 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Pravastatin sodium (5 g) was dissolved in a 1:1 mixture of ethanol:water (5 ml). The pH was raised to 8.5 by addition of 2M sodium hydroxide in water (1.2 ml) and the solution was heated to 50° C. Acetonitrile (90 ml) was added to the mixture and then the mixture was stirred at elevated temperature for one hour. The mixture was allowed to cool to 20-25° C. (“ambient temperature”), was held at ambient temperature for two hours and then cooled to 5° C. and maintained at 5° C. for 12 hours, whereupon pravastatin sodium crystallized. The crystals were then isolated by filtration and washed with acetonitrile (2×10 ml) and dried under vacuum at 50° C. X-ray diffraction analysis revealed the presence of Form A. Pravastatin Form A was obtained in 92% yield.
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.[C:29]([C:31]1[CH:32]=[C:33]([NH:37][C:38](=[O:51])[O:39][CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45](Br)=[CH:44][C:43]=2[CH2:49][CH3:50])[CH:34]=[CH:35][CH:36]=1)#[N:30]>>[C:29]([C:31]1[CH:32]=[C:33]([NH:37][C:38]([O:39][CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([B:25]([OH:27])[OH:26])=[CH:44][C:43]=2[CH2:49][CH3:50])=[O:51])[CH:34]=[CH:35][CH:36]=1)#[N:30]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Reactant: CCc1cc(Br)ccc1CCOC(=O)Nc1cccc(C#N)c1
Product: CCc1cc(B(O)O)ccc1CCOC(=O)Nc1cccc(C#N)c1
Yield: 61 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 56A (630 mg, 1.69 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 56B (350 mg, 61%) as a solid. 1H NMR (400 MHz, MeOD-d4) δ ppm 0.98 (t, 3 H) 2.42 (q, 2 H) 2.73 (t, 2 H) 4.10 (t, 2 H) 6.82 (d, 1 H) 7.02 (d, 1 H) 7.09 (t, 2 H) 7.15 (t, 1 H) 7.36 (d, 1 H) 7.58-7.63 (m, 1 H).
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:7]=3[NH:8][C:9](=[O:10])[C:4]2=[N:3][CH:2]=1.CS(C)=O.O.[C:23]([OH:27])(=[O:26])[CH:24]=[O:25].[H-].[Na+]>O.C(O)(=O)C>[O:10]=[C:9]1[NH:8][C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[CH:17]([CH:24]([OH:25])[C:23]([OH:27])=[O:26])[C:6]=2[N:5]2[CH:1]=[CH:2][N:3]=[C:4]12
Reactant: O=CC(=O)O
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C(O)C1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Temperature: 20 °C
Reaction time: 18 h
Yield: 63.9 %

Procedure:
To a stirred mixture of 6.7 g of 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 140 ml of dimethyl sulphoxide and 4.15 g of glyoxylic acid monohydrate, under an argon atmosphere, are added portionwise 4.95 g of 80% sodium hydride while maintaining the temperature at about 20° C. The stirring is continued for 18 hours, and the reaction medium is acidified using acetic acid (11 ml) and is heated at a temperature in the region of 80° C. for 2 hours. The reaction mixture is filtered and the solid is washed with acetone (3×75 ml), with methanol (75 ml), again with acetone (2×75 ml) and dried under vacuum (1 mmHg; 0.13 kPa). The light-beige-coloured solid obtained (10.1 g) is dissolved in 500 ml of distilled water and the aqueous solution is washed with ethyl acetate (2×100 ml), then treated with 0.5 g of animal black and filtered. The filtrate is acidified with 45 ml of 1N hydrochloric acid and the precipitate formed is filtered off, washed with distilled water (50 ml) and with acetone (3×75 ml), and dried at 70° C. under vacuum (1 mmHg; 0.13 kPa). 5.7 g of (4,5-dihydro-4-oxo-10H-imidazo(1,2-a]indeno[1,2-e]pyrazin-10-yl)glycolic acid are obtained in the form of a pale yellow solid melting above 260° C. (1H NMR spectrum (200 MHz, (CD3)2 SO-d6, δ in ppm): 4.60 (d, J=3 Hz, 1H: H 10); 5.09 (d, J=3 Hz, 1H: CHO); 5.60 (broad mult., 1H: OH); from 7.25 to 7.50 (mt, 2H: H 7 and H 8); 7.45 and 7.85 (2 broad d, J=7.5 Hz, 1H each: H 6 and H 8); 7.57 and 8.23 (2 broad s, 1H each: H of the imidazole); 12.35 (broad s, 1H: NH 5)).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]2([CH3:16])[CH3:15])#[CH:2].[CH2:17]([O:19][C:20](=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][C:23]=1[F:29])[CH3:18].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:17]([O:19][C:20](=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[O:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]3([CH3:16])[CH3:15])=[CH:24][C:23]=1[F:29])[CH3:18]
Reactant: C#Cc1ccc2c(c1)C(C)(C)CC(C)(C)O2
Reactant: CCOC(=O)Cc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)(C)O3)cc1F

Procedure:
Following general procedure F and using 6-ethynyl-2,2,4,4-tetramethylchroman (0.204 g, 0.95 mmol), ethyl-2-fluoro-4-iodo phenyl acetate (Reagent C, 0.263 g, 0.86 mmol), triethyl amine, tetrahydrofiran, copper(I)iodide (0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as the eluent, the title compound was obtained (0.21 g, 62%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]2=[CH:4][C:3]=1[CH:13]=[O:14].C(=O)([O-])[O-].[K+].[K+].[CH:21]1([CH2:26][NH:27][CH2:28][CH3:29])[CH2:25][CH2:24][CH2:23][CH2:22]1.O>CN(C=O)C>[CH:21]1([CH2:26][N:27]([CH2:28][CH3:29])[C:2]2[N:7]=[C:6]3[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]3=[CH:4][C:3]=2[CH:13]=[O:14])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1nn(C)c2nc(Cl)c(C=O)cc12
Reactant: CCNCC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC1CCCC1)c1nc2c(cc1C=O)c(C)nn2C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
A suspension of 6-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (5 g, 0.023 mol) and potassium carbonate (9.9 g, 0.0717 mol) in DMF (75 mL) was stirred for 20 min at RT. Cyclopentylmethyl ethyl amine (4.25 g, 33.0 mmol) was then added and the reaction was refluxed for 8 h. After cooling the reaction to RT, water (500 mL) was added to the reaction mixture and extracted with ethyl acetate (3×400 mL) and the combined organic layers were dried and concentrated. The residue was purified by silica gel (100-200 mesh) column chromatography. Elution with 10% ethyl acetate in hexanes gave the pure product as a colorless, gummy mass (yield: 76%).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[N+:7]([CH3:10])([O-:9])=[O:8].N12CCCC1=NCCC2>C(O)(C)C>[N+:7]([CH2:10][CH:3]1[CH2:4][CH2:5][C:1](=[O:6])[CH2:2]1)([O-:9])=[O:8]
Reactant: O=C1C=CCC1
Reactant: C[N+](=O)[O-]
Agent: C1CN=C2CCCN2C1
Solvent: CC(C)O
Product: O=C1CCC(C[N+](=O)[O-])C1
Reaction time: 5 h
Yield: 88 %

Procedure:
100 g of 2-cyclopentenone are dissolved together with 666 ml of nitromethane and 5 g of 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) in 1.1 l of isopropanol, and the solution is left to stand at room temperature for 5 h. The isopropanol is then substantially distilled in vacuo, and the residue is dissolved in ethyl acetate and the solution is washed twice with 0.5 l of dilute sulphuric acid each time. The organic phase is dried with sodium sulphate and evaporated. In this way 154 g (88% of theory) of 3-(nitromethyl)cyclopentanone are obtained sufficiently pure for the next reaction.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.Br[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:1]2[C:5]3=[CH:6][N:7]=[CH:8][CH:9]=[C:4]3[CH:3]=[CH:2]2)=[CH:12][CH:13]=1
Reactant: Clc1ccc(Br)cc1
Reactant: c1cc2cc[nH]c2cn1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Clc1ccc(-n2ccc3ccncc32)cc1
Yield: 91 %

Procedure:
A suspension of 1H-pyrrolo[2,3-c]pyridine (1.18 g, 10.0 mmol), 1-bromo-4-chlorobenzene (2.87 g, 15.0 mmol), copper(I) iodide (95.0 mg, 0.50 mmol), K3PO4 (4.46 g, 21.0 mmol) and trans-diaminocyclohexane (250 μL, 2.00 mmol) in 1,4-dioxane (15 mL) was heated to reflux for 5 days. The mixture was concentrated and the residue was purified by flash chromatography (EtOAc) to yield the title compound as a light brown solid (2.08 g, 90%). MS (ESI+) m/z=229, 231 (M+H)+.