Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][NH:7][C:8](=[O:19])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1)=[O:5])[CH3:2].Cl>C(O)C>[CH2:1]([O:3][C:4]([CH2:6][NH:7][C:8](=[O:19])[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][OH:18])=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CNC(=O)COc1ccc(C=O)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CNC(=O)COc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a mixture of N-(ethoxycarbonylmethyl)-2-(4-formylphenoxy)acetamide (4.6 g) and ethanol (150 ml) was added under ice cooling sodim borohydride (0.25 g), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 3% hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gave N-(ethoxycarbonylmethyl)-2-(4-hydroxymethylphenoxy)acetamide (4.03 g).
Reaction SMILES: C(C1NC=CC=1)(OC(C)(C)C)=O.[C:13]([O:17][C:18]([NH:20][C:21]1[CH:22]=[C:23]([C:27]([NH:29][C:30]2[CH:31]=[C:32]([C:36]([NH:38][C:39]3[CH:40]=[C:41]([C:45]([O:47]C)=[O:46])[N:42]([CH3:44])[CH:43]=3)=[O:37])[N:33]([CH3:35])[CH:34]=2)=[O:28])[N:24]([CH3:26])[CH:25]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[OH-].[Na+]>CO.CCOCC>[C:13]([O:17][C:18]([NH:20][C:21]1[CH:22]=[C:23]([C:27]([NH:29][C:30]2[CH:31]=[C:32]([C:36]([NH:38][C:39]3[CH:40]=[C:41]([C:45]([OH:47])=[O:46])[N:42]([CH3:44])[CH:43]=3)=[O:37])[N:33]([CH3:35])[CH:34]=2)=[O:28])[N:24]([CH3:26])[CH:25]=1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)c1cc(NC(=O)c2cc(NC(=O)c3cc(NC(=O)OC(C)(C)C)cn3C)cn2C)cn1C
Agent: CC(C)(C)OC(=O)c1ccc[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: Cn1cc(NC(=O)c2cc(NC(=O)c3cc(NC(=O)OC(C)(C)C)cn3C)cn2C)cc1C(=O)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
The Boc pyrrole trimer (5) (0.6 g, 1.2 mmol) was dissolved in MeOH (5 mL) and treated with NaOH solution (0.1 g in 5 mL H2O). The reaction mixture was stirred overnight then heated at 60° C. for 2 hours. The MeOH was removed in vacuo and the aqueous fraction extracted with EtOAc (25 mL). The aqueous layer was adjusted to pH 2-3 with 1M HCl solution then extracted with EtOAc (3×30 mL). The combined organic layers were dried over MgSO4 then concentrated in vacuo to give an orange solid. The solid was suspended in Et2O (10 mL) and collected on a filter then dried in vacuo to give an orange solid 0.431 g (74%). 1H NMR d6-DMSO δ 12.11 (1H, s, OH), 9.89 (1H, s, N—H), 9.86 (1H, s, N—H), 9.09 (1H, s, Boc-N—H), 7.43 (1H, d, J=1.9 Hz, Py-H), 7.22 (1H, d, J=1.7 Hz, Py-H), 7.06 (1H, d, J=1.7 Hz, Py-H), 6.90 (1H, s, Py-H), 6.86 (1H, d, J=1.9 Hz, Py-H), 6.84 (1H, s, Py-H), 3.85 (3H, s, N—CH3), 3.83 (3H, s, N—CH3), 3.82 (3H, s, N—CH3), 1.46 (9H, s, Boc-H); 13C NMR d6-DMSO δ 161.9, 158.4, 158.4, 152.8, 122.8, 122.7, 122.5, 122.4, 122.3, 120.2 (CH), 119.5, 118.4 (CH), 117.0 (CH), 108.4 (CH), 104.7 (CH), 103.8 (CH), 78.2, 36.1 (CH3), 36.0 (CH3), 28.1 ([CH3]3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH:14]2[C:19]([F:22])([F:21])[F:20])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[O:23]=[C:24]1[C:28]2[CH:29]=[CH:30][C:31]([CH2:33][CH:34]=O)=[CH:32][C:27]=2[CH2:26][O:25]1.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:34][CH2:33][C:31]3[CH:30]=[CH:29][C:28]4[C:24](=[O:23])[O:25][CH2:26][C:27]=4[CH:32]=3)[CH2:15][CH:14]2[C:19]([F:21])([F:22])[F:20])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: O=CCc1ccc2c(c1)COC2=O
Reactant: COc1cc(CCN2CCNCC2C(F)(F)F)ccc1C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc(CCN2CCN(CCc3ccc4c(c3)COC4=O)CC2C(F)(F)F)ccc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 2-methoxy-4-{2-[2-(trifluoromethyl)piperazin-1-yl]ethyl}benzonitrile (116 mg, 0.28 mmol) and (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (49 mg, 0.28 mmol) in methanol (1.0 mL) at 0° C. was added sodium cyanoborohydride (18 mg, 0.28 mmol) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and purified by mass-directed HPLC to provide 2-methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(trifluoromethyl)piperazin-1-yl}ethyl)benzonitrile. LC-MS (IE, m/z): 474.4 [M+1]+. (0.27 μM)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:19]([F:22])([F:21])[F:20])=[C:7]([CH:18]=1)[C:8]([O:10]CC1C=CC=CC=1)=[O:9])#[N:2].[H][H]>[Pd].CO>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:19]([F:20])([F:21])[F:22])=[C:7]([CH:18]=1)[C:8]([OH:10])=[O:9]
Reactant: [H][H]
Reactant: N#Cc1ccc(C(F)(F)F)c(C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: NCc1ccc(C(F)(F)F)c(C(=O)O)c1
Reaction time: 8 h
Yield: 50 %

Procedure:
Combine benzyl 5-cyano-2-(trifluoromethyl)benzoate (3.9 g, 12.78 mmol, 1.0 equiv), palladium (10 wt % on carbon, 400 mg, 0.38 mmol, 0.03 equiv), and methanol (128 mL), and purge the mixture with hydrogen. Stir overnight under a hydrogen atmosphere. Filter the mixture through a pad of diatomaceous earth, and then rinse the pad with hot methanol (3×150 mL) to bring through precipitated product. Concentrate the filtrate under reduced pressure to give the title compound (1.4 g, 50%). MS (m/z) 220 (M+1).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](#[N:16])[CH2:14][CH3:15].[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[C:25](=[O:32])[CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1.P([O-])([O-])([O-])=O>C1COCC1.CCCCCC>[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[C:25]([OH:32])([CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)[CH:14]([CH3:15])[C:13]#[N:16]
Reactant: O=C(Cn1cncn1)c1cc(F)ccc1F
Reactant: CCC#N
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C#N)C(O)(Cn1cncn1)c1cc(F)ccc1F
Temperature: -30 °C
Reaction time: 0.25 h

Procedure:
To a solution of diisopropylamine (11 g) in dry THF (100 ml) 1.6 M solution of butyllithium in hexane (63 ml) was slowly added at −78° C. under nitrogen atmosphere. The mixture was allowed to warm up to −30° C., then re-cooled to −78° C. before propionitrile (5.4 g) was slowly added (exothermic reaction, cooling). The mixture was stirred at this temperature for ca. 15 min, 1-(2,5-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (10 g) was added, the reaction mixture warmed up to −20° C. within ca. 1 hr and finally poured on aqueous solution of phosphate buffer (pH 7). The aqueous phase was extracted 3 times with ethylacetate (300 ml) and the combined organic phase was twice with water, dried with sodium carbonate, filtered and evaporated under reduced pressure providing the title compound: 9 g. The analytical data were identical with published in U.S. Pat. No. 6,300,353 and WO99/45008 for (2S,3R)-enantiomer.
Reaction SMILES: [CH:1]1([O:4][C:5]2[N:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.O[C@H:13]1[CH2:17][CH2:16][NH:15][C:14]1=[O:18]>>[CH2:2]1[CH2:3][CH:1]1[O:4][C:5]1[N:10]=[CH:9][C:8]([O:11][C@@H:13]2[CH2:17][CH2:16][NH:15][C:14]2=[O:18])=[CH:7][CH:6]=1
Reactant: O=C1NCC[C@@H]1O
Reactant: Oc1ccc(OC2CC2)nc1
Product: O=C1NCC[C@H]1Oc1ccc(OC2CC2)nc1

Procedure:
Typical Procedure 3 was followed. Reaction of 6-cyclopropoxy-pyridin-3-ol and (S)-3-hydroxy-pyrrolidin-2-one provided the title compound. MS ESI+: m/z=235 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]1[C:18]2[N:17]([CH2:19][CH:20]([OH:29])[CH2:21][NH:22][CH2:23][C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:15]1[C:16]2[N:17]([CH2:19][CH:20]([OH:29])[CH2:21][N:22]([CH2:23][C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)[S:2]([CH3:1])(=[O:4])=[O:3])[C:18]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: OC(CNCc1ccco1)Cn1c2ccccc2c2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(Cc1ccco1)CC(O)Cn1c2ccccc2c2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
Methanesulfonyl chloride (0.650 mL, 8.4 mmol) was added dropwise to a cold stirring solution of 1-(9H-carbazol-9-yl)-3-((furan-2-ylmethyl)amino)propan-2-ol (2.7 g, 8.4 mmol) and triethylamine (1.3 mL, 9.2 mmol) in anhydrous methylene chloride (55 mL), which was kept at 0-5° C. with an external ice bath. The solution was stirred at 0° C. for 2 hours and then diluted with methylene chloride and successively washed with 0.25N aqueous hydrochloric acid twice, water, and saturated aqueous sodium chloride. The organics were dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-10% ethyl acetate in methylene chloride) to give the desired product as a white solid (1.5 g, 45%). 1H NMR (d6-DMSO, 300 MHz) δ 8.09-8.06 (d, 2H, J=8.1 Hz), 7.42-7.37 (m, 5H), 7.18-7.14 (m, 2H), 6.37-6.35 (dd, 1H, J=1.8, 3 Hz), 6.31-6.30 (d, 1H, J=3 Hz), 4.52-4.39 (dd, 2H, J=15.9, 24.6 Hz), 4.39-4.30 (dd, 1H, J=3.3, 14.4 Hz), 4.22-4.10 (m, 1H), 4.20-4.05 (br m, 1H), 3.40-3.33 (m, 1H) 3.26-3.17 (m, 1H), 2.90 (s, 3H). ESI (m/z): 398.9 (M+H). HPLC analysis: (C18, 10-90% acetonitrile in water+0.1% trifluoroacetic acid over 10 min: retention time, % area at 254 nm): 8.6 min, 97.9%.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:23]=[C:22]([CH2:24][O:25][CH3:26])[O:21][C:15]=3[C:16]([O:19][CH3:20])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[NH2:27][C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[CH:30][C:29]=1[Cl:35]>>[Cl:35][C:29]1[CH:30]=[N:31][CH:32]=[C:33]([Cl:34])[C:28]=1[NH:27][C:11]([C:13]1[C:14]2[CH:23]=[C:22]([CH2:24][O:25][CH3:26])[O:21][C:15]=2[C:16]([O:19][CH3:20])=[N:17][CH:18]=1)=[O:12]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: COCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC)c2o1
Product: COCc1cc2c(C(=O)Nc3c(Cl)cncc3Cl)cnc(OC)c2o1
Yield: 90.8 %

Procedure:
Starting from 7-methoxy-2-methoxymethylfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (300 mg) and 4-amino-3,5-dichloropyridine (54 mg). Purification by column chromatography on silica eluting with 1% methanol in dichloromethane gave the title compound (115 mg) as a white solid.
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[C:8]([C:13]([OH:15])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:16]O>>[CH3:16][O:14][C:13]([C:8]1[C:7]([Br:6])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:15]
Reactant: CO
Reactant: O=C(O)c1ncccc1Br
Agent: O=S(=O)(O)O
Product: COC(=O)c1ncccc1Br
Temperature: 25 °C
Reaction time: 14 h

Procedure:
H2SO4 (1.2 mL, 23.4 mmol, 1.0 eq.) was added to a solution of 3-bromopyridine-2-carboxylic acid (4.7 g, 23.4 mmol, 1.0 eq.) in MeOH (50 mL). The resulting solution was stirred for 14 hours while the temperature was maintained at reflux in an oil bath. The mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in EtOAc (50 mL) and the pH was adjusted to 10 with Na2CO3 (5 mol/L). The resulting solution was extracted with EtOAc (100 mL). The organic layer was washed with water (1×100 mL) and saturated aqueous NaCl (2×100 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:20) to yield 3-bromopyridine-2-carboxylic acid methyl ester (4.0 g) as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([CH:33]=1)[CH2:7][C@H:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@H:19]([CH2:23][CH3:24])[C:20]([OH:22])=O)=[O:17])[CH2:12][C:11](=[N:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:10][CH2:9]1.C(Cl)Cl.C(C1NC=CN=1)(C1[NH:42]C=CN=1)=O.[NH4+].[OH-]>C(Cl)(Cl)Cl>[C:20]([C@H:19]([NH:18][C:16]([N:13]1[C:14](=[O:15])[C@H:8]([CH2:7][C:6]2[CH:33]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:34][CH3:35])[CH2:9][NH:10][C:11](=[N:25][O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:12]1)=[O:17])[CH2:23][CH3:24])(=[O:22])[NH2:42]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC[C@@H](NC(=O)N1CC(=NOc2ccccc2)NC[C@@H](Cc2cc(Cl)ccc2OC)C1=O)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC[C@@H](NC(=O)N1CC(=NOc2ccccc2)NC[C@@H](Cc2cc(Cl)ccc2OC)C1=O)C(N)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 35.2 %

Procedure:
To the compound 54 (114 mg) in a methylene chloride (2 ml) solution, carbonyl diimidazole (45 mg) was added, and the mixture was stirred at room temperature for 45 minutes. The reaction solution was cooled to 0° C., then 28% ammonia aqueous solution (2 ml) was added, and the mixture was stirred at that temperature for 1 hour. The reaction solution was diluted with chloroform and the resultant mixture successively washed with water, 1M hydrochloric acid, and brine. The organic layer was dried over anhydrous sodium sulfate, then was concentrated. The residue was purified by flash column chromatography (silica gel, chloroform/ethyl acetate=7/3 to 1/2) to obtain the title compound (40 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[S:16]([C:19]1[CH:31]=[CH:30][C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][C:21]=2[CH:20]=1)(=[O:18])=[O:17])([CH3:3])[CH3:2].O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:35].[Na+].[Na+].C(O)(=O)C>O>[CH:13]([C:6]1[CH:7]=[C:8]([CH:10]([CH3:11])[CH3:12])[CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]=1[S:16]([C:19]1[C:20](=[O:35])[C:21]2[C:29](=[CH:30][CH:31]=1)[C:28]1[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH:22]=2)(=[O:18])=[O:17])([CH3:15])[CH3:14]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)c2ccc3c(c2)Cc2ccccc2-3)c(C(C)C)c1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)C2=CC=C3C(=Cc4ccccc43)C2=O)c(C(C)C)c1
Yield: 40.3 %

Procedure:
A portion of the 2-(2,4,6-triisopropylphenylsulfonyl)fluorene just described (8.67 g, 20.0 mmol) was placed in a 1 liter flask (equipped with a magnetic stirrer and reflux condenser) along with 17.9 g (60.0 mmol, 3.0 eq) of sodium dichromate dihydrate and 500 ml of glacial acetic acid. The mixture was refluxed for 15 hours, cooled, and poured into 2.0 liters of water. The solids were collected by filtration and washed with additional water (2×1.0 liter). The crude product was dried and purified by chromatography. A total of 3.60 g (8.06 mmol, 40.3%) of pure 2-(2,4,6-triisopropylphenylsulfonyl)fluorenone was obtained in this manner. Its structure was confirmed by IR, NMR, and ultraviolet-visible (UV-VIS) spectroscopy, FDMS, and combustion analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]2[C:7]3=[N:8][C:9]([C:14]#[N:15])=[C:10]([C:12]#[N:13])[N:11]=[C:6]3[C:5](=O)[C:4]=2[CH:3]=1.Cl.[NH2:21][NH:22][C:23]([NH2:25])=[O:24]>C(#N)C>[NH2:25][C:23]([NH:22][N:21]=[C:5]1[C:6]2[C:7](=[N:8][C:9]([C:14]#[N:15])=[C:10]([C:12]#[N:13])[N:11]=2)[C:16]2[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][C:4]1=2)=[O:24]
Reactant: NNC(N)=O
Reactant: N#Cc1nc2c(nc1C#N)-c1ccc(Cl)cc1C2=O
Agent: Cl
Solvent: CC#N
Product: N#Cc1nc2c(nc1C#N)-c1ccc(Cl)cc1C2=NNC(N)=O

Procedure:
A mixture of 600 mg (2.25 mmol) 17g and 329 mg (2.92 mmol) semicarbazide hydrochloride in 20 ml acetonitrile was heated 14 h under reflux. After that time, TLC indicated complete conversion of the starting product. After evaporation of the solvent, the crude product was recrystallised from aqueous ethanol, and compound 43 was obtained in slightly greenish crystals (90%). 1H-NMR (d6-DMSO, 400 MHz): δ (ppm)=7.40 (sl, 1H); 7.70 (sl, 1H); 7.71 (d, J=8 Hz, 1H); 8.17 (d, J=8 Hz, 1H); 8.89 (s, 1H); 10.95 (s, 1H). ESI+MS: calcd for C14H6ClN7O: 323.70; found: 324 (MH+).
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:17]=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:18]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25](O)=[O:26])[CH:19]([CH3:21])[CH3:20].C(OCC)(=O)C>C(#N)C>[CH2:18]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25]([N:5]1[CH2:4][CH2:3][N:2]([C:8]2[CH:17]=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:7][CH2:6]1)=[O:26])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: c1ccc2nc(N3CCNCC3)cnc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2cnc3ccccc3n2)CC1

Procedure:
Prepared in analogy to example 1.1 (b) from 2-piperazin-1-yl-quinoxaline hydrochloride and 2-isobutoxy-5-methanesulfonyl-benzoic acid (example 2.4) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a yellowish foam.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[C:21]1([CH3:38])[CH:26]=[CH:25][C:24](S(OCC2CCCCC2)(=O)=O)=[CH:23][CH:22]=1>>[CH:21]1([CH2:38][N:8]2[C:9]([O:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCCC2)cc1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2CC2CCCCC2)c1
Yield: 54.3 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and (cyclohexyl)methyl para-toluenesulfonate were reacted by the same way with the example 1 to obtain the titled compound (201 mg, yield: 54.3%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[OH:30].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:30][C:22]3[CH:23]=[CH:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][C:21]=3[F:20])=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccnc2cc(OCc3ccccc3)ccc12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(OCc4ccccc4)ccc23)c(F)c1
Temperature: 115 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a suspension of 7-(benzyloxy)-4-chloroquinoline (45 g, 0.17 mol) and 2-fluoro-4-nitrophenol (28.9 g, 0.18 mol) in toluene (42 mL) was added DIPEA (25.9 g, 0.2 mol). The suspension was heated to 115° C. for 12 hours and then concentrated in vacuo. The residue was diluted with EtOH (45 mL), stirred at 60° C. for 30 minutes, and then allowed to cool down to 0° C. in an ice bath. The solid was collected through filtration, dried in vacuo at 45° C. for 24 hours to afford the title compound as a light grey solid (59.1 g, 91%)
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:7]([C:12]#[N:13])([CH3:11])[CH2:8][O:9][CH3:10])C.[BH4-].[Na+].C(O)(=O)C>CO.O.[Co](Cl)Cl>[CH2:14]([N:6]1[C:7]([CH2:8][O:9][CH3:10])([CH3:11])[CH2:12][NH:13][C:4](=[O:3])[CH2:5]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CN(Cc1ccccc1)C(C)(C#N)COC
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COCC1(C)CNC(=O)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 545 mg (1.78 mmol) [benzyl-(1-cyano-2-methoxy-1-methyl-ethyl)-amino]-acetic acid ethyl ester in 10 mL MeOH was added 460 mg (3.57 mmol) cobalt(II) chloride. The mixture was cooled with ice and 270 mg (7.13 mmol) sodium borohydride was added. The resulting mixture was stirred at RT for 1 h. The reaction mixture was diluted with a small amount of water, acidified with acetic acid and stirred for 30 min. The organic solvent was removed by distillation; the residue was alkalized with 4 N aqueous NaOH solution and filtered through Celite. The solvent was extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:9]=[O:10])=[C:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(C=O)c1ccccc1
Reactant: CC(C)c1cccc(OCc2ccccc2)c1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1cc(OCc2ccccc2)ccc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104 %

Procedure:
A mixture of N-methylformanilide (9.92 g) and phosphoryl chloride (11.3 g) was stirred at room temperature for 30 minutes, and benzyloxy-3-isopropylbenzene (16.6 g) was added to the mixture. After being stirred at room temperature overnight, ice was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford 4-benzyloxy-2-isopropylbenzaldehyde (19.4 g) as a crude product. An aqueous solution (200 mL) of sodium chlorite (33.2 g) was added dropwise to an ice-cooled suspension of the crude 4-benzyloxy-2-isopropylbenzaldehyde and potassium dihydrogenphosphate (50.0 g) in tert-butylalcohol (200 mL)/2-methyl-2-butene (100 mL) with stirring. The mixture was stirred at room temperature for 3 hrs. To the resulting mixture was added water, and the insoluble materials were removed by filtration. The filtrate was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford 4-benzyloxy-2-isopropylbenzoic acid (23.3 g) as a crude product. A suspension of the crude 4-benzyloxy-2-isopropylbenzoic acid, ethyl iodide (13.7 g) and potassium carbonate (15.2 g) in N,N-dimethylformamide (300 mL) was stirred at room temperature for30 minutes. The reaction mixture was partitioned between diethyl ether and water. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to afford ethyl 4-benzyloxy-2-isopropylbenzoate (16.8 g). A suspension of ethyl 4-benzyloxy-2-isopropylbenzoate and 10% palladium-carbon (0.1 g) in ethanol (100 mL) was stirred at room temperature for 30 minutes under an atmosphere of hydrogen. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to afford the title compound (1.1 g).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]3OCC[O:11]3)[N:5]=2)[CH2:3][CH2:2]1>Cl.C1COCC1>[CH:1]1([C:4]2[N:5]=[C:6]([CH:10]=[O:11])[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: c1cc(C2CC2)nc(C2OCCO2)c1
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1cccc(C2CC2)n1
Temperature: 0 °C
Yield: 84.4 %

Procedure:
A mixture of 2-cyclopropyl-6-(1,3-dioxolan-2-yl)pyridine of Step C (538.2 mg, 2.82 mmol) in 10% aqueous HCl (5 mL) and THF (10 mL) was heated at reflux for 18 h. The cooled reaction mixture was cooled to 0° C. and quenched with saturated aqueous NaHCO3. The reaction mixture was poured into CHCl3 (20 mL). The phases were separated. The aqueous phase was extracted with CHCl3 (10 mL). The combined organic phases were dried (MgSO4), filtered and concentrated. The resulting residue was purified on a Biotage 40S column using 10% ethyl acetate in hexane as the eluent to afford 351.0 mg (2.38 mmol, 85%) of the desired aldehyde as a clear oil.