Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:16][O:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCCCCC1c1cccc(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1cccc(C2CCCCNC2=O)c1

Procedure:
A suspension of hexahydro-3-(3-hydroxyphenyl)-2H-azepin-2-one (4.1 g), anhydrous potassium carbonate (5.6 g) and dimethyl sulphate (2.52 g) was heated under reflux with stirring in acetone (50 ml). After cooling the solution was filtered and evaporated to dryness under reduced pressure. The product was recrystallised from diisopropyl ether/ethyl acetate affording the title compound, identical to that obtained by the method of Example 1.
Reaction SMILES: C[CH2:2][N:3](C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.NC1N=CN=C(N[C@H]([C:53]2[N:54]=[C:55]3[CH:60]=[CH:59][CH:58]=[C:57]([C:61]([OH:63])=O)[N:56]3[C:64]=2[C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)C)C=1C#N.CN>CN(C=O)C>[CH3:2][NH:3][C:61]([C:57]1[N:56]2[C:64]([C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=3)=[CH:53][N:54]=[C:55]2[CH:60]=[CH:59][CH:58]=1)=[O:63]
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(C(=O)O)n2c1-c1ccccc1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc2ncc(-c3ccccc3)n12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of DIEA (0.207 mL, 1.18 mmol), PyBOP (0.768 g, 1.475 mmol), and (S)-2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-3-phenylimidazo-[1,2-a]pyridine-5-carboxylic acid (0.236 g, 0.590 mmol) in DMF (3.93 mL) was added methanamine (2.0M in THF, 0.738 mL, 1.48 mmol). The solution was stirred at rt for 1 h then was loaded onto silica gel and purified by MPLC (eluted with a gradient of 0-10% MeOH in DCM) to afford a solid that was repurified by reverse phase analytical HPLC (eluted with a gradient of 10-60% MeCN in water with 0.1% TFA) to afford (S)-2-(14(6-amino-5-cyanopyrimidin-4-yl)amino)-ethyl)-N-methyl-3-phenylimidazo[1,2-a]pyridine-5-carboxamide as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (d, J=6.65 Hz, 3H) 2.16 (d, J=4.70 Hz, 3H) 5.29 (quin, J=6.90 Hz, 1H) 6.83 (d, J=7.63 Hz, 1H) 6.93 (dd, J=6.85, 1.17 Hz, 1H) 7.18-7.46 (m, 8H) 7.74 (dd, J=9.00, 1.17 Hz, 1H) 7.94 (s, 1H) 8.51 (q, J=4.56 Hz, 1H). LC-MS (ESI) m/z 413.1 [M+H]+.
Reaction SMILES: [Li][CH2:2]CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[N:8]=1.IC>C1COCC1>[Cl:6][C:7]1[CH:12]=[C:11]([CH3:2])[CH:10]=[C:9]([Cl:13])[N:8]=1
Reactant: [Li]CCCC
Reactant: Clc1cccc(Cl)n1
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc(Cl)nc(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
A solution of n-BuLi (21.1 mL, 33.8 mmol, 1.6 M) in THF is cooled to −78° C. before a solution of 2,6-dichloropyridine (5.0 g, 33.8 mmol) in THF (36 mL) is added dropwise over a period of 20 min. The reaction mixture is stirred at −78° C. for 30 min, and then iodomethane (4.79 g, 33.8 mmol) is added. The mixture is stirred for 30 min before it is quenched with sat. aq. NH4Cl solution at −78° C. The mixture is extracted with diethyl ether, the org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 19:1 to give 2,6-dichloro-4-methyl-pyridine (2.34 g) as a colourless oil containing the regio isomer 2,6-dichloro-3-methyl-pyridine; LC-MS: tR=0.89 min, [M+1]+=161.97.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=O)=[CH:15][CH:14]=3)[C:9]2=[O:24])=[CH:4][CH:3]=1.[NH3:25]>O1CCCC1.CN(C)C=O>[NH2:25][C:21]([CH2:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([N:10]2[CH2:11][CH2:12][N:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[C:9]2=[O:24])=[CH:18][CH:17]=1)=[O:23]
Reactant: O=C(O)CCc1ccc(N2CCN(c3ccc(Br)cc3)C2=O)cc1
Reactant: N
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)CCc1ccc(N2CCN(c3ccc(Br)cc3)C2=O)cc1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
9.2 g of 3-(4-bromophenyl)-1-[4-(2-carboxyethyl)phenyl]-imidazolidin-2-one are mixed with 3.8 g of N,N'-carbonyldiimidazole in a mixture of 50 ml of tetrahydrofuran and 25 ml of dimethylformamide and the resulting mixture is stirred for 2.5 hours at 80° C. After cooling, it is poured onto a mixture of 20 ml of concentrated aqueous ammonia and 100 g of ice and stirred for 15 minutes. The product is suction filtered and dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:13]C)=[C:6]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8][CH2:7]2.[Cl-].[Al+3].[Cl-].[Cl-].Cl.ClCCl>ClCCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8][CH2:7]2
Reactant: COc1ccc(F)c2c1CCCC2=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C1CCCc2c(O)ccc(F)c21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 8-fluoro-5-methoxytetralone (Owton, W. M. J. Chem. Soc., Perkin Trans. 1 (1994), 2131-2135) (7.0 g, 36 mmol) in 1,2-dichlorethane (150 mL) was treated with aluminum chloride-(21 g, 157 mmol), refluxed for 3.5 hours, cooled to ambient temperature, poured carefully into 4M HCl (500 mL), stirred for 16 hours, treated with dichloromethane (400 mL) and thoroughly shaken. A black solid was removed by filteration through Celite®. The dichloromethane layer was isolated, combined with the black solid and extracted with 5% sodium hydroxide solution (3×150 mL). The combined sodium hydroxide extracts were acidified with 4M hydrochloric acid and the resulting solid was collected by filtration to provide the desired product as a brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([O:19]C)=[O:18])[C:5]([CH3:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O[Li].O>O1CCOCC1.CN(C=O)C.CCN(CC)CC.C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Pd].O.CO.CCOC(C)=O>[C:38]([O:37][C:35]([N:32]1[CH2:33][CH2:34][CH:29]([C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:2]3[N:7]=[C:6]([CH2:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[CH2:16][C:17]([OH:19])=[O:18])[C:5]([CH3:21])=[CH:4][N:3]=3)=[CH:24][CH:25]=2)[CH2:30][CH2:31]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Cl)ncc1C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cnc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1CCc1ccccc1CC(=O)O
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a suspension of methyl 2-(2-((2-chloro-5-methylpyrimidin-4-yl)ethynyl)phenyl)acetate (K7) (110 mg, 0.366 mmol) in 1,4-dioxane (5 mL) was added tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (101 mg, 0.366 mmol), Cs2CO3 (477 mg, 1.46 mmol), Pd2(dba)3 (33 mg, 0.037 mmol) and Xantphos (63 mg, 0.11 mmol). The resulting suspension was degassed with nitrogen for 5 minutes then heated under microwave irradiation for 30 minutes at 120° C. The volatiles were removed under reduced pressure and the residue was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.) to give a yellow oil. A suspension of 10% Pd/C (100 mg) in DMF (10 mL) and Et3N (1 mL) was added and the resulting mixture stirred under an atmosphere of hydrogen for 16 hours. EtOAc (60 mL) was added and the resulting mixture filtered through Celite. The filtrate was evaporated under reduced pressure and the residue was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridges, 0-60% EtOAc in petroleum benzine 40-60° C.) to give a yellow oil. This was taken up in THF (7 mL), MeOH (7 mL) and H2O (1.5 mL) to which LiOH.H2O (115 mg, 2.74 mmol) was added. The resulting mixture was stirred at room temperature overnight then the volatiles were removed under reduced pressure. The residue was partitioned between EtOAc (50 mL) and aqueous HCl (2 M; 50 mL) then the layers were separated. The aqueous phase was extracted with EtOAc (2×50 mL) then the organics were combined, washed with brine and dried over MgSO4. The volatiles were removed in vacuo to give the title compound A55 as yellow oil (127 mg, 87%); LCMS-A: rt 6.272 min; m/z 531 [M+H]+.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][CH2:19][OH:20].C(N(CC)CC)C>ClCCl>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][CH:19]=[O:20]
Reactant: OCCCc1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=CCCc1ccccn1
Reaction time: 0.33 h

Procedure:
Dimethyl sulphoxide (3.3 ml) was added dropwise to a solution of oxalyl chloride (3.9 ml) in dichloromethane (25 ml) at -78° under nitrogen. After gas evolution had ceased (5 min) a solution of 2-pyridinepropanol (4.0 g) in dichloromethane (20 ml) was added over 5 min and the solution stirred at -78° for 20 min. Triethylamine (5 ml) was added dropwise to the solution, then the resulting dark green mixture warmed to 20° and washed with 2M sodium carbonate solution (20 ml). The organic phase was dried and evaporated in vacuo to give 2-pyridinepropanal. This aldehyde was immediately dissolved in THF (30 ml) and added dropwise to a 3M solution of methylmagnesium chloride in THF (20 ml) at 0°-5° under nitrogen. After 1 h, water (10 ml) was cautiously added followed by sufficient 2M hydrochloric acid to dissolve all the magnesium residues (resulting pH~7 ). The solution was extracted with dichloromethane (3×30 ml) and the organic extracts dried and evaporated in vacuo to a dark oil. Kugelrohr bulb to bulb distillation (b.p. 130°-135°/0.7 mm) afforded the title compound as a pale yellow oil (0.91 g), t.l.c. ethyl acetate Rf 0.17.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][C:10](=[O:14])[NH:11]2)=[CH:7][CH:6]=1)#[N:4].Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1>>[C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[C:23]([O:26][CH3:27])[CH:24]=4)[N:19]=[CH:18][N:17]=3)[C:10](=[O:14])[NH:11]2)=[CH:7][CH:6]=1)#[N:4]
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: N#Cc1ccc2c(c1)NC(=O)C2
Agent: [H-]
Agent: [Na+]
Product: COCCOc1cc2ncnc(C3C(=O)Nc4cc(C#N)ccc43)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
Sodium hydride (100 mg, 2.6 mmol) was added to a solution of 6-cyanooxindole (350 mg, 2.2 mmol) in dry degassed DMF (10 ml) under argon and the suspension stirred for 30 minutes at ambient temperature. A solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (200 mg, 0.74mmol), (prepared as described for the starting material in Example 2), in dry degassed DMF (2 ml) was added dropwise and the reaction mixture was heated at 60° C. for 2 hours. The mixture was allowed to cool and the DMF was removed by evaporation and the residue was partitioned between ethyl acetate (50 ml) and water (50 ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (50 ml×3). The organic extracts were combined, dried (MgSO4) and the solvent removed by evaporation. The solid residue was purified by flash column chromatography eluting with methylene chloride/methanol/ammonia (99/1/1 and then 95/5/1). The purified solid was triturated in hot ether and collected by filtration and then triturated in hot methylene chloride/methanol (1/1), collected by filtration and dried to give 4-(6-cyanooxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline (84 mg, 29%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH2:16]=[O:17].B(O)(O)O.Cl>CCOCC.CCCCC.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH2:16][OH:17])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: C=O
Agent: Cl
Agent: OB(O)O
Solvent: CCCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)c1cc(CO)c(O)c(C(C)(C)C)c1
Temperature: 80 °C

Procedure:
2,4-Di-t-butylphenol (20.63 gr., 0.1 mole), paraformaldehyde (3.0 gr., 0.1 mol), boric acid (6.18 g., 0.1 mol) and toluene (50 ml.) were charged into a flask and heated at 80° C. under nitrogen for 48 hours. The mixture was filtered and the solvent removed to provide a brown oil. This oil was dissolved in ether and stirred with an equal volume of 1 N HCl for 2 hours. The ether layer was removed, washed with water, dried (MgSO4) and evaporated to form a soft yellow solid. This solid was stirred in pentane and then filtered to afford a white solid with a melting point of 97°-99° C. The structure was confirmed by NMR and FD/MS.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH3:20])[C:12](=[C:13]=[S:14])[C:11](=[C:15]=[S:16])[CH2:10][CH2:9][C:8]2=[CH:17][CH:18]=[O:19])[CH:2]=1.[BH4-].[Na+].C(OCC)(=O)C.O>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH3:20])[C:12](=[C:13]=[S:14])[C:11](=[C:15]=[S:16])[CH2:10][CH2:9][C:8]2=[CH:17][CH2:18][OH:19])[CH:2]=1
Reactant: CC1(c2cccnc2)C(=C=S)C(=C=S)CCC1=CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(c2cccnc2)C(=C=S)C(=C=S)CCC1=CCO
Yield: 66.7 %

Procedure:
A solution of 2-(pyrid-3-yl)-2-methyldithiocarbonyl-1-formylmethylenecyclohexane (890 mg, 3 mmol) in methanol (20 ml) at 25° C. was treated with sodium borohydride (127 mg, 3.36 mmol). After 30 mins at 25° C. the solution was treated with ethyl acetate (50 ml) and water (20 ml) was added dropwise. The organic phase was removed and dried over magnesium sulphate. Concentration in vacuo yielded a crude oil. Purification over silica gel, eluting with ethyl acetate/n-hexane (7:3) afforded 2-(pyrid-3-yl)-2-methyldithiocarbonyl-1-(2-hydroxyethylidene)cyclohexane (590 mg, 2 mmol) as an orange solid, m.p. 139°-140° C.;
Reaction SMILES: [Al].[Li].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:8][C:9]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13](=O)[NH:14]2.[CH3:21][CH2:22][O:23]CC>>[C:22]([N:14]1[C:15]2[C:10](=[C:9]([CH3:8])[CH:18]=[C:17]([CH3:19])[CH:16]=2)[CH2:11][CH2:12][CH2:13]1)(=[O:23])[CH3:21]
Reactant: Cc1cc(C)c2ccc(=O)[nH]c2c1
Reactant: CCOCC
Agent: [Al+3]
Agent: [Al]
Agent: [Cl-]
Product: CC(=O)N1CCCc2c(C)cc(C)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium aluminum. hydride (687 mg) was suspended in ether (16 ml), and aluminum chloride (4.2 g) was added. A solution of 5,7-dimethylquinolone (1.6 g) in ether (16 ml) was dropwise added and the mixture was refluxed for 0.5 hr. The reaction mixture was poured into ice water (100 ml) and extracted with chloroform (100 ml). After washing with water, the chloroform layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained 5,7dimethyl-1,2,3,4-tetrahydroquinoline was dissolved in chloroform (30 ml), and acetic anhydride (929 mg) was added, which was followed by stirring at room temperature for 1 hr. Chloroform (100 ml) was added to the reaction mixture, and the mixture was washed successively with saturated aqueous solution of sodium hydrogencarbonate and water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/benzene=1/5−1/1) to give 1.5 g of oily 1-acetyl-5,7-dimethyl-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([NH:13][NH2:14])=[O:12])=[CH:5][CH:4]=1.[N+:15]([C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16]>CO>[N+:15]([C:18]1[O:22][C:21]([CH:23]=[N:14][NH:13][C:11](=[O:12])[CH:10]=[CH:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: COc1ccc(C=CC(=O)NN)cn1
Solvent: CO
Product: COc1ccc(C=CC(=O)NN=Cc2ccc([N+](=O)[O-])o2)cn1

Procedure:
To a solution, heated to 50°-60° C., of 0.9 g (4.66 mmol) of 3-(6-methoxy-3-pyridyl)-2-propenoic acid hydrazide in 50 ml of methanol, 0.66g (4.7 mmol) of 5-nitrofuran-2-carbaldehyde is added.
Reaction SMILES: [H-].[CH2:2]1[O:6][C:5]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:4]=2[O:3]1.Cl[CH:13]([C:19]([CH3:21])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15].O>CN(C=O)C>[CH2:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH:13]([C:19]([CH3:21])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][C:5]=2[O:6]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Oc1ccc2c(c1)OCO2)C(C)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.2 %

Procedure:
In 1 L DMF, sodiul hydride (8.7 g, 0.36 mole, 1 eq.) was added under N2 at room temperature. Then sesamol (50 g, 0.36 mole) was added portionwise to the reaction mixture and stirred 20 minutes at room temperature. Ethyl 2-chloroacetoacetate (59.6 g, 1 eq.) was added slowly and the mixture was heated to 100° C. using an oil bath for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate, dried over magnesium sulfate and evaporated. The residue was flash chromatographed using hexane ethyl acetate 10%, to give: 50 g (52% yield) of ethyl 2-(3,4-methylenedioxyphenoxy)acetoacetate.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][Si:11]([CH2:14][CH2:15][O:16][CH2:17]Cl)([CH3:13])[CH3:12].[CH2:19]([O:26][C:27]1[CH:28]=[C:29]([CH:34]=[C:35]([C:37]2[NH:41][N:40]=[N:39][N:38]=2)[CH:36]=1)[C:30]([O:32][CH3:33])=[O:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:19]([O:26][C:27]1[CH:28]=[C:29]([CH:34]=[C:35]([C:37]2[N:41]([CH2:17][O:16][CH2:15][CH2:14][Si:11]([CH3:13])([CH3:12])[CH3:10])[N:40]=[N:39][N:38]=2)[CH:36]=1)[C:30]([O:32][CH3:33])=[O:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(-c2nnn[nH]2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1cc(OCc2ccccc2)cc(-c2nnnn2COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
With cooling with ice, diisopropylethylamine (1.5 mL) and trimethylsilylethoxymethyl chloride (1.6 mL) were added to a CHCl3 (70 mL) solution of methyl 3-benzyloxy-5-(tetrazol-5-yl)benzoate (2.32 g), and stirred at room temperature for 1 hour. Sodium bicarbonate water was added to the reaction liquid, and extracted with chloroform. The organic layer was washed with water and saturated saline water, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound as a brown oil. Not purified, this was used in the next step.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:6].[NH:23]1C=CN=[CH:24]1>>[N:2]1([CH2:3][CH2:4][C:5]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:6])[CH:1]=[CH:24][N:23]=[CH:22]1
Reactant: c1c[nH]cn1
Reactant: CN(C)CCC(=O)c1c(-c2ccccc2)[nH]c2ccccc12
Product: O=C(CCn1ccnc1)c1c(-c2ccccc2)[nH]c2ccccc12

Procedure:
3-(Dimethylamino)-1-(2-phenyl-1H-indol-3-yl)-1-propanone was converted to the methiodide (36 g) which was then reacted with imidazole (34 g) to give a solid which was crystallised from methanol, to give the title compound (15.40 g), m.p. 206°-208°; λmax (EtOH) 255 nm (ε19,650), λmax 307.5 nm (ε12,840), identical with the material obtained in Example 3.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(CBr)c(F)c1
Temperature: 68 °C
Yield: 60.5 %

Procedure:
To a solution of 1-methyl-2-fluoro-4-nitrobenzene (4.96 g, 32 mmol) and NBS (6.05 g, 34 mmol) in CCl4 (80 mL) was added BPO (0.39 g, 1.6 mmol). The mixture was heated at 68° C. for 5 h, then filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=20:1) to give the title compound as a yellow solid (4.53 g, 60%).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]([CH3:20])[C:18]#[N:19])=[CH:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]([CH3:20])[C:18]#[N:19])=[CH:9]1
Reactant: CC(C#N)c1cn(C(=O)OC(C)(C)C)c2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C#N)c1c[nH]c2ccccc12
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a stirred solution of 2-(1-tert-butoxycarbonylindol-3-yl)propionitrile (4.00 g, 14.8 mmol) in DCM (10 mL) was added TFA (10 mL) with caution. After 1 hour, the reaction was diluted with DCM (40 mL), washed with water (2×40 mL) and brine, then dried (Na2SO4), and concentrated under reduced pressure to give 2-(1H-indol-3-yl)propionitrile (2.5 g, 99%) as a pale brown solid; 1H-NMR (CDCl3): δ 8.25 (1H, d), 7.69 (1H, s), 7.65 (1H, d), 7.45 (1H, app t), 7.37 (1H, app t), 4.12 (1H, q), 1.79 (3H, d).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:39]1[NH:44][CH2:43][CH2:42][N:41]2[CH2:45][CH2:46][CH2:47][CH2:48][CH:40]12>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:44]3[CH2:43][CH2:42][N:41]4[CH2:45][CH2:46][CH2:47][CH2:48][CH:40]4[CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: C1CCN2CCNCC2C1
Product: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN2CCCCC2C1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with octahydro-pyrido[1,2-a]pyrazine (Aldrich) to give the title compound as a mixture of diastereomers. HR-MS (ES, m/z) calculated for C39H49N4O2Cl2 [(M+H)+] 675.3227, observed 675.3224.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:14])[C:8](=[O:13])[N:9]2[OH:12])=[CH:4][CH:3]=1.[N+:15]([O-])([O-:17])=[O:16].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:14])[C:8](=[O:13])[N:9]2[OH:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: O=c1[nH]c2ccc(F)cc2n(O)c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2n(O)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
In 20 ml of sulfuric acid was dissolved 1.34 g of 7-fluoro-1-hydroxyquinoxaline-2,3-(1H,4H)-dione followed by addition of 0.76 g of potassium nitrate under ice-cooling. The mixture was cooled to at room temperature, and after 1 hour, the reaction mixture was poured in ice-water. The resulting crystals were recovered by filtration, rinsed with water and recrystallized from ethanol-water to provide 0.82 g (50%) of 7-fluoro-1-hydroxy-6-nitroquinoxaline-2,3-(1H,4H)-dione.