Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.Cl.[N:17]1([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)CC)C>ClCCl.CN(C=O)C.C(OC(=O)C)C>[F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5]([N:20]1[CH2:21][CH2:22][N:17]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[CH2:18][CH2:19]1)=[O:6]
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(/C=C/C(F)(F)F)N1CCN(c2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (28 mg, 0.2 mmol) was dissolved in dichloromethane (1 ml), oxalyl chloride (18 μl, 0.2 mol) and one drop of DMF were added and the resulting solution was stirred at room temperature for 10 minutes. This solution was added to a solution of 2-piperazin-1-ylquinoline hydrochloride (25 mg, 0.1 mmol) in DMF (0.5 ml). Triethylamine (42 μl, 0.3 mmol) was added and the resulting mixture was stirred at room temperature for two hours. The mixture was diluted with ethylacetate and the resulting mixture was washed with saturated sodium bicarbonate solution, brine and dried (MgSO4). The solvent was removed under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 15 mg of a solid (0.046 mmol, 46%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:18]/[O:19][C:20](=[O:22])[CH3:21])/[C:15]([OH:17])=[O:16])[N:13]=1.C(OC(C)C)(C)C>C(O)=O>[CH:1]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:18]/[O:19][C:20](=[O:22])[CH3:21])/[C:15]([OH:17])=[O:16])[N:13]=1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O/N=C(\C(=O)O)c1csc(N)n1
Solvent: CC(C)OC(C)C
Solvent: O=CO
Product: CC(=O)O/N=C(\C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To acetic anhydride (20.6 ml) was added formic acid (16.6 ml) at 15° C. The mixture was stirred at room temperature for 30 minutes. To the mixture was 2-(2-aminothiazol-4-yl)-2-(Z)-(acetoxyimino)acetic acid (10 g) under ice-cooling, and the reaction mixture was stirred at room temperature for 20 hours. To the mixture was added isopropyl ether (37.2 ml) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The resulting precipitate was collected by filtration to give 2-(2-formylaminothiazol-4-yl)-2-(Z)-(acetoxyimino)acetic acid (9.39 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.Cl.[NH2:16][CH:17]([CH3:25])[C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20].CCN(C(C)C)C(C)C>CC(N(C)C)=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:16][CH:17]([CH3:25])[C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: COC(=O)C(C)(C)C(C)N
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)C(C)(C)C(C)Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 110 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
To a solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 1.0 gm, 3.64 mmol) and methyl 3-amino-2,2-dimethylbutanoate hydrochloride (1.0 g, 5.50 mmol) in DMA (10 ml) was added DIPEA (3.14 ml, 18.2 mmol) at rt. The reaction mixture was stirred at 110° C. overnight. Upon completion, the reaction mixture was cooled to rt and DMA was removed under reduced pressure to give a dark oily compound. It was dissolved in ethyl acetate (50 ml) and washed with water (20 ml). The aqueous layer was extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried over anhyd. sodium sulfate, filtered and concentrated under vacuum. The crude compound was purified by column chromatography using 40% ethyl acetate in hexanes as the eluting solvent to give the title compound (700 mg, 50%). 1NMR (400 MHz, DMSO-d6): δ 1.22-1.24 (m, 9H), 3.57-3.574 (s,3H), 4.47-4.51 (m, 1H), 7.046 (s, 1H), 7.89 (s, 1H), 8.24 (s, 1H), 10.92-10.94 (d, J=9.2 Hz).
Reaction SMILES: [I:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([S:11](Cl)(=[O:13])=[O:12])[CH:3]=1.[CH3:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].N1C=CC=CC=1>ClCCl>[I:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([S:11]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH3:15])(=[O:13])=[O:12])[CH:3]=1
Reactant: O=S(=O)(Cl)c1cc(I)c2occc2c1
Reactant: Cc1ccccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccccc1NS(=O)(=O)c1cc(I)c2occc2c1
Reaction time: 8 h

Procedure:
7-Iodo-1-benzofuran-5-sulfonyl chloride (10 g, 29.2 mmol; Intermediate 56) and 2-methyl aniline (3.43 mL, 32.1 mmol) were dissolved in dichloromethane (150 mL) and pyridine (3.53 mL, 43.8 mmol) was added. The solution was stirred overnight and washed with 1 M HCl (2×100 mL), dried over sodium sulfate and evaporated to give the crude solid product that was recrystallized from methanol. Yield: 5.32 g (44%) of a beige solid.
Reaction SMILES: [CH2:1]([NH:8][CH2:9]CC1C2C(=CC=C(F)C=2OC)N(C)C=1)C1C=CC=CC=1.[F:24][C:25]1[C:26]([O:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[CH:29]=[C:28]2[CH2:35][CH2:36]O>>[F:24][C:25]1[C:26]([O:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[CH:29]=[C:28]2[CH2:35][CH2:36][N:8]([CH3:9])[CH3:1]
Reactant: COc1c(F)ccc2c1c(CCNCc1ccccc1)cn2C
Reactant: Cn1cc(CCO)c2c(OCCc3ccccc3)c(F)ccc21
Product: CN(C)CCc1cn(C)c2ccc(F)c(OCCc3ccccc3)c12
Yield: 72 %

Procedure:
Following the procedure (step 6, scheme 17) used to prepare compound 17-7, compound 18-1 gave compound 18-2 in 72% yield as a colorless oil, which was converted to the hydrochloride salt. 1H NMR (DMSO-d6, 300 MHz) δ (ppm) (HCl salt): 9.92 (br, 1H), 7.23-7.32 (m, 5H), 7.21 (s, 1H), 7.10 (dd, J=9.1, 4.1 Hz, 1H), 7.04 (dd, J=12.1, 8.8 Hz, 1H), 4.40 (td, J=7.4, 1.6 Hz, 2H), 3.70 (s, 3H), 3.16-3.21 (m, 2H), 3.11 (t, J=7.1 Hz, 2H), 3.00-3.06 (m, 2H), 2.73 (s, 6H). LRMS: calc 340.2 found 341.2 [MH]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.CC(C)([O-])C.[Na+]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:3][CH:4]=1
Reactant: C1COCCN1
Reactant: COc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: COc1ccc(N2CCOCC2)cc1
Yield: 94.7 %

Procedure:
According to the general procedure B, 4-chloroanisole (82 mg, 0.55 mmol) reacted with morpholine (46 mg, 0.53 mmol) using 1 mol % of catalyst and sodium tert-butoxide (63 mg, 0.60 mmol) at 70° C. for 27 h to give the title compound (97 mg, 95%) as a solid: 1H-NMR (400 MHz, CDCl3): δ 6.92-6.85 (m, 4H), 3.87 (t, 4H, J=4.8 Hz), 3.78 (s, 3H), 3.07 (t, 4H, J=4.8 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 153.92, 145.60, 117.77, 114.47, 67.00, 55.52, 50.78. GC/MS(EI); m/z 193 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[C:27](OCC)(=[O:33])[C:28](OCC)=[O:29]>C(OCCO)C>[CH:22]1([N:21]2[C:3]3[N:4]=[C:5]([NH:8][C:9]4[CH:14]=[CH:13][C:12]([N:15]5[CH2:16][CH2:17][O:18][CH2:19][CH2:20]5)=[CH:11][CH:10]=4)[N:6]=[CH:7][C:2]=3[NH:1][C:28](=[O:29])[C:27]2=[O:33])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Nc1cnc(Nc2ccc(N3CCOCC3)cc2)nc1NC1CCCC1
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCOCCO
Product: O=c1[nH]c2cnc(Nc3ccc(N4CCOCC4)cc3)nc2n(C2CCCC2)c1=O
Yield: 49 %

Procedure:
A mixture of 0.354 g (1 mmol) of 5-amino-4-(cyclopentylamino)-2-[[4-(morpholin-4-yl)phenyl]amino]pyrimidine and 5 mL (32 mmol) of diethyl oxalate in 20 mL of 2-ethoxyethanol is heated under reflux for 3 hours and then cooled to give 0.20 g (49%) of the title compound (Compound 23): mp (EtOH) 283–286° C. 1H NMR [(CD3)2SO]: δ 11.87 (br, 1H, exchangeable with D2O, H-5), 9.29 (br, 1H, exchangeable with D2O, 2NH), 8.12 (s, 1H, H-4), 7.50 (br d, J=9.0 Hz, 2H, H-2′,6′), 6.90 (d, J=9.1 Hz, 2H, H-3′,5′), 5.62 (pentet, J=8.8 Hz, 1H cyclopentyl CH), 3.74 (br t, J=4.7 Hz, 4H, CH2O)), 3.03 (br t, J=4.7 Hz, 4H, CH2N), 2.21–2.11 (m, 2H, cyclopentyl), 1.97–1.84 (m, 2H, cyclopentyl), 1.84–1.74 (m, 2H, cyclopentyl), 1.63–1.52 (m, 2H, cyclopentyl).
Reaction SMILES: Cl.[N:2]1[C:6]2[CH2:7][CH2:8][CH:9]([C:11]([OH:13])=O)[CH2:10][C:5]=2[NH:4][CH:3]=1.[C:14]1([CH:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:14]1([CH:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([C:11]([CH:9]3[CH2:8][CH2:7][C:6]4[N:2]=[CH:3][NH:4][C:5]=4[CH2:10]3)=[O:13])[CH2:21]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)C1CCc2nc[nH]c2C1
Reactant: c1ccc(C2CNc3ccccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(C1CCc2nc[nH]c2C1)N1CC(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.5 %

Procedure:
A mixed solution of 518 mg of hydrochloride (racemic form) of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid, 500mg of (+)-3-phenylindoline, and 15 ml of dimethyl formamide was cooled to 0° C. The cooled solution and 736 mg of hydrochloride of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide added thereto were gradually heated to normal room temperature and stirred at the same temperature for 12 hours. The resultant reaction solution was concentrated under a reduced pressure. The residue of this concentration was neutralized by addition of an aqueous potassium carbonate solution and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and then distilled. The residue of this distillation was refined by silica gel column chromatography to obtain 725 mg of 5-(3-phenylindolin-1-ylcarbonyl)-4,5,6,7-tetrahydrobenzimidazole (82.5%) as an epimer mixture.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14]2=[O:15])=[CH:8][CH:7]=1>>[O:23]=[C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14](=[O:15])[N:13]1[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:11][CH:10]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccccc1
Reactant: O=S(=O)(O)Cl
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(S(=O)(=O)Cl)cc1
Temperature: 60 °C
Yield: 73 %

Procedure:
Under N2 atmosphere, 11.26 mL chlorosulfonic acid was cooled in an ice bath, and under stirring 10.00 g n-benzylphthalimide was added portionwise over a period of 20 min. The ice bath was removed and the mixture was heated to 60° C. for 30 min. After cooling to room temperature, the mixture was cautiously poured into ice water and extracted twice with chloroform. The combined organic layers were dried over MgSO4 and concentrated to a small volume. The product was obtained by trituration of the concentrate with PA to give 10.44 g (73%) of a white powder. 1H NMR (400 MHz, CDCl3) δ 4.95 (s, 2H), 7.67 (d, J=8.43 Hz, 2H), 7.73-7.78 (m, 2H), 7.85-7.90 (m, 2H), 8.00 (d, J=8.43 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([NH:12][C:13](=[O:23])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].C1(C)C=CC=CC=1.CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6]([OH:8])=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[C:13](=[O:23])[NH:12]2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Cc1cccc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cccc(-c2c(O)c3ccc(Cl)cc3[nH]c2=O)c1
Reaction time: 1.5 h

Procedure:
To a solution of the foregoing amide (0.50 g, 1.5 mmol) in tetrahydrofuran (20 ml) was added a solution of potassium hexamethyldisilazide in toluene (0.5M, 8 ml, 4 mmol) and the resulting mixture stirred for 1.5 h under a nitrogen atmosphere. Methanol (3 ml) was then added and the solution evaporated. The residue remaining was partitioned between diethyl ether (10 ml) and aqueous sodium hydroxide (0.5M, 20 ml) and the aqueous layer acidified with hydrochloric acid (5M). The precipitated solid was collected, washed with water and recrystallised from dimethylformamide to afford the title compound as a colourless solid; m.p.>320° C. (dec) (Found: C, 63.44; H, 3.89; N, 4.54. C16H12ClNO3 requires C, 63.69; H, 4.01; N, 4.64%); δH (DMSO-d6) 3.76 (3H, s, OCH3), 6.88-6.94 (3H, m, ArH), 7.20 (1H, dd, J 8.7 and 2.1 Hz, 6-H), 7.28-7.32 (2H, m, ArH), 7.91 (1H, d, J 8.7 Hz, 5-H), 10.24 (1H, br s, OH) and 11.48 (1H, s, NH); m/z 301 (M+).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=2[N:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(=O)([O-])O.[Na+]>>[N:14]1([C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=3[N:3]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1cccc2[nH]c(Cl)nc12
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=[N+]([O-])c1cccc2[nH]c(N3CCOCC3)nc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-4-nitro-1H-benzimidazole (300 mg) and morpholine (1 ml) was stirred at 50° C. for 8 hours. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The organic layer was washed with brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo. The residue was washed with isopropyl ether and collected by vacuum filtration to give 2-(morpholin-4-yl)-4-nitro-1H-benzimidazole (288 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:28])[N:5]([CH:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=1)[CH2:13][CH:14]([OH:16])[CH3:15])[C:6]2=[O:11].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:28])[N:5]([CH:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=1)[CH2:13][C:14](=[O:16])[CH3:15])[C:6]2=[O:11]
Reactant: CCOc1cc(C(CC(C)O)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOc1cc(C(CC(C)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.4 %

Procedure:
A mixture of 4-amino-2-[1-(3-ethoxy-4-methoxyphenyl)-3-hydroxybutyl]isoindoline-1,3-dione (0.7 g, 1.82 mmol), pyridinium chlorochromate (0.79 g, 3.64 mmol) and Celite (0.6 g) in methylene chloride (40 mL) was stirred at room temperature for 4 hours. The mixture was filtered through celite and the filtrate was washed with water, brine, dried and concentrated. The residue was purified by chromatography (silica gel, methylene chloride:ethyl acetate 95:5) to give 4-amino-2-[1-(3-ethoxy-4-methoxyphenyl)-3-oxobutyl]isoindoline-1,3-dione as a white solid (0.49 g, 71%); 1H NMR (CDCl3) δ 7.38-7.31 (t, J=7.3 Hz, 1H), 7.08-7.05 (m, 3H), 6.81-6.77 (m, 2H), 5.74-5.67 (dd, J=5.9 and 9.4 Hz, 1H), 5.20 (s, 2H), 4.11 (q, J=7.0 Hz, 2H), 3.98-3.87 (dd, J=9.5 and 17.8 Hz, 1H), 3.83 (s, 3H), 3.33-3.23 (dd, J=5.6 and 17.7 Hz, 1H), 2.18-(s, 3H), 1.44 (t, J=6.9 Hz, 3H).
Reaction SMILES: C1(N=C=O)C=CC=CC=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)#[CH:11].[N+:22]([CH2:25][CH3:26])([O-])=[O:23].C(N(CC)CC)C>C1C=CC=CC=1.O>[CH3:26][C:25]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)[O:23][N:22]=1
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Reactant: CC[N+](=O)[O-]
Solvent: O=C=Nc1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)on1

Procedure:
4.25 ml (39.18 mmol) of phenyl isocyanate are added dropwise at room temperature to a solution of 5 g (29.38 mmol) of 1-ethynyl-4-(trifluoromethyl)benzene, 0.7 ml (9.79 mmol) of nitroethane and 0.27 ml (1.95 mmol) of triethylamine in 40 ml of benzene. The reaction mixture is subsequently stirred under reflux for 12 h. After cooling, the suspension is mixed with water (20 ml) and stirred at room temperature for a further 4 h. The precipitate is filtered off with suction and washed with benzene (10 ml). The organic phase of the filtrate is separated off, dried with magnesium sulfate and concentrated. The residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 9:1). 1.83 g (82% of theory) of the title compound are obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1)[CH2:6][C:5]2([CH3:22])[CH3:21]>[Fe].C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:22])[CH3:21]
Reactant: CC1(C)CC(c2cccc([N+](=O)[O-])c2)Nc2ccc(Cl)cc21
Agent: [Fe]
Solvent: CCO
Solvent: O
Product: CC1(C)CC(c2cccc(N)c2)Nc2ccc(Cl)cc21
Yield: 95.9 %

Procedure:
Iron powder (43.0 g, 762 mmol), ethanol/water (3:1, 720 ml) and 6-chloro-4,4-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline (24.1 g, 76 mmol) were heated to reflux for 2 h. iron powder was filtered and the solvent was removed to afford 3-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine as yellow solid (20.9 g, yield: 90%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>C(Cl)(Cl)Cl.ClCCl>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(cc1[N+](=O)[O-])OCO2
Yield: 90 %

Procedure:
5-Methyl-1,3-benzodioxole (8.00 g, 58.8 mmol) was dissolved in chloroform (160 ml), and the mixture was stirred under ice-cooling. To this solution was gradually added 60% nitric acid (20 ml), and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with dichloromethane, washed with water and saturated aqueous sodium hydrogen carbonate, and dried over potassium carbonate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (9.58 g, yield 90%) as a pale-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10](Cl)[N:9]=[C:8]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21].[NH3:22]>>[NH2:22][C:10]1[N:9]=[C:8]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[N:11]=1
Reactant: N
Reactant: COc1cccc2c(Nc3ccccc3C)nc(Cl)nc12
Product: COc1cccc2c(Nc3ccccc3C)nc(N)nc12
Yield: 31 %

Procedure:
8-Methoxy-4-(2-methylphenylamino)-2-chloroquinazoline (1.8 g, 0.006 mol) was dissolved in ethanolic ammonia and heated in a sealed vessel at 120° for 3 hours. After cooling, removal of excess solvent and chromatography (silica gel, 2% methanolic ammonia in chloroform) the 2 amino-4-(2-methylphenylamino)-8-methoxyquinazoline was isolated as crystals (0.52 g, 31%) from ethanol, m.p. 218°-220°.
Reaction SMILES: [C:1]([O:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH:12]2[C@:7]1([CH3:17])[CH2:8][CH2:9][CH2:10][CH:11]2[OH:16])([CH3:4])([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.C(OCC)C>[C:1]([O:5][C@H:6]1[CH2:15][CH2:14][CH2:13][C@@H:12]2[C@:7]1([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)O[C@H]1CCCC2C(O)CCC[C@@]21C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)O[C@H]1CCC[C@H]2C(=O)CCC[C@]12C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a solution of 3.4 g (14.1 mMol) of (1RS,4aS,5S,8aRS)-5-tert-Butoxy-4a-methyl-decahydro-naphtalen-1-ol in 34 ml methylenechloride was added under stirring 3.66 g (17.0 mMol) of pyridiniumchlorochromate and the reaction mixture was kept under stirring overnight. Then the reaction was diluted with 33 ml diethylether, kept stirring for 15 minutes and filtered over florisil®. The filtrate was evaporated to dryness in vacuo and the residue dissolved in 33 ml of tetrahydrofuran. Under stirring and argon atmosphere, 1.65 ml of a one molar solution of potassium-tertio-butoxide in tetrahydrofuran was added and the reaction was kept overnight. This equilibration is monitored by TLC (silica gel, hexane/ethylacetate 4/1), which shows the almost complete disappearance of one of the two epimers. The reaction mixture is evaporated in vacuo to dryness, the residue is taken up in water and extracted three times with diethylether. The combined organic phase is washed with water and brine, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed over 120 g of silica gel with hexane/ethylacetate 9/1 to yield 2.39 g (71%) of pure (4aS,5S,8aR)-5-tert-Butoxy-4a-methyl-octahydro-naphtalen-1-one. An analytical sample was obtained by crystallization from hexane with a m.p. of 78-79° C.
Reaction SMILES: [C:1]1([NH:7]C(=O)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1.[OH-].[K+]>[Cu]Cl.O.C1(C)C(C)=CC=CC=1>[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: Fc1cccc(Br)c1
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1C
Product: Fc1cccc(Nc2ccccc2)c1
Temperature: 180 °C
Yield: 48.3 %

Procedure:
In a round bottom flask equipped with a condenser was placed N-phenylacetamide (1.0 g, 7.40 mmol), copper (I) chloride (0.146 g, 1.480 mmol), potassium carbonate (1.329 g, 9.62 mmol), 1-bromo-3-fluorobenzene (1.942 g, 11.10 mmol) and xylene (5 mL). The suspension was heated to 180° C. and refluxed for 66 h. The suspension was filtered; and the filtrate was concentrated. The dark brown residue was dissolved in ether; filtered; and the filtrate was concentrated. The dark brown residue was dissolved in ethanol (10.00 mL), treated with potassium hydroxide (1.909 g, 34.0 mmol) and refluxed for 2 h. The solution was poured into of water (80 mL) and extracted with DCM. The combined DCM extract was washed with water (6 X), dried over MgSO4 and concentrated to afford the title compound as a dark brown solid (0.669 g,). LCMS m/z=188.2 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[CH3:22][C:23]([CH3:29])([CH3:28])[CH2:24][C:25](Cl)=[O:26].N1C=CC=CC=1.O>ClCCCl>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:25](=[O:26])[CH2:24][C:23]([CH3:29])([CH3:28])[CH3:22])[CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)CC(C)(C)C
Yield: 94.6 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.00 g) obtained from Referential Example 7 was suspended in 1,2-dichloroethane (40 ml), 3,3-dimethylbutanoyl chloride (1.07 g) and pyridine (627 mg) were added, and the mixture was refluxed for 2 hours. Water was added to the reaction mixture, separated, the organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, to thereby obtain 2.53 g of the titled compound (Yield: 90.1%).