Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][C:21]4[N:22]([C:24](Br)=[CH:25][N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:35](B1OB(C=C)OB(C=C)O1)=[CH2:36].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][C:21]4[N:22]([C:24]([CH:35]=[CH2:36])=[CH:25][N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nn4c(Br)cnc4cc3-c3ccccc3)cc2)CCC1
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C=Cc1cnc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn12
Reaction time: 0.5 h

Procedure:
133 mg (0.256 mmol) {1-[4-(3-Bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, intermediate example Int-2-1, 61.6 mg (0.256 mmol) 2,4,6-trivinyl-cyclotriboroxane, 29.6 mg (0.026 mmol) tetrakis triphenylphosphine palladium(0) and 35.4 mg (0.256 mmol) potassium carbonate in 2 mL dimethoxyethane and 0.7 mL water were heated in a microwave vial (heating block) at 110° C. for 16 hours. The reaction mixture was poured on water/saturated ammonium chloride/dichloromethane and vigorously stirred for 30 minutes. The organic phase was separated, washed with brine, dried, and the solvent was removed. The crude product (168 mg>100%) was used in the next step without further purification.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([C:15](=O)[C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=3)=[C:6]([CH2:10][C:11](OC)=[O:12])[CH:7]=2)[O:2]1.O.[NH2:28][NH2:29].C(O)C>>[CH2:1]1[O:2][C:3]2=[CH:4][C:5]3[C:15]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=4)=[N:29][NH:28][C:11](=[O:12])[CH2:10][C:6]=3[CH:7]=[C:8]2[O:9]1
Reactant: COC(=O)Cc1cc2c(cc1C(=O)c1ccc([N+](=O)[O-])c(C)c1)OCO2
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from methyl 4,5-methylenedioxy-2-(3-methyl-4-nitrobenzoyl)phenylacetate (1.4 g, 3.9 mmol) and hydrazine hydrate (1.0 mL, 18 mmol) in ethanol (25 mL) as a yellow solid (0.65 g, 1.9 mmol, 49%), mp: 275°-277° C. 1H NMR (CDCl3) 8.65 (s, 1H), 8.02 (d, J=8.5, 1H), 7.62 (s, 1H), 7.56 (d, J=8.5, 1H), 6.85 (s, 1H), 6.56 (s, 1H), 6.06 (s, 2H), 3.48 (s, 2H), 2.64 (s, 3H). Anal. Calcd. for C17H13N3O5 : C, 60.18; H, 3.86; N, 12.38. Found: C, 60.22; H, 3.83; N, 12.28.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([O:16][CH3:17])[C:7]1=2)C.[OH-].[Li+].Cl>C1COCC1.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([O:16][CH3:17])[C:7]=2[CH:6]([CH2:5][C:4]([OH:19])=[O:3])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(OC)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(O)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.9 %

Procedure:
To a solution of ethyl-2-(1,6-dihydroxy-4-methoxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (133 mg, 0.50 mmol) in THF (2 mL) was added aqueous lithium hydroxide (102 mg, 2.5 mmol) in 3 mL of water at 0° C. The reaction mixture was stirred at room temperature for 1.5 hr and acidified to pH=2 using diluted hydrochloride acid. The resulting mixture was extracted with ethyl acetate (15 mL×2) and the combined organic layers were dried over anhydrous and concentrated in vacuo. The residue was purified by HPLC to give the title as a white solid (63 mg, Yield: 53%). 1H NMR (400 MHz, DMSO-d) δ 9.49 (s, 1H), 9.15 (s, 1H), 6.65 (s, 1H), 6.48 (s, 1H), 5.31-5.34 (m, 1H), 3.77 (s, 3H), 3.04-3.09 (m, 1H), 1.98-2.04 (m, 1H). MS (ESI) m/z=239 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[Cl:13]N1C(=O)CCC1=O>CC(O)=O>[Cl:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2[nH]nc(Cl)c2c1
Temperature: 50 °C
Yield: 43.4 %

Procedure:
5-Nitroindazole (5 g, 30.7 mmol) was suspended in glacial AcOH (150 mL) and the mixture heated to 50° C. N-Chlorosuccinimide (4.9 g, 36.8 mmol) was added and the mixture heated at relux (solution forms) for 1 hour. The reaction mixture was concentrated and partitioned between EtOAc and brine. The organic phase was washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated to a yellow solid. Recrystallisation from EtOH provided the title compound as a pale yellow solid (2.63 g, 43%); 1H NMR (400 MHz, DMSO) δ 7.73 (1H, d), 8.21 (1H, dd), 8.51 (1H, d), 13.97 (1H, brs); MS (ES−) m/e=196.
Reaction SMILES: [N:1]1[C:2]2[N:3]([C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:4]=[CH:5][C:6]=1[C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([F:14])[CH:8]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:26](C)=O.[Na+]>ClCCCl>[N:1]1[C:2]2[N:3]([C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:4]=[CH:5][C:6]=1[C:7]1[CH:13]=[CH:12][C:10]([NH:11][CH3:26])=[C:9]([F:14])[CH:8]=1
Reactant: Nc1ccc(-c2ccn3c(n2)nc2ccccc23)cc1F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: CNc1ccc(-c2ccn3c(n2)nc2ccccc23)cc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 21.4 %

Procedure:
To a suspension of 4-(Benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)-2-fluoroaniline (20 mg, 0.072 mmol) in 1 mL DCE was added paraformaldehyde (4.5 mg, 0.14 mmol), followed by NaBH(AcO)3 (51 mg, 0.24 mmol). The reaction was stirred at rt for 6 h and quenched by adding Na2CO3 (5 mL, saturated). The mixture was extracted with EtOAc (2×10 mL) and the combined organic phase was washed with water (2×20 mL) and concentrated under reduced pressure. The residue was subjected to reversed phase HPLC (TFA buffered water/MeCN) to afford 4-(Benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)-2-fluoro-N-methylaniline as orange solid (4.5 mg, 21%). 1H NMR (400 MHz, methanol-d4): δ 9.10 (d, J=7.2 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 8.01 (d, J=11.2 Hz, 2H), 7.75 (d, J=8.4 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.51 (t, J=7.2 Hz, 1H), 7.38 (d, J=7.2 Hz, 1H), 6.94 (t, J=8.8 Hz, 1H), 2.90 (s, 3H); MS (ESI) m/z [M+H]+293.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:40])[CH2:37][C:38]#[N:39])[CH2:31]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)=[CH:13][CH:12]=3)[C:3]=12.[CH3:41][C:42]([CH3:46])([CH3:45])[CH:43]=O.N1CCCCC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:40])[C:37]([C:38]#[N:39])=[CH:41][C:42]([CH3:46])([CH3:45])[CH3:43])[CH2:31]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:29])[C:19]4[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: CC(C)(C)C=O
Reactant: N#CCC(=O)N1CCCC(n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc3)c3c(N)ncnc32)C1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)C=C(C#N)C(=O)N1CCCC(n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc3)c3c(N)ncnc32)C1
Temperature: 30 °C
Reaction time: 24 h
Yield: 27 %

Procedure:
Into a 50-mL round-bottom flask, was placed N-(4-[4-amino-1-[1-(2-cyanoacetyl)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl)-4-(trifluoromethyl)benzamide (130 mg, 0.24 mmol, 1.00 equiv), 2,2-dimethylpropanal (2 mL), piperidine (1 mL), and methanol (30 mL). The resulting solution was stirred for 24 h at 30° C. in an oil bath. The resulting mixture was concentrated under vacuum and residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50/1 to give 40 mg (27%) of N-[4-(4-amino-1-[1-[2-cyano-2-(2,2-dimethylpropylidene)acetyl]piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]-4-(trifluoromethyl)benzamide as a white solid. MS (ESI, pos. ion) m/z: 617 (M+1), 1HNMR (300MHz, CDCl3, ppm), 8.364 (1H, s), 8.212 (1H,s), 8.086˜8.059(2H,t), 7.929˜7.901 (2H, d,J=8.4), 7.827˜7.800 (2H, d,J=8.1), 7.742˜7.715 (2H, d,J=8.1), 6.963(1H,s), 6.3(2H,s), 5.031˜4.934 (1H,m),4.8˜3.05 (4H,m), 2.738˜2.067 (5H,m), 1.274 (9H,s).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]12[CH2:12][CH:11]([C:13]([OH:15])=O)[C:10]1=[CH:9][CH:8]=[CH:7][CH:6]=2.C1C=CC=CC=1>ClCCl>[C:5]12[CH2:12][CH:11]([C:13]([Cl:3])=[O:15])[C:10]1=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1Cc2ccccc21
Solvent: c1ccccc1
Solvent: ClCCl
Product: O=C(Cl)C1Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (0.5 ml) was added to a solution of bicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid [14381-41-0] (0.001 mol) in dichloromethane. The reaction mixture was refluxed for 1 hour. Then stirred overnight at room temperature. The solvents were co-evaporated 2 times with benzene to obtain bicyclo[4.2.0]octa-1,3,5-triene-7-carbonyl chloride [1473-47-8] which was dissolved in DIPE. The obtained solution was added dropwise to a cooled mixture (0° C.) of N-allyl-2-adamantanamine [24161-63-5] and sodium carbonate in DIPE. The reaction mixture was stirred for 30 minutes on ice and then for 2 hours at room temperature. The mixture was poured out into water and extracted with dichloromethane. The organic layer was filtered through Extrelut™ and the filtrate was evaporated. The residue was purified by flash column chromatography on TRIKONEX FlashTube™ (eluent: CH2Cl2/EtOAc 90/10). The product fractions were collected and the solvents were evaporated, yielding 0.13 g of intermediate 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH:13]([OH:15])[CH3:14])[N:9]=2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13](=[O:15])[CH3:14])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(O)c1noc(-c2ccc(F)cc2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)c1noc(-c2ccc(F)cc2)n1
Reaction time: 3 h
Yield: 63.2 %

Procedure:
To a stirred solution of 1-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)ethanol (0.34 g, 1.92 mmol) in DCM (40 mL) was added Dess-Martin periodinane (2.7 g, 6.5 mmol) at room temperature and the mixture stirred for 3 h. The reaction mixture was filtered and washed with DCM (15 mL). To the filtrate was added NaHCO3 solution (10 mL) and DCM (30 mL). The organic layer was separated, washed with water (20 mL) followed by brine solution (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to get crude compound. The crude compound was purified by silica gel column chromatography (100-200 mesh; using 10% methanol in DCM) to obtain 1-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)ethanone as off-white solid (0.25 g, 72% yield). 1H NMR (400 MHz, CDCl3): δ 2.76 (s, 3H), 7.23 (t, 2H), 7.23 (dd, 2H), LC-MS m/z calculated for [M+H]+ 207.17, found 206.87.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=2)[CH:17]=1.C1N=C[N:30](C(N2C=NC=C2)=O)C=1.[OH-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:30])=[O:23])=[CH:20][N:19]=2)[CH:17]=1
Reactant: Cn1nnc(-c2ccccc2Cl)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccccc2Cl)c1-c1cn(-c2ccc(C(N)=O)cn2)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a solution of 6-(4-(4-(2-chlorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (74 mg, 0.194 mmol) in DMF (3 mL) was added CDI (38 mg, 0.233 mmol) and the resulting mixture stirred at 60° C. for 1 h. After cooling to room temperature ammonium hydroxide (305 μL, 1.94 mmol) was added and reaction mixture was stirred for 1 h and then evaporated. Purification by chromatography (reverse phase HPLC) afforded the title compound (54 mg, 73%) as a white foam. MS: m/e=380.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH:17]([CH2:21][CH:22]=[CH2:23])[C:18](=O)[CH3:19]>C(O)C>[CH2:9]([O:8][C:7]1[C:2]2[N:3]([C:17]([CH2:21][CH:22]=[CH2:23])=[C:18]([CH3:19])[N:1]=2)[CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C=CCC(Cl)C(C)=O
Reactant: Nc1ncccc1OCc1ccccc1
Solvent: CCO
Product: C=CCc1c(C)nc2c(OCc3ccccc3)cccn12
Yield: 7.4 %

Procedure:
A solution of 2-amino-3-benzyloxypyridine (3 g) and 3-chloro-5-hexen-2-one (2.981 g) in ethanol (15 ml) was stirred and refluxed for 45 hours and then evaporated in vacuo. To the residue was added an aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The oily residue was purified by column chromatography on silica gel (50 g) using methylene chloride and then chloroform as eluents. The eluate with chloroform was evaporated in vacuo and the residual solid was recrystallized from diisopropyl ether to give 8-benzyloxy-3-allyl-2-methylimidazo[1,2-a]pyridine (0.31 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[H-].[Na+].Br[CH2:16][CH2:17][Cl:18]>CN(C)C=O>[Cl:18][CH2:17][CH2:16][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5](=[O:12])[C:6]1=[O:11]
Reactant: ClCCBr
Reactant: O=C1Nc2ccc(F)cc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(CCCl)c2ccc(F)cc21
Temperature: 0 °C

Procedure:
5-Fluoro-1H-indol-2,3-dione (8.92 g) was dissolved in dimethylformamide (60 ml). Sodium hydride (60% dispersion in mineral oil, 3.08 g) was added in portions with stirring and cooling (ice-water bath) and the mixture was stirred until gas evolution ceased. 1-Bromo-2-chloroethane (5.4 ml, 9.3 g) was added dropwise. The mixture was stirred at room temperature for 24 hours and then quenched into water and extracted into chloroform. The combined organic phases were washed with water, dried (MgSO4), filtered and concentrated under reduced pressure. The resulting oil was purified by chromatography on silica gel, eluent chloroform, to give 1-(2-Chloroethyl)-5-fluoro-1H-indole-2,3-dione as a red solid.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[NH2:11].C([O-])(=O)C.[Na+].C(O)(=O)C.[Br:21]Br>O>[Br:21][C:10]1[N:2]([CH3:1])[C:3]2[C:8]([N:9]=1)=[C:7]([NH2:11])[N:6]=[CH:5][N:4]=2
Reactant: BrBr
Reactant: Cn1cnc2c(N)ncnc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(Br)nc2c(N)ncnc21
Reaction time: 2 h

Procedure:
Fifteen grams (0.1 mol) of 9-methyladenine of Example 1 was dissolved in 1.5 liters of buffer prepared from 30.8 g of sodium acetate, 1.4 liters of water and sufficient acetic acid to provide a pH of 4.0. To this solution was added dropwise 25 ml of bromine in 2 liters of water over a period of two hours. The reaction was stirred a further two hours and the resulting solid filtered off and rinsed with the water. The solid was air dried and warmed to about 50° in about 80 ml of methanol, stripped to a hazy suspension and filtered. The precipitate after rinsing with water and drying at 40° under vacuum overnight weighed 15.6 g. The filtrate was stripped of methanol and a further 1.6 g was collected. The combined solids were triturated in about 100 ml of acetone for three hours and then allowed to sit overnight. The resulting precipitate was filtered and washed with acetone to yield 13.3 g after drying at 40° on a vacuum pump overnight.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:19])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.CS(C)=[O:22]>>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10](=[O:22])[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[O:19])=[CH:12][CH:13]=1
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Reactant: CS(C)=O
Product: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of 1,2-bis(4-methoxyphenyl)ethan-1-one (1 g, 3.90 mmol) in DMSO (20 mL) was added SeO2 (1.76 g, 15.86 mmol) in several batches at 100° C. over 30 min, and then stirred for 3 hr at this temperature. The reaction was quenched by the addition of water (200 mL) and extracted with dichloromethane (3×50 mL), dried over magnesium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (1%˜10% ethyl acetate in petroleum ether) to afford 1,2-bis(4-methoxyphenyl)ethane-1,2-dione as a brown solid (600 mg, 76%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](O)[C:5]2[CH2:11][O:10][CH2:9][CH2:8][C:6]=2[N:7]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:4]1[C:5]2[CH2:11][O:10][CH2:9][CH2:8][C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Nc1nc(O)c2c(n1)CCOC2
Reactant: O=P(Cl)(Cl)Cl
Product: Nc1nc(Cl)c2c(n1)CCOC2
Yield: 22 %

Procedure:
By reacting 2-amino-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-4-ol (562 mg, 3.36 mmol) and phosphorous oxychloride (3 ml), there was obtained the object compound (136 mg, 22%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1.[N+:13]([O-])([OH:15])=[O:14].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[C:8]=2[N+:13]([O-:15])=[O:14])[N:3]=1
Reactant: Cc1ccc2nc(Cl)ccc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccc2nc(Cl)ccc2c1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
4.12 g of 2-chloro-6-methylquinoline (J. Med. Chem. 1992, pp. 2761-2768) is added at 0° C. to a solution that consists of 15 ml of 100% nitric acid and 2 ml of 96% sulfuric acid. After 4 hours at 0° C., it is added to water, and the product is filtered off. 4.66 g of 2-chloro-6-methyl-5-nitroquinoline is obtained as a beige solid. The latter is reacted for 80 hours at 100° C. in 46 ml of glacial acetic acid and 26 ml of water. The thus obtained 6-methyl-5-nitroquinolin-2(1H)-one is filtered off from the reaction solution. The 3.45 g of product that is obtained is reacted on activated carbon to form aniline with hydrogen under normal pressure in methanol on palladium. 2.89 g of the title compound is obtained as a beige solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].CC(O)=O.[CH3:9][C:10]([CH3:21])([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:11]=[CH2:12]>CC(OC(C)=O)=O>[CH3:9][C:10]([CH3:21])([CH:11]=[CH2:12])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:1]([O-:4])=[O:2]
Reactant: C=CC(C)(C)CCc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: C=CC(C)(C)CCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
In a flask, was loaded fuming HNO3 (18.7 mL, 90%, d=1.5), HOAc (18 mL), Ac2O (14 mL), which was allowed to cool back to room temperature before proceeding. This solution was added dropwise to 3,3-dimethyl-5-phenyl-1-pentene (45.8 g, 0.263 mol), which was prepared using the procedure of Reike and coworkers referenced as 12 in the manuscript, in Ac2O (120 mL). The reaction was kept between 0 and −5° C. during the addition. After the addition, the mixture was stirred at 0° C. for 12 h. The reaction mixture was poured into crushed ice (300 g) The product was extracted with ethyl ether (3×200 mL) and the combined organic layers were washed with portions of saturated NaHCO3 (˜300 mL total) until no gas formed on addition of the basic aqueous solution. The organic solution was filtered, and the separated solids were washed with ether (50 mL). The combined aqueous layers were extracted with ether (3×200 mL). The combined ether solutions were dried with MgSO4. The volatiles were removed in vacuo providing the product as a yellow oil in 97% yield (55.95 g) as a mixture of isomers. GC/FID analysis displayed an ortho:para ratio of 49:51. The compound was used without further purification.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:15]=[C:14]([CH3:16])[C:13]([Cl:17])=[CH:12][C:8]=1[C:9](O)=[O:10]>>[CH3:5][O:6][C:7]1[CH:15]=[C:14]([CH3:16])[C:13]([Cl:17])=[CH:12][C:8]=1[C:9]([Cl:3])=[O:10]
Reactant: COc1cc(C)c(Cl)cc1C(=O)O
Reactant: O=S(Cl)Cl
Product: COc1cc(C)c(Cl)cc1C(=O)Cl
Temperature: 30 °C
Yield: 233.4 %

Procedure:
In a 500 ml flask equipped with a refrigerant, there are introduced 87 g of thionyl chloride and about 31 g of 2-methoxy-4-methyl-5-chlorobenzoic acid and the mixture is heated on a water bath at 30° C. Dissolution occurs almost immediately, followed by reprecipitation. Then 31 g of acid is added. There is obtained a very thick, rose-colored precipitate. 41 g of thionyl chloride are added and the mixture is heated at 50°-55° C. At the end of 3/4 of an hour at this temperature, if dissolution is not complete, heating is continued to dissolution (70°-75° C). The excess thionyl chloride is removed under vacuum. There are obtained 79 g (yield 99%) of 2-methoxy-4-methyl-5-chlorobenzoyl chloride (m.p. 106°-107° C).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][NH:16][C:15]2=[O:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.[NH4+].[OH-]>ClC(Cl)C.CO>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][NH:16][C:15]2=[O:24])[CH2:12][CH2:13]1
Reactant: O=C1NCc2ccccc2N1C1CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CO
Product: O=C1NCc2ccccc2N1C1CCNCC1
Temperature: 25 °C

Procedure:
To a solution of 1-(1-benzyl-4-piperidinyl)-3,4-dihydroquinazolin-2(1H)-one (947 g, 295 mmol) from Step 4 in dry dichloroethane (20 mL) was added 1-chloroethyl chloroformate (0.35 mL, 3.2 mmol). The reaction was refluxed for 3 h. The solvent was rmoved under reduced pressure and the residue was dissolved in MeOH (50 mL) and the solution was refluxed for 1 h. The reaction was cooled to ambient temperature, conc. NH4OH (1 mL) was added, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 90:10:1 CHCl3 :MeOH:NH4OH as eluant. 1-(4-Piperidinyl)-3,4-dihydroquinazolin-2(1H)-one was obtained as an oil (48% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[OH:8].[CH2:9](O)[CH:10]=[CH2:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[O:8][CH2:11][CH:10]=[CH2:9]
Reactant: Oc1cnccc1Cl
Reactant: C=CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCOc1cnccc1Cl
Temperature: 0 °C
Yield: 32.6 %

Procedure:
A solution of diazenedicarboxylic acid diethyl ester (0.1572 mol) in THF (163 ml) was added dropwise to a mixture of 4-chloro-3-pyridinol (0.1429 mol), 2-propen-1-ol (0.1572 mol) and triphenyl-phosphine (0.1572 mol) in THF (276 ml), that was cooled with an ice-water bath and under nitrogen flow. The formed mixture was stirred on the ice-water bath for 15 minutes and at room temperature overnight. The mixture was concentrated under vacuum and the residue was washed with a saturated Na2CO3− solution. The mixture was extracted with DCM and the separated organic layer was dried, filtered and the solvent was evaporated until dry. The residue was treated with DIPE and the formed solid was filtered off and discarded. The filtrate was evaporated until dry and the residue was treated with diethyl ether and the formed solid was filtered off and discarded again. The filtrate was evaporated until dry and the residue was purified by open column chromatography over silica gel (eluent: DCM/2-propanone 99/1;98/2). The product fractions were collected and the solvent was evaporated, yielding 7.9 g of 4-chloro-3-(2-propenyloxy)-pyridine (intermediate (44).