Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:24][C:25](OCC)=[O:26])([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C.ClCCl>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[C:11]1([CH2:24][CH2:25][OH:26])[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: CCOC(=O)CC1(c2ccc3ccccc3c2)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: OCCC1(c2ccc3ccccc3c2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
Ethyl 2-(1-benzyl-4-(2-naphthyl)piperidin-4-yl)ethanoate (5.8 g) (see Preparation 4) was dissolved in anhydrous diethyl ether (100 ml), cooled in an ice-bath and lithium aluminium hydride (0.57 g) added, portionwise. The mixture was stirred at room temperature for 30 minutes, water (0.8 ml) was then carefully added followed by 2N aqueous sodium hydroxide solution (0.8 ml) and further water (1.6 ml). The mixture was stirred for 20 minutes and the resulting granular precipitate removed by filtration. The solvent was removed from the filtrate under reduced pressure to give a solid which was dissolved in dichloromethane, dried over anhydrous sodium sulphate and the solvent again removed under reduced pressure to yield 4-(2-naphthyl)-4-(2-hydroxyethyl)-N-benzylpiperidine (2.2 g) as a white solid.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18]Br>CN(C)C=O>[CH2:17]1[CH2:18][O:6][C:5]2=[CH:7][CH:8]=[CH:9][C:1](=[C:3]2[OH:4])[O:2]1
Reactant: Oc1cccc(O)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1c2cccc1OCCO2
Temperature: 80 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
A suspension of pyrogallol (126 g) and potassium carbonate (138 g) in dimethylformamide (500 mL) was stirred at 80° C. for 2 hours. 1,2-Dibromoethane (188 g) was then added dropwise over a 4 hour period and the resulting mixture was stirred at 80° C. overnight. Upon cooling, the mixture was filtered, and the filtrate was evaporated, dissolved in water (200 mL) and acidified with concentrated hydrochloric acid. The resulting mixture was extracted with toluene. The orgainc extract was washed with water, dried over sodium sulfate, filtered and evaporated. Fractional distillation (82° C., 0.05 mm) afforded 54.7 g of 2,6-ethylenedioxyphenol, as an oil. Similary, using the above procedure but substituting 1,3-dibromopropane for 1,2-dibromoethane 2,3-propylenedioxyphenol, mp 110°-111° C. was prepared.
Reaction SMILES: [CH3:1][CH:2]([CH3:41])[C@H:3]([NH:36][C:37](=[O:40])[O:38][CH3:39])[C:4](=[O:35])[N:5]1[CH:9]([C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][CH:16]=3)=[CH:13][N:14]=2)[CH2:8][C:7]2([CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH2:6]1.Br[C:43]1[CH:48]=[CH:47][C:46]([C:49]2[NH:53][C:52]([C@H:54]3[N:59]4[C:60](=[O:71])[C@@H:61]([NH:66][C:67](=[O:70])[O:68][CH3:69])[CH2:62][CH2:63][C:64](=[O:65])[N:58]4[CH2:57][CH2:56][CH2:55]3)=[N:51][CH:50]=2)=[CH:45][CH:44]=1.C(=O)(O)[O-].[Na+]>C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].C(O)(C)(C)C>[CH3:69][O:68][C:67](=[O:70])[NH:66][C@H:61]1[CH2:62][CH2:63][C:64](=[O:65])[N:58]2[CH2:57][CH2:56][CH2:55][C@@H:54]([C:52]3[NH:53][C:49]([C:46]4[CH:45]=[CH:44][C:43]([C:18]5[CH:17]=[CH:16][C:15]([C:12]6[NH:11][C:10]([CH:9]7[CH2:8][C:7]8([CH2:34][CH2:33][O:32][CH2:31][CH2:30]8)[CH2:6][N:5]7[C:4](=[O:35])[C@@H:3]([NH:36][C:37]([O:38][CH3:39])=[O:40])[CH:2]([CH3:1])[CH3:41])=[N:14][CH:13]=6)=[CH:20][CH:19]=5)=[CH:48][CH:47]=4)=[CH:50][N:51]=3)[N:59]2[C:60]1=[O:71]
Reactant: COC(=O)N[C@H]1CCC(=O)N2CCC[C@@H](c3ncc(-c4ccc(Br)cc4)[nH]3)N2C1=O
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CCOCC2)CC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])O
Solvent: CC(C)(C)O
Product: COC(=O)N[C@H]1CCC(=O)N2CCC[C@@H](c3ncc(-c4ccc(-c5ccc(-c6cnc(C7CC8(CCOCC8)CN7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]6)cc5)cc4)[nH]3)N2C1=O
Temperature: 90 °C
Yield: 45.2 %

Procedure:
In a 10 mL seal tube, methyl (2S)-3-methyl-1-oxo-1-(3-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)-8-oxa-2-azaspiro[4.5]decan-2-yl)butan-2-ylcarbamate (45 mg, 79.4 μmol), methyl (4S,7S)-4-(5-(4-bromophenyl)-1H-imidazol-2-yl)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepin-7-ylcarbamate (37.8 mg, 79.4 μmol) and sodium bicarbonate (sat solution, 0.4 ml) were combined with tert-butanol (2.6 ml) to give a light brown suspension and deoxygenated for 5 min. PdCl2(DPPF) (5.81 mg, 7.94 μmol) was added and flushed with nitrogen. It was sealed heating at 90° C. for 4 hr. The reaction mixture was diluted with EtOAc (10 ml), filtered and concentrated in vacuo. The residue was purified on a silica gel column (CH2Cl2, 2%, 3%, 5%, 8% MeOH/CH2Cl2) to afford {(4S,7S)-4-[5(4′-{2-[2-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-8-oxa-2-aza-spiro[4.5]dec-3-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-6,10-dioxo-octahydro-pyridazino[1,2-a][1,2]diazepin-7-yl}-carbamic acid methyl ester as a light yellow solid (30 mg, 42.9%). ESI-LRMS m/e calcd for C44H53N9O8, [M+] 835. found 836 [M+H]. 1H NMR (DMSO-d6) δ: 12.09-12.45 (m, 1H), 7.57-7.99 (m, 11H), 7.49 (d, J=8.3 Hz, 2H), 5.80 (br. s., 1H), 4.93-5.16 (m, 1H), 4.46 (d, J=11.3 Hz, 2H), 3.92-4.27 (m, 1H), 3.64 (br. s., 3H), 3.50-3.60 (m, 10H), 2.88 (t, J=10.3 Hz, 1H), 1.77-2.36 (m, 6H), 1.63 (br. s., 2H), 1.48 (d, J=11.5 Hz, 1H), 0.77-1.02 (m, 6H), 0.67 (d, J=6.5 Hz, 2H), 0.12 (d, J=6.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([Cl:21])=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)Cl
Temperature: 40 °C
Yield: 41.6 %

Procedure:
6-(4-Fluorophenyl)-2-methyl-3-pyridinecarboxylic acid (0.2 g, 0.866 mol) was suspended in DCM (14 mL) and DMF (1 drop) was added. The mixture was cooled in an ice-bath and oxalyl chloride (0.226 mL, 2.598 mmol) was added portion wise over 5 minutes. The mixture was heated to 40° C. for 90 minutes. The mixture was allowed to cool and the solvent removed under vacuum to give 6-(4-fluorophenyl)-2-methyl-3-pyridinecarbonyl chloride as a yellow solid (0.270 g) which was used directly in step 2.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18](I)[C:17]([O:21][CH3:22])=[CH:16][C:15]=2[F:23])[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2].[F:24][C:25]([F:64])([F:63])[C:26]1[CH:27]=[C:28]([C@H:36]2[O:40][C:39](=[O:41])[N:38]([CH2:42][C:43]3[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:46]=[CH:45][C:44]=3B3OC(C)(C)C(C)(C)O3)[C@H:37]2[CH3:62])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1.C>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[C:1]([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18]([C:44]3[CH:45]=[CH:46][C:47]([C:49]([F:52])([F:51])[F:50])=[CH:48][C:43]=3[CH2:42][N:38]3[C@@H:37]([CH3:62])[C@@H:36]([C:28]4[CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=[C:26]([C:25]([F:24])([F:63])[F:64])[CH:27]=4)[O:40][C:39]3=[O:41])[C:17]([O:21][CH3:22])=[CH:16][C:15]=2[F:23])[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2]
Reactant: COc1cc(F)c(C2CCN(C(=O)COC(C)=O)CC2)cc1I
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Product: COc1cc(F)c(C2CCN(C(=O)COC(C)=O)CC2)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
A mixture of 2-[4-(2-fluoro-5-iodo-4-methoxyphenyl)piperidin-1-yl]-2-oxoethyl acetate (Step A; 33 mg; 0.076 mmol) and (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (Intermediate 9; 68 mg, 0.114 mmol) was treated with 1,1′-bis(di-t-butylphosphino)ferrocene palladium dichloride (˜5 mg) as described earlier. The product was purified by chiral HPLC (ChiralPak IA column, 15% IPA/heptane) to afford 2-{4-[2′-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-fluoro-6-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]piperidin-1-yl}-2-oxoethyl acetate as a colorless glass. LCMS=779.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers) δ 7.86 (s, 1 H), 7.69 (s, 2 H), 7.68-7.60 (m, 2 H), 7.32 (d, J=7.8 Hz, 1 H), 6.96-6.91 (m, 1 H), 6.72 (dd, J=11.9, 2.1 Hz, 1 H), 5.59-5.54 (m, 1 H), 4.90 (d, J=15.6 Hz, 1 H), 4.80-4.65 (m, 3 H), 4.13-4.04 (m, 1 H), 3.88-3.72 (m, 2 H), 3.78 (s, 3H), 3.21-3.04 (m, 2H), 2.72-2.67 (m, 1H), 2.17 (s, 3H), 1.96-1.83 (m, 2 H), 1.70-1.59 (m, 2 H), 0.42-0.39 (m, 3 H)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[N:7][N:8]=1.CCN(C(C)C)C(C)C.[CH:19]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20]1>N1C=CC=CC=1>[O:9]=[C:4]1[C:3]([CH2:2][NH:1][C:23]([CH:19]2[CH2:22][CH2:21][CH2:20]2)=[O:24])=[N:8][N:7]=[CH:6][NH:5]1
Reactant: NCc1nnc[nH]c1=O
Reactant: O=C(Cl)C1CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: O=C(NCc1nnc[nH]c1=O)C1CCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-aminomethyl-4H-[1,2,4]triazin-5-one (500 mg, 3.96 mmol) and DIEA (0.829 mL, 4.76 mmol) in anhydrous N,N-DMF (20 mL) and anhydrous pyridine (2 mL) was dropwise charged with cyclobutanecarbonyl chloride (0.451 mL, 3.96 mmol) at 0° C. then warmed to rt and stirred for an additional 1.5 h. The reaction mixture was quenched with H2O (2 mL) and concentrated in vacuo and was purified by chromatography on silica gel [eluting with 5% MeOH in DCM (200 mL)×10% MeOH in DCM (800 mL)], affording the title compound; 1H NMR (DMSO-d6, 400 MHz) δ 1.7-1.82 (m, 1H), 1.70-1.92 (m, 1H); 1.97-2.07 (m, 2H); 2.07-2.19 (m, 2H); 3.55-3.67 (m, 1H); 4.19 (d, 2H); 7.97 (br. t, J=5.6 Hz, 1H); 8.67 (s, 1H); MS (ES+): m/z 209.25 (100) [MH+], HPLC: tR=1.56 min (MicromassZQ, polar—5 min).
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]([NH2:10])=[CH:8][C:7]([CH3:11])=[N:6]1)([CH3:4])[CH3:3].[CH:12]1(/[C:15](/O)=[CH:16]/[C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1>C(O)(=O)C>[CH:12]1([C:15]2[CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]3[C:7]([CH3:11])=[N:6][N:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:9]=3[N:10]=2)[CH2:13][CH2:14]1
Reactant: CCOC(=O)C(=O)/C=C(\O)C1CC1
Reactant: Cc1cc(N)n(C(C)(C)C)n1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C(C)(C)C

Procedure:
1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-amine (166 mg, 1.086 mmol), ethyl (3Z)-4-cyclopropyl-4-hydroxy-2-oxo-3-butenoate (200 mg, 1.086 mmol) and acetic acid (10 mL) were heated to reflux for 2 hours. The solvent was removed in vacuo and the residue purified by silica gel chromatography (eluent: 0% to 7% EtOAc:Hex). The product was collected as 278 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.07 (dt, 2 H), 1.13-1.20 (m, 2 H), 1.46 (t, J=7.20 Hz, 3 H), 1.78 (s, 9 H), 2.18 (m, J=7.99, 7.99, 4.74, 4.55 Hz, 1 H), 2.65 (s, 3 H), 4.47 (q, J=7.07 Hz, 2 H), 7.43 (s, 1 H). LCMS(ES) [M+H]+ 302.2
Reaction SMILES: Cl(O)(=O)(=O)=O.[C:6]1([C:12]2[O:13][CH2:14][CH2:15][N:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[OH-].[Na+]>>[C:6]1([CH:12]2[N:16]=[CH:15][CH2:14][O:13]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc(C2=NCCO2)cc1
Agent: Cl
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Product: C1=NC(c2ccccc2)OC1
Yield: 88 %

Procedure:
50 g of 2-phenyl-3-oxazoline are polymerized at the temperature of 150° C. for 40 minutes in the presence of an equimolar complex of perchloric acid with 2-phenyl-2-oxazoline taken in the ratio of the monomer to the initiator equal to 100:1. The resulting poly-N-benzoylethylenimine is hydrolyzed first with an aqueous solution of hydrochloric acid at reflux. The thus-prepared polymer is boiled in a solution of caustic soda. Linear polyethylenimine is dried over phosphorus pentoxide to give 12.8 g of an anhydrous polymer; the yield is 88%, intrinsic viscosity of the polymer [η]20 =0.18 dl/g (abs.alcohol) which corresponds to the molecular mass of 5,000.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)[CH:7]=[CH:6]2.[C:22](Cl)(=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[C:17]=1[C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(-c3cc4ccccc4o3)ccc2c1
Reactant: CCCCC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCCC(=O)c1c(-c2ccc3cc(OC)ccc3c2)oc2ccccc12
Temperature: -20 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
To a stirring mixture of 2-(6-methoxy-2-naphthyl)-1-benzofuran (4.02 g, 14.7 mmol) in chloroform (70 mL) chilled in an ice bath was added valeryl chloride (2.6 mL, 22 mmol). The reaction mixture was chilled to −20° C. and tin (IV) chloride (2.2 mL, 19 mmol) was added, dropwise. The mixture was then stirred at room temperature for one hour and then refluxed for 3 hours, 20 minutes. It was allowed to cool to room temperature and poured into ice. The organic phase was diluted with excess ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and solvent evaporated. The residue was purified twice by flash chromatography (Biotage apparatus) using 2% ethyl acetate in hexane and 10-50% chloroform in hexane to afford 1-[2-(6-methoxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone as a yellow gum (3.17 g). Mass spectrum (+EI, M+) m/z358. 1HNMR (400 MHz, DMSO-d6): δ8.35 (s, 1H), 8.0-8.05 (m, 3H), 7.8 (dd, 1H, J=8.5 Hz and 1.7 Hz), 7.7-7.75 (m, 1H), 7.4-7.45 (m, 3H), 7.25-7.3 (m, 1H), 3.9 (s, 3H), 2.7 (t, 2H, J=7.3 Hz), 1.5-1.6 (m, 2H), 1.1-1.2 (m, 2H), and 0.7 ppm (t, 3H, J=7.4 Hz).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[NH:9][C:8]2=O)(=[O:3])[CH3:2].CN(C=O)C.O=S(Cl)[Cl:32]>>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[N:9]=[C:8]2[Cl:32])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2nc(-c3cccc([N+](=O)[O-])c3)nc(Cl)c2c1

Procedure:
A suspension of 2-(3-nitrophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl acetate (3.30 g, 10.1 mmol) in SOCl2 (65 mL) was added DMF (2 mL). The mixture was refluxed for 2.5 h, upon which the volatiles were removed in vacuo. The residue was taken up in CHCl3 (450 mL) and washed with sat NaHCO3 (200 ml) and water (200 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give the product 4-chloro-2-(3-nitrophenyl)quinazolin-6-yl acetate (3.53 g, 10.3 mmol). HPLC retention time 9.748 min.
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])[CH2:5]2.[CH:12](OCC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[C:6](=[O:11])[CH2:5]2
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCOC(OCC)OCC
Product: CCOC(OCC)N1C(=O)Cc2cc(F)ccc21
Yield: 40 %

Procedure:
A solution of 5-fluorooxindole (980 mg, 6.5 mmol), (prepared according to Synthesis 1993, 51), in triethyl orthoformate (25 ml) was stirred and heated at reflux for 8 hours. The volatiles were removed by evaporation and the crude product purified by flash chromatography using petroleum ether/ether 7/3 as eluent to give 5-fluoro-1-diethoxymethyloxindole (637 mg, 40%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[CH:16](Br)([CH3:18])[CH3:17]>>[C:2]1([CH3:1])[CH:7]=[CH:6][C:5]([C:8]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Cn2cncn2)cc1
Reactant: CC(C)Br
Product: Cc1ccc(C(=Cn2cncn2)OC(C)C)cc1

Procedure:
Analogously to Example 1a,b, after reacting 1-(4-methylphenyl)-2-[1,2,4]triazol-1-yl-ethanone with isopropyl bromide there was obtained 1-[2-(4-tolyl)-2-isopropoxy-vinyl]-1H-[1,2,4]triazole. After reaction with HCl in dioxan there was obtained a salt of the composition C14H17N3O.HCl.[M+H]+ =243.
Reaction SMILES: [C:1]([NH:9][C:10]([C:37]([O:39][CH3:40])=[O:38])=[CH:11][C:12]1[N:13]=[C:14]([F:36])[N:15]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pt]=O>[CH:2]1([C:1]([NH:9][CH:10]([C:37]([O:39][CH3:40])=[O:38])[CH2:11][C:12]2[N:13]=[C:14]([F:36])[N:15]([C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:16]=2)=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)C(=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1)NC(=O)c1ccccc1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1)NC(=O)C1CCCCC1

Procedure:
4-(2-Benzoylamino-2-methoxycarbonylvinyl)-2-fluoro-1-triphenylmethylimidazole was hydrogenated in EtOAc using prehydrogenated fully active platinum oxide catalyst (Adams' catalyst) for 2.5 days. Work-up gave 4-(2-cyclohexylcarbonylamino-2-methoxycarbonylethyl)-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. in CDCl3 : 1.0-2.3 (m, 11H); 2.85 (d, 2H); 3.6 (s, 3H); 4.2 and 4.27 (d of t, 1H); 6.24 (s, 1H); 6.8 (d, 1H); 7.0-7.5 (m, 15H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH3:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)=[O:26].[OH-].[Na+]>CN(C=O)C.CO>[C:25]([C:27]1[CH:32]=[CH:31][C:30]([NH:33]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:29][CH:28]=1)(=[O:26])[CH3:24]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-aminoacetophenone in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3C=NC=C[CH:16]=3)=[CH:10][C:5]2=[N:4][C:3]=1[NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19].ClCC(NC(NCC)=O)=[O:26].C(N(C(C)C)C(C)C)C>CN(C)C=O.O>[C:11]([C:9]1[CH:8]=[CH:7][N:6]2[CH:2]=[C:3]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])[N:4]=[C:5]2[CH:10]=1)(=[O:26])[CH3:16]
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)ccn2c1Cl
Reactant: CCNC(=O)NC(=O)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)Nc1cn2ccc(C(C)=O)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 156.7 %

Procedure:
A mixture of compound (2) (0.4 g, 1.27 mmol), N-(chloroacetyl)-N′-ethylurea (0.3 g, 1.8 mmol) and N-ethyldiisopropylamine (0.33 g, 2.5 mmol) in dry DMF (“dimethylformamide”) (5 mL) was stirred at room temperature overnight. The mixture was diluted with water to give 0.49 g of (3) as a solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][C:28]1([CH3:40])[O:32][CH:31]([CH2:33][N:34]2[CH:38]=[C:37]([NH2:39])[CH:36]=[N:35]2)[CH2:30][O:29]1.CCN(C(C)C)C(C)C>O1CCOCC1.C(OCC)(=O)C>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:21]=[CH:22][N:23]=[C:24]([NH:39][C:37]4[CH:36]=[N:35][N:34]([CH2:33][CH:31]5[CH2:30][O:29][C:28]([CH3:40])([CH3:27])[O:32]5)[CH:38]=4)[N:25]=3)[CH2:16][CH2:15]2)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCC(Cn2cc(N)cn2)O1
Reactant: Clc1ncnc(N2CCN(c3ncc(Cc4ccccc4)cn3)CC2)n1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OCC(Cn2cc(Nc3ncnc(N4CCN(c5ncc(Cc6ccccc6)cn5)CC4)n3)cn2)O1
Temperature: 25 °C
Yield: 126.1 %

Procedure:
A solution of 2-(4-(5-benzylpyrimidin-2-yl)piperazin-1-yl)-4-chloro-1,3,5-triazine (110 mg, 0.3 mmol), 1((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-amine (90 mg, 0.45 mmol) and Hunig's base (80 mg, 0.6 mmol) in 1,4-dioxane (4 mL) was stirred at 60° C. for 5 h. LCMS showed the reaction was completed. The reaction mixture was cooled to RT and diluted with ethyl acetate (40 mL). The organic phase was washed with water (40 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated to give 4-(4-(5-benzylpyrimidin-2-yl)piperazin-1-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-1,3,5-triazin-2-amine (200 mg, crude) as a yellow solid, which was directly used in the next step without further purification. MS (ES+) C26H30N10O2 requires: 528, found: 529 [M+H]+.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[N:14][NH:15][CH:16]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[H-].[Na+].Br[CH2:20][C:21]1[C:30]([Cl:31])=[C:29]([Cl:32])[CH:28]=[C:27]2[C:22]=1[N:23]=[C:24]([O:35][CH3:36])[C:25]([O:33][CH3:34])=[N:26]2.[Cl-].[NH4+]>O>[Cl:31][C:30]1[C:21]([CH2:20][N:15]2[CH:16]=[C:12]([CH2:11][CH2:10][CH2:9][N:3]3[CH2:8][CH2:7][O:6][CH2:5][CH2:4]3)[CH:13]=[N:14]2)=[C:22]2[C:27](=[CH:28][C:29]=1[Cl:32])[N:26]=[C:25]([O:33][CH3:34])[C:24]([O:35][CH3:36])=[N:23]2
Reactant: c1n[nH]cc1CCCN1CCOCC1
Reactant: COc1nc2cc(Cl)c(Cl)c(CBr)c2nc1OC
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: O
Product: COc1nc2cc(Cl)c(Cl)c(Cn3cc(CCCN4CCOCC4)cn3)c2nc1OC
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
4-[3-(4-Morpholinyl)propyl]pyrazole dihydrochloride (268 mg, 1 mmol) was added to a stirred suspension of sodium hydride (120 mg, 80% oil dispersion, 4 mmol) at 0° C. under nitrogen. After 30 minutes, the mixture was cooled to -40° C. and 5-bromomethyl-6,7-dichloro-2,3-dimethoxyquinoxaline (Preparation 1, 235 mg, 0.67 mmol) was added. The mixture was allowed to warm to -20° C. over 1 hour and saturated aqueous ammonium chloride (20 mL) was added. The mixure was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The extracts were washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with dichloromethane, then ethyl acetate then finally ethyl acetate:methanol:triethylamine (100:3:1) to give 6,7-dichloro-2,3-dimethoxy-5-{4-[3-(4-morpholinyl)propyl]pyrazol-1-ylmethyl}quinoxaline (278 mg, 89%) as a colourless gum.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F-:11].[K+]>CS(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([F:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(F)cc1
Temperature: 170 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
157 g of 4-nitrochlorobenzene, 200 g of dimethylsulfoxide, 62.7 g of potassium fluoride, and 2.49 g of (N,N-dimethylimidazolidino)tetramethyl-guanidinium chloride were placed in a 1 liter four-neck flask equipped with thermometer, anchor stirrer, and reflux condenser with bubble counter. The mixture was heated with stirring to 170° C. and kept at this temperature for 5 hours. The reaction mixture was then cooled to room temperature, water was added at a volumetric ratio of 1:1, the phases that formed were separated, and, from the organic phase, by fractional distillation at reduced pressure, 4-nitrofluorobenzene was obtained in a yield of 96% of theory.