Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:47]=[CH:46][C:5]([C:6]([NH:8][C@:9]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:36]=2)([C:21]2[CH:26]=[C:25]([O:27][C:28]([F:33])([F:32])[CH:29]([F:31])[F:30])[CH:24]=[C:23]([F:34])[CH:22]=2)[CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][CH:12]=2)=[O:7])=[CH:4][C:3]=1[C:48]([F:51])([F:50])[F:49].C([BH-](CC)CC)C.[Li+]>C1COCC1>[F:1][C:2]1[CH:47]=[CH:46][C:5]([C:6]([NH:8][C@:9]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([C:42]([F:43])([F:44])[F:45])[CH:36]=2)([C:21]2[CH:26]=[C:25]([O:27][C:28]([F:33])([F:32])[CH:29]([F:30])[F:31])[CH:24]=[C:23]([F:34])[CH:22]=2)[CH2:10][C:11]2[CH:20]=[CH:19][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=2)=[O:7])=[CH:4][C:3]=1[C:48]([F:51])([F:50])[F:49]
Reactant: COC(=O)c1ccc(C[C@](NC(=O)c2ccc(F)c(C(F)(F)F)c2)(c2cc(F)cc(OC(F)(F)C(F)F)c2)c2ccc(F)c(C(F)(F)F)c2)cc1
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(N[C@@](Cc1ccc(CO)cc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 79 %

Procedure:
To a solution of (R)-methyl 4-(2-(4-fluoro-3-(trifluoromethyl)benzamido)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)benzoate prepared as described in Procedure 96, 97, 98, 56 and 57 (29 mg, 0.039 mmol) in THF at −78° C. was added a solution of lithium triethylborohydride (1.0 M in THF, 0.5 mL, 0.5 mmol). The resulting mixture was stirred at −78° C. for 1.5 h. The reaction was quenched by addition of 1 N NaOH (1 mL) and the aqueous layer was extracted with EtOAc (15 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by ISCO (12 g silica gel column, 0-50% EtOAc/hexane over 30 min) to yield (R)-4-fluoro-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-(4-(hydroxymethyl)phenyl)ethyl)-3-(trifluoromethyl)benzamide (Example 299) as a colorless film (22 mg, 79% yield). LCMS: RT=2.10 min [M+H] 714.31 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H2O containing 0.1% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220 nm); HPLC: RT=4.0 min (Phenomenex Luna C18 4.6×50 mm column, eluting with 10-90% MeOH/H2O containing 0.2% PPA, flow rate 4 mL/min, wavelength 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 7.98-7.80 (1H, m), 7.85-7.89 (1H, m), 7.39-7.43 (3H, m), 7.31 (1H, t, J=9.23 Hz), 7.19-7.27 (1H, m), 6.99 (1H, d, J=8.79 Hz), 6.76-6.83 (5H, m), 5.89 (1H, t, J=53.0 Hz), 4.16 (1 H, d, J=13.18 Hz), 4.02 (1H, d, J=13.18 Hz).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1.[Br:17]Br>C1COCC1>[Br:17][C:11]1[C:12](=[O:16])[O:13][C:14]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][Br:1])[CH:15]=2
Reactant: O=c1ccc2ccc(OCCCBr)cc2o1
Reactant: BrBr
Solvent: C1CCOC1
Product: O=c1oc2cc(OCCCBr)ccc2cc1Br

Procedure:
Into a 500 mL round bottom flask containing a 2.5 cm stirring bar was added 13 g of 7-(γ-bromopropyloxy)coumarin and 120-150 mL of THF. When the 7-(γ-bromopropyloxy)coumarin was completely dissolved, 3 mL of bromine was added by syringe. After stirring for 2-5 hours at room temperature, the solution was concentrated by rotary evaporator. 50 mL of a 1:1 mixture of ethyl acetate and hexane was added to the concentrate and the mixture was stirred for 30 minutes at room temperature. The solution was then filtered and the solids washed 3 times with 1:1 ethyl acetate and hexane and then dried for 2 hours. To obtain additional product, the filtrate was concentrated by rotary evaporator and 30 mL of a 1:1 mixture of ethyl acetate and hexane was added to the concentrate. The resulting mixture was then filtered, the solids washed three times with 1:1 ethyl acetate and hexane and then dried for 2-5 hours. The product was checked by TLC (ethyl acetate:hexane (4:6)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH2:13][CH3:14])[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CN([CH:23]=[O:24])C.[Cl-].[NH4+]>C1COCC1>[CH2:13]([C:8]1([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[CH:23]=[O:24])[O:12][CH2:11][CH2:10][O:9]1)[CH3:14]
Reactant: CN(C)C=O
Reactant: CCC1(c2cccc(Br)c2)OCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC1(c2cccc(C=O)c2)OCCO1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
17.8 g (70 mmol) of 2-(3-bromophenyl)-2-ethyl-[1,3]dioxolane are dissolved in 300 ml of THF and the mixture is cooled to −78° C. 34 ml (85 mmol) of a 2.5 M solution of butyllithium are added slowly, and the mixture is stirred for 30 minutes. 8.1 ml (105 mmol) of DMF are then added, and the mixture is brought back to 0° C., then treated with a saturated solution of ammonium chloride. After extraction with ethyl ether, the desired aldehyde is obtained in the form of yellow oil (m=14 g; Y=97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=O)[CH2:13][N:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=[S:38])[CH2:13][N:14]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(CCc2cc3c(s2)NC(=O)CN=C3c2ccccc2Cl)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CCc2cc3c(s2)NC(=S)CN=C3c2ccccc2Cl)cc1
Yield: 132.6 %

Procedure:
A suspension of 7 g of 5-(2-chlorophenyl)-7-[2-(4-methoxyphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one, melting at 196°-198° C. and 5 g of Lawesson reagent in 100 ml of toluene is stirred at 45°-48° C. for an hour. The resultant solution is concentrated under reduced pressure, and the residue is subjected to chromatography on silica gel and then eluted with chloroform-methanol (100:1 to 100:2). The objective fraction is concentrated under reduced pressure to give 7 g of 5-(2-chlorophenyl)-7-[2-(4-methoxyphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione, melting at 185°-186° C. with decomposition.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][NH:8][C:9]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[C:27]([F:32])[C:26]=3[F:33])=[N:13][CH:12]=2)=[O:10])[C:4]([CH3:34])=[N:3]1.[H-].[Na+].I[CH2:38][CH3:39].O>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][N:8]([CH2:38][CH3:39])[C:9]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[C:27]([F:32])[C:26]=3[F:33])=[N:13][CH:12]=2)=[O:10])[C:4]([CH3:34])=[N:3]1
Reactant: Cc1nn(C)cc1CNC(=O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(Cc1cn(C)nc1C)C(=O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Reaction time: 0.25 h

Procedure:
To a solution of N-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carboxamide (508) (70 mg, 0.143 mmol) in DMF (1.5 mL) was added sodium hydride (60% in mineral oil, 7 mg, 0.172 mmol) and the reaction was stirred for 15 minutes. Iodoethane (13 mL, 0.172 mmol) was added and stirred for 1 hour. Water was added slowly and the reaction was extracted with 1:1 EtOAc:Hexane, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (90-100% EtOAc in hexanes) to afford N-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-N-ethyl-1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carboxamide (519). 1H NMR (400 MHz, CDCl3) δ: 7.33 (s, 1H), 7.18-6.91 (m, 6H), 6.82-6.73 (m, 1H), 4.37 (s, 2H), 4.34 (s, 2H), 3.77 (s, 3H), 3.37 (q, J=7.0, 2H), 2.16-2.06 (m, 3H), 1.25-1.00 (m, 3H). LC-MS ESI m/z; found 518.0 [M+H]+.
Reaction SMILES: C([O:4][C:5](=[O:54])[C@H:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:53])[NH:24][CH2:25][CH2:26][C@H:27]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:28](=[O:44])[NH:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][N:41]=[N+:42]=[N-:43])=[CH:18][CH:17]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])C=C.C(N(CC)CC)C.C(O)=O>O1CCCC1.O>[N:41]([CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][NH:29][C:28](=[O:44])[C@@H:27]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:26][CH2:25][NH:24][C:23]([O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][C@@H:6]([C:5]([OH:54])=[O:4])[NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])=[CH:21][CH:20]=1)=[O:53])=[N+:42]=[N-:43]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCOCCOCCOCCN=[N+]=[N-])cc1)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCOCCOCCOCCN=[N+]=[N-])cc1)C(=O)O
Temperature: 25 °C

Procedure:
276 mg (0.344 mmol) of the compound from example 23A was dissolved in approx. 15 ml tetrahydrofuran. 235 μl (1.68 mmol) Triethylamine, 63 μl (1.68 mmol) formic acid and 39 mg (0.034 mmol) tetrakis(triphenylphosphin)palladium(0) were added. The reaction mixture was stirred over night at room temperature. The reaction was diluted with approx. 20 ml water and twice extracted with approx. 20 ml dichloromethane. The combined organic phases were extracted with brine, dried over sodium sulfate and concentrated to dryness under reduced pressure. The raw product was purified by preparative RP-HPLC on a C18 column with a water/methanol gradient to yield 167 mg (65% of theory) product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]3[CH:13]=[C:14]([C:17]#[C:18][CH:19]([CH:21]4[CH2:24][CH:23]([O:25][Si](C(C)(C)C)(C)C)[CH2:22]4)[OH:20])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH3:33])[N:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]3[CH:13]=[C:14]([C:17]#[C:18][CH:19]([CH:21]4[CH2:22][CH:23]([OH:25])[CH2:24]4)[OH:20])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH3:33])[N:3]=1
Reactant: Cc1nc2ccc(C#CC(O)C3CC(O[Si](C)(C)C(C)(C)C)C3)cc2n1-c1ncnc(N)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc2ccc(C#CC(O)C3CC(O)C3)cc2n1-c1ncnc(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
In a solution of 3-[3-(4-amino-[1,3,5]triazin-2-yl)-2-methyl-3H-benzoimidazol-5-yl]-1-[3-(tert-butyl-dimethyl-silanyloxy)-cyclobutyl]-prop-2-yn-1-ol (50 mg, 0.1 mmol) in tetrahydrofuran (20 ml) was added tetrabutylammonium fluoride (70 mg, 0.3 mmol). Then the solution stirred overnight at room temperature. The reaction mixture was washed with water and purified by column to afford title compound (20 mg, 57%): 1H NMR (400 MHz, MeOD) delta 1.80-2.20 (m, 3H), 2.32-2.43 (m, 2H), 2.94 (s, 3H), 3.56-3.70 (m, 0.5H), 4.05-4.17 (m, 0.5H), 4.45-4.48 (m, 0.5H), 7.35-7.51 (m, 2H), 8.53-8.57 (m, 2H). LCMS: m/z=+350.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:12].[C:13](=O)([O-])[OH:14].[K+]>CO.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:14][CH3:13])[CH:5]=[CH:4][N+:3]=1[O-:12]
Reactant: O=C([O-])O
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: COc1cc[n+]([O-])c(C)c1C
Reaction time: 10 h
Yield: 94.4 %

Procedure:
2,3-Dimethyl-4-nitropyridine-1-oxide (5 g) was dissolved in methanol (30 ml). To the solution were added tetrabutylammonium bromide (0.5 g) and potassium hydrogen carbonate (5.6 g), and the mixture was heated (temperature 80°-85° C.) under reflux with stirring for 10 hours. The solid matter was removed from the reaction mixture by filtration, and the filtrate was concentrated and applied to a silica gel (100 g) column. Elution with methanol-dichloromethane (1:9) and recrystallization from ethyl acetate-hexane gave 4.3 g of white 2,3-dimethyl-4-methoxypyridine-1-oxide. Melting point 85°-86° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)[CH:4]=[CH2:5].[CH2:16](I)[C:17]([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[CH2:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:10]2)[CH:4]=[CH2:5]
Reactant: C=CCOc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOc1ccc2c(ccn2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of sodium hydride (60%, 254 mg, 6.35 mmol) in 15 mL tetrahydrofuran (THF) was added 5-allyloxyindole (Step A; 1.0 g, 5.77 mmol) in 5 mL THF and the mixture was stirred for 1 hour at ambient temperature. Neopentyl iodide (0.69 mL, 6.35 mmol) was added and the reaction heated to reflux for 21 hours. After cooling, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, concentrated in vacuo, and the crude residue purified by flash chromatography on silica gel (15% ethyl acetate/hexane) to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]#[C:12][Si:13]([CH3:16])([CH3:15])[CH3:14].[N:17]1[CH:22]=NN=[CH:19][N:18]=1>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[C:12]([Si:13]([CH3:15])([CH3:14])[CH3:16])=[CH:19][N:18]=[N:17][CH:22]=1
Reactant: C[Si](C)(C)C#Cc1cc([N+](=O)[O-])ccc1F
Reactant: c1nncnn1
Solvent: C1COCCO1
Product: C[Si](C)(C)c1cnncc1-c1cc([N+](=O)[O-])ccc1F

Procedure:
(2-Fluoro-5-nitrophenylethynyl)trimethylsilane (8.8 g, 37.1 mmol) and 1,4-dioxane were added to a solution of 1,2,4,5-tetrazine (35 ml, 18.6 mmol, 0.53 M in dichloromethane). The dichloromethane was distilled off and the dioxane solution was stirred at reflux for 36 hours. The solvent was removed to leave a brown oil. Purification by chromatography on silica gel eluting with dichloromethane, then with dichloromethane containing 1% methanol, gave 4-(2-fluoro-5-nitrophenyl)-5-trimethylsilanylpyridazine as a brown oil: m/z (ES+) 292 (M++H) and 249 (M+-3CH2).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[C:7]([O:9][CH:10]([CH3:12])[CH3:11])[CH:6]=[CH:5][C:4]=1B(O)O.Cl.Cl.COC1C=CC([C:28]2[CH:29]=[C:30]3[C:35]4=[C:36]([CH2:38][CH2:39][CH2:40][N:34]4[CH2:33][C@@H:32]4[CH2:41][NH:42][CH2:43][C@@H:31]34)[CH:37]=2)=C(C(F)(F)F)C=1>>[CH:10]([O:9][C:7]1[CH:6]=[CH:5][C:4]([C:28]2[CH:29]=[C:30]3[C:35]4=[C:36]([CH2:38][CH2:39][CH2:40][N:34]4[CH2:33][C@@H:32]4[CH2:41][NH:42][CH2:43][C@@H:31]34)[CH:37]=2)=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:8]=1)([CH3:12])[CH3:11]
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNC[C@H]2CN4CCC3)c(C(F)(F)F)c1
Reactant: CC(C)Oc1ccc(B(O)O)c(C(F)(F)F)c1
Agent: Cl
Product: CC(C)Oc1ccc(-c2cc3c4c(c2)[C@@H]2CNC[C@H]2CN4CCC3)c(C(F)(F)F)c1

Procedure:
Using 2-trifluoromethyl-4-isopropoxyphenyl boronic acid and following the procedures described in EXAMPLE 34, (±)-trans tert-butyl 2-bromo-5,6,8a,9,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline-10(8H)-carboxylate from EXAMPLE 7, Part A was converted into the title compound of EXAMPLE 35 as a yellow semi-solid. 1H NMR (500 MHz, CDCl3) δ 1.26 (s, 1H), 1.30 (d, 6H, J=6.1 Hz), 1.85-2.05 (m, 2H), 2.15 (m, 1H), 2.74 (m, 4H), 2.96 (t, 1H, J=7 Hz), 3.23 (m, 1H), 3.32 (m, 4H), 3.57 (t, 1H, J=7 Hz), 4.58 (sept, 1H, J=6.1 Hz), 6.59 (s, 1H), 6.77 (s, 1H), 6.99 (dd, 1H, J=2.5, 8.4, Hz), 7.18 (s, 1H), 7.24 (m, 1H). LRMS (ES)+: 417 (M+H)+.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][C:13]2=[C:16]([C:19]#[N:20])[C:17]#[N:18])=[CH:8][CH:7]=1>C1COCC1.[Cu]I>[CH3:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][C:13]2([CH:16]([C:19]#[N:20])[C:17]#[N:18])[CH3:1])=[CH:8][CH:7]=1
Reactant: COc1ccc2c(c1)C(=C(C#N)C#N)CCC2
Reactant: C[Mg]Br
Agent: [Cu]I
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(C)(C(C#N)C#N)CCC2
Yield: 66.6 %

Procedure:
To a solution of methylmagnesium bromide (3.0 M in diethyl ether (12.0 mL, 36.0 mmol)) and copper(I) iodide (6.86 g, 36.0 mmol) in THF (100 mL) was added 48.1 (6.73 g, 30.0 mmol) at room temperature. The resulting mixture was refluxed for 4 hours. The mixture was then cooled in an ice-bath, quenched with aqueous NH4Cl (200 mL), extracted with ether, concentrated, and purified by silica gel column chromatography to give 48.2 (4.8 g, 66% yield). MS ESI (pos.) M/E: 241 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.O>CN(C)C=O>[OH:16][CH:15]([CH2:17][N:38]1[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC1CO1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC(O)CN1CCN(C)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
(2-{[6-Methoxy-7-(2-oxiranylmethoxy)-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (39 mg) and 4-methylpiperazine (27 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (40 mg, yield 84%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12.[CH2:22]([Mg]Br)[CH3:23].C(OCC)C.O>O1CCCC1>[CH2:22]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12)[CH3:23]
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Reactant: CC[Mg]Br
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCc1c2ccccc2nc2c1c(C)nn2-c1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
To an ice-cold solution of 4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (2.95 g, 10.0 mmol) in tetrahydrofuran (100 mL), a solution of 3M ethylmagnesium bromide in diethyl ether (4.00 mL, 12.0 mmol) was added dropwise under an argon atmosphere, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was poured into iced water, and the organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvents were evaporated under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography (hexane:ethyl acetate=2:1) to give the title compound (0.33 g, 11% yield).
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([CH2:15][NH:16][C:17]([NH:19]C(=O)C3C=CC=CC=3)=[S:18])=[CH:13][CH:14]=2)[N:9]=1)[NH2:3].[OH-].[Na+]>CO>[NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([CH2:15][NH:16][C:17]([NH2:19])=[S:18])=[CH:13][CH:14]=2)[N:9]=1)[NH2:3]
Reactant: NC(N)=Nc1nc(-c2ccc(CNC(=S)NC(=O)c3ccccc3)o2)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=S)NCc1ccc(-c2csc(N=C(N)N)n2)o1
Temperature: 60 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
A suspension of 2-(diaminomethyleneamino)-4-[5-{3-(benzoyl)thioureido}methylfuran-2-yl]thiazole (3.20 g) and sodium hydroxide (0.32 g) in methanol (30 ml) was stirred at 60° C. for one hour. The reaction mixture was cooled in an ice bath and the resulting precipitate was collected by filtration and washed with methanol to afford 2-(diaminomethyleneamino)-4-(5-thioureidomethylfuran-2-yl)thiazole (1.73 g).
Reaction SMILES: [I:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][NH:14][CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:16]=O.[BH4-].[Na+]>CO.O>[I:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: Cn1c2c(c3cccc(I)c31)CNCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCc2c(c3cccc(I)c3n2C)C1
Temperature: 0 °C
Yield: 15 %

Procedure:
6-Iodo-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (3.85 g, 12.3 mmol) was suspended in methanol (40 mL). Formaldehyde (14 mL of 37%) was added and heated at reflux for 2 h. The reaction was cooled to 0° C. in an ice bath and sodium borohydride (1.7 g, 46 mmol) was added slowly over 15 minutes and stirred for two h at 0-10° C. The reaction was diluted with water (200 mL) and extracted with CH2Cl2 (3×150 mL). The organics were collected, washed with brine (250 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The product was purified by silica gel column chromatography (3% MeOH/CH2Cl2) to give 6-iodo-2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.6 g, 15%). 1H NMR (CDCl3 300 MHz) δ 7.59 (d, 1H, J=7.4 Hz), 7.33 (d, 1H, J=7.6 Hz), 6.73 (t, 1H, J=7.7 Hz), 3.98 (s, 3H), 3.62 (s, 2H), 2.83 (s, 4H), 2.55 (s, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[C:7](=[O:21])[O:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[O:19][CH3:20])[CH:10]=1)=[O:4]>[Pd].CO>[CH3:1][O:2][C:3]([NH:5][CH:6]([CH2:10][CH2:9][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=1[O:19][CH3:20])[C:7]([OH:21])=[O:8])=[O:4]
Reactant: COC(=O)NC1=CC(c2cccc(OC)c2OC)OC1=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)NC(CCc1cccc(OC)c1OC)C(=O)O
Temperature: 64 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
150 g of 3-methoxycarbonylamino-5(2,3-dimethoxyphenyl)-2,5-dihydro-furan-2-one and 1190 ml of CH3OH are placed into 2000 ml flasks of a Parr hydrogenator, then they are heated until complete dissolution with stirring (T about 64° C.); 30 g of 5% Pd/C are added and hydrogenation Is started at 35 psi until H2 is no longer absorbed (about 60 minutes). The disappearance of the starting compound is checked by TLC, then the mixture is filtered through Celite and the filtrate is evaporated to dryness, the resulting oil is precipitated with stirring by adding ethyl ether and petroleum ether, stirring is continued for about 30 minutes, then the mixture is filtered and dried under vacuum at 60° C. 141.6 g are obtained. (Yield 93%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:12]OS(OC)(=O)=O>>[CH3:12][O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: COc1ccc(O)c(C=O)c1
Product: COc1ccc(OC)c(C=O)c1

Procedure:
As discussed above, the present invention provides a process for preparing 2,5-dimethoxy benzaldehyde comprising the steps of: (a) reacting a 2-hydroxy-5-methoxy benzaldehyde with a metal hydroxide to produce a reaction mixture comprising a metal salt of 2-hydroxy-5-methoxy benzaldehyde; (b) separating the metal salt of 2-hydroxy-5-methoxy benzaldehyde from the reaction mixture of step (a) to obtain an at least substantially pure metal salt of 2-hydroxy-5-methoxy benzaldehyde; and (c) alkylating the metal salt of 2-hydroxy-5-methoxy benzaldehyde of step (b) with dimethylsulfate to produce 2,5-dimethoxy benzaldehyde.