Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N+:7]([O-])=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Br)(Br)([Br:17])=O.[OH-].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:17][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c2ccccc12
Reactant: O=P(Br)(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(Br)nc2ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
4-Nitroquinoline 1-oxide (940 mg, 4.9 mmol) in chloroform (12 mL) was cooled to 0° C. To this solution, POBr3 (1.77 g, 6.2 mmol) was added in small portions. The mixture was stirred at 0° C. for 2 h and diluted with DCM (50 mL), and poured on ice (50 g). To this suspension, 1 M NaOH was added to adjust pH to about 9. Layers were separated and the organic layer was washed with water (2×50 mL) and dried over MgSO4 and concentrated. The crude product was purified by silica chromatography to afford 2-bromo-4-nitroquinoline as a yellow solid (620 mg, 50%). 1H NMR (400 MHz, CDCl3): δ 7.63-7.94 (m, 2H), 8.06 (s, 1H), 8.17 (t, J=7.16, 6.84 Hz, 1H), 8.38 (d, J=8.76 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[BH4-].[Na+].O.C(O)(=O)C>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[CH:10]([OH:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)C(=Cc1ccc(Cl)cc1)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)C(O)C(=Cc1ccc(Cl)cc1)n1cncn1
Reaction time: 3 h
Yield: 69 %

Procedure:
The II-A isomer (2.9 g, 0.01 mole; m.p. 108°-109° C.) of 1-(4-chlorophenyl)-4,4-dimethyl-2-(1,2,4-triazole-1-yl)-1-pentene-3-one (Compound No. 1') was dissolved in methanol (50 ml). Sodium borohydride (0.38 g, 0.01 mole) was added thereto while keeping the temperature of the reaction solution at 20° C. or less with ice-cooling. The reaction mixture was kept at 20° C. for 3 hours, and then decomposed with addition of water (100 ml) and acetic acid (1 ml). The organic layer was extracted with ethyl acetate (100 ml), and the extract was washed with a 5% aqueous sodium hydrogen carbonate solution (50 ml) and dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure, and the residue obtained was recrystallized from isopropanol to obtain 2.0 g (yield 69%) of the I'-A isomer having a melting point of 153°-155° C. The elementary analysis and NMR spectrum of the compound are shown below.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:23])=[C:4]([NH:10][S:11]([N:14]2[CH2:18][C@@H:17]([OH:19])[CH2:16][C@H:15]2[C:20](O)=[O:21])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C1CCC(N=C=NC2CCCCC2)CC1.C1C([N+]([O-])=O)=CC=C(O)C=1>C(#N)C>[OH:19][C@@H:17]1[CH2:18][N:14]2[C@H:15]([C:20](=[O:21])[N:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=3[CH3:23])[S:11]2(=[O:13])=[O:12])[CH2:16]1
Reactant: Cc1c(NS(=O)(=O)N2C[C@@H](O)C[C@H]2C(=O)O)ccc(C#N)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: CC#N
Product: Cc1c(N2C(=O)[C@@H]3C[C@H](O)CN3S2(=O)=O)ccc(C#N)c1Cl
Temperature: 25 °C
Yield: 51.9 %

Procedure:
To a solution of 4B (57 mg, 0.158 mmol) in 5 mL of acetonitrile at rt was added DCC (33 mg, 0.158 mmol) followed by p-nitrophenol (44 mg, 0.317 mmol). The suspension was refluxed for 1 h, cooled to rt and filtered. The filtrate was concentrated under reduced pressure and the residue dissolved in EtOAc, washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, EtOAc/Hexanes, 50:50 and 75:25) to afford the title compound (28 mg) as a beige solid. 1H NMR (DMSO-d6) δ 2.25, 2.28 (s, 3H), 2.31-2.38 (m, 2H), 3.46-3.50 (m, 1H), 3.86 (d, J=12.1, 1H), 4.24 (s, 1H), 4.93, 5.07 (d, J=7.2, 1H), 5.42, 5.51 (s, 1H), 7.27, 7.50 (d, J=8.2, 1H), 7.98, 8.03 (d, J=8.3, 1H); 13C NMR (DMSO-d6) δ 15.06, 15.74, 37.57, 60.55, 60.72, 64.84, 65.37, 68.30, 114.37, 115.61, 128.85, 129.59, 132.65, 132.79, 134.96, 136.96, 138.35, 139.36, 169.16; HPLC a) column: Phenominex LUNA C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA; 1 min hold, 4 mL/min UV detection at 220 nm, 2.62 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 254 nm, 2.45 min retention time (100%); HPLC c) column: Daicel Chiralcel OD 4.6×250 mm, Isocratic 25% Isopropanol/Hexanes, 30 min, 1 mL/min, UV detection at 220 nm, 12.65 min retention time (99%); MS (ES) m/z 340 [M−H]−.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C@H:8]1[C@H:33]([OH:34])[C@@:32]2([CH3:35])[C:11](=[CH:12][CH:13]=[C:14]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:27])[CH2:20][CH2:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[CH2:10][C@H:9]1[OH:37])(=[O:3])[CH3:2].N1C(C)=CC=C[C:39]=1[CH3:45].FC(F)(F)S(O[Si:52]([CH2:57][CH3:58])([CH2:55][CH3:56])[CH2:53][CH3:54])(=O)=O>ClCCl>[C:1]([O:4][CH2:5][CH2:6][O:7][C@H:8]1[C@H:33]([O:34][Si:52]([CH2:57][CH3:58])([CH2:55][CH3:56])[CH2:53][CH3:54])[C@@:32]2([CH3:35])[C:11](=[CH:12][CH:13]=[C:14]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:27])[CH2:20][CH2:21][CH2:22][C:23]([O:26][Si:52]([CH2:57][CH3:58])([CH2:55][CH3:56])[CH2:53][CH3:54])([CH3:25])[CH3:24])[CH2:10][C@H:9]1[O:37][Si:52]([CH2:39][CH3:45])([CH2:55][CH3:56])[CH2:53][CH3:54])(=[O:3])[CH3:2]
Reactant: Cc1cccc(C)n1
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)OCCO[C@@H]1[C@H](O)CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)CCCC(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]1O
Solvent: ClCCl
Product: CC[Si](CC)(CC)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)CCCC(C)(C)O[Si](CC)(CC)CC)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O[Si](CC)(CC)CC)[C@@H]1OCCOC(C)=O
Reaction time: 1.5 h
Yield: 75.6 %

Procedure:
To a dichloromethane (15 ml) solution of compound 3 (260 mg, 502 μmol) obtained in Example 1, and 2,6-lutidine (877 μl, 7.53 mmol), triethylsilyl trifluoromethanesulfonate (1.14 ml, 5.02 mmol) was added with ice cooling in an argon atmosphere, and the mixture was stirred for 1.5 hours at the same temperature. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (5% ethyl acetate/hexane) to give colorless oily compound 4 (327 mg, 76%).
Reaction SMILES: [Si:1]([O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH2:18][OH:19])=[CH:11][C:10]=1[CH2:20][CH2:21][CH3:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.C(OCC)C>[Si:1]([O:8][C:9]1[C:10]([CH2:20][CH2:21][CH3:22])=[CH:11][C:12]([CH:18]=[O:19])=[CH:13][C:14]=1[CH2:15][CH2:16][CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCCc1cc(CO)cc(CCC)c1O[Si](C)(C)C(C)(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCc1cc(C=O)cc(CCC)c1O[Si](C)(C)C(C)(C)C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
To a solution of 5.03 g (15.4 mmol)of t-butyldimethylsilyloxy-2,6-dipropyl-4-hydroxymethyl benzene in 30 mL of methylene chloride was added 8.7 g of pyridinium dichromate (PDC). The reaction mixture was stirred for 3 hours and then diluted with 300 mL of ethyl ether. The solution was then filtered through a pad of a 1:1 mixture of florisil and celite. Concentration of the filtrate gave 4.85 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=O.Cl[C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][N:17]=1.ClC1C=C(Cl)C=CC=1C1[C:37]([C:38]2[NH:39][CH:40]=[CH:41][N:42]=2)=[CH:36][N:35]=[C:34]([NH:43][CH2:44][CH2:45][NH:46]C2C=CC([N+]([O-])=O)=CN=2)[N:33]=1>>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]1[C:37]([C:38]2[NH:39][CH:40]=[CH:41][N:42]=2)=[CH:36][N:35]=[C:34]([NH:43][CH2:44][CH2:45][NH:46][C:16]2[N:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=2)[N:33]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: N#Cc1ccc(Cl)nc1
Product: N#Cc1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(C(F)(F)F)cc3F)n2)nc1

Procedure:
6-{[2-({4-[2-fluoro-4-(trifluoromethyl)phenyl]-5-imidazol-2-ylpyrimidin-2-yl}amino)ethyl]amino}pyridine-3-carbonitrile was prepared from 2-fluoro-4-(trifluoromethyl)benzoyl chloride and 2-chloro-5-(cyano)pyridine using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [BH4-].[K+].[F:3][C:4]([F:17])([F:16])[C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH:14]=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=2.O1CCCC1.O>CCOCC>[F:17][C:4]([F:3])([F:16])[C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][OH:15])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=Cc1c(C(F)(F)F)[nH]c2ccccc12
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1c(C(F)(F)F)[nH]c2ccccc12
Reaction time: 1 h
Yield: 64.6 %

Procedure:
2 g of potassium borohydride were added in small fractions at +5° C. to a solution of 4.6 g of the product of Step A, 150 ml of tetrahydrofuran and 30 ml of water and the mixture was stirred for one hour. The mixture was allowed to return to ambient temperature and the tetrahydrofuran was eliminated under reduced pressure. The resulting mixture was diluted with ether, washed with water, dried and concentrated under reduced pressure. The residue was chromatographed over silica (eluent: hexaneethyl acetate 7-3) to obtain 3 g of 2-trifluoromethyl-(1H)-indol-3-yl methanol melting at 106° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[F:21][C:22]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=1[C:24](O)=[O:25]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:24](=[O:25])[C:23]2[CH:27]=[C:28]([F:32])[C:29]([F:31])=[CH:30][C:22]=2[F:21])=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1cc(F)c(F)cc1F
Agent: Cl
Product: O=C(CNC(=O)c1cc(F)c(F)cc1F)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 2,4,5-trifluorobenzoic acid.
Reaction SMILES: [I:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[N:10]=2)=[CH:4][C:3]=1[CH3:16].CI.[C:19]([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[I:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]([C:9]2[CH:14]=[CH:13][N:12]([CH3:19])[C:11](=[O:15])[N:10]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(-c2cc[nH]c(=O)n2)cc(C)c1I
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccn(C)c(=O)n2)cc(C)c1I
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 4-(4-iodo-3,5-dimethylphenyl)pyrimidin-2(1H)-one (500 mg), methyliodide (165 μL) and K2CO3 (254 mg) in N,N-dimethylformamide (10 mL) is stirred for 12 hours at room temperature. Then the mixture is partitioned between water and dichloromethane. The aqueous phase is extracted twice with dichloromethane and the combined organic phases are washed with brine. After drying (MgSO4) the solvents are evaporated. The residue is triturated with diethylether. The solid is filtered off and dried to give the title compound. Yield: 380 mg; LC (method 11): tR=0.96 min; Mass spectrum (ESI+): m/z=341 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:29][S:30]([CH2:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)(=[O:32])=[O:31]>>[ClH:1].[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][NH:16][C:14]1[N:13]([CH3:25])[C:12]2[CH:26]=[CH:27][C:9]([N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]4[CH:39]=[CH:40][C:34]([CH2:33][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:35][CH:36]=4)[N:7]=3)[CH3:28])=[CH:10][C:11]=2[N:15]=1
Reactant: CS(=O)(=O)Cc1ccc(N)cc1
Reactant: CN(c1ccc2c(c1)nc(NCc1cccc(F)c1)n2C)c1ccnc(Cl)n1
Product: CN(c1ccc2c(c1)nc(NCc1cccc(F)c1)n2C)c1ccnc(Nc2ccc(CS(C)(=O)=O)cc2)n1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example two with N5-(2-chloro-pyrimidin-4-yl)-N2-(3-fluoro-benzyl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (99 mg, 0.25 mmol) and 4-[(methylsulfonyl)methyl]aniline (46 mg, 0.25 mmol) as a white solid (44 mg, 30%). 1H NMR (300 MHz, d6-DMSO) δ 10.64 (s, 1H), 9.82 (s, 1H), 7.93 (d, J=6.9 Hz, 1H), 7.57-7.66 (m, 3H), 7.28-7.43 (m, 7H), 7.12 (m, 1H), 5.94 (s, 1H), 4.80 (d, J=5.7 Hz, 2H), 4.41 (s, 2H), 3.76 (s, 3H), 3.50 (s, 3H), 2.87 (s, 3H). MS (ESI) m/z=546 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][OH:5].Cl[C:7]1[C:16]2[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][N:8]=1>C1COCC1>[CH2:4]([O:5][C:7]1[C:16]2[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][N:8]=1)[CH3:3]
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ncnc2c([N+](=O)[O-])cccc12
Reaction time: 0.25 h

Procedure:
A solution of 8-nitroquinazolin-4(3H)-one (Intermediate-7, step-1, 300 mg, 1.57 mmol) in POCl3 (3 mL) was heated at reflux for 2 h. Then the reaction mixture was concentrated and dried to afford 4-chloro-8-nitroquinazoline which was used for the next step without further purification. Then NaH (263 mg, 11.54 mmol, 95%) was added to EtOH (2 mL) at 0° C. and stirred at that temperature for 15 minutes before it was added to a solution of 4-chloro-8-nitroquinazoline in THF (2 mL) at 0° C. Then the reaction mixture was stirred at rt for 4 h. Then the reaction mixture was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 200 mg of the title product. MS (m/z): 220.23 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[CH:3]=1.[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1C=CC=CC=1.O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([CH2:14][CH2:15][C:16]2([CH3:17])[O:21][CH2:20][CH2:19][O:18]2)[CH:3]=1
Reactant: OCCO
Reactant: COc1ccc2cc(CCC(C)=O)cc(F)c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc2cc(CCC3(C)OCCO3)cc(F)c2c1
Temperature: 25 °C
Yield: 53 %

Procedure:
4-(4-Fluoro-6-methoxy-2-naphthyl)butan-2-one (4.2 g), ethane-1,2-diol (30 ml) and toluene-4-sulphonic acid (0.2 g) were heated under reflux in benzene for 18 hours with continuous removal of water by means of a Dean-Stark trap. The solution was then cooled to room temperature and sodium hydrogen carbonate solution was added. The aqueous layer was washed with ether. The combined organic layers were washed with water and dried over anhydrous sodium sulphate. Evaporation of the solvent under reduced pressure gave a crude product which was dissolved in 60-80 petroleum ether. The precipitated impurities were removed by filtration and the solvent was removed under reduced pressure to give a yellow oil which was triturated with cold 40-60 petroleum ether to give the title compound as pale yellow crystals (2.6 g., 53%; m.p. 51°-53°).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=1)[CH3:2].[Cl:10]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:10][C:4]1[CH:5]=[C:6]([CH:8]=[O:9])[S:7][C:3]=1[CH2:1][CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1ccc(C=O)s1
Solvent: O
Solvent: CN(C)C=O
Product: CCc1sc(C=O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a solution of 5-ethyl-2-thiophenecarboxaldehyde (6.0 g) in N,N-dimethylformamide (60 ml) was added N-chlorosuccinimide (8.57 g), and the mixture was stirred at room temperature for 2 hours, and subsequently stirred under heating at 60° C. for 2 hours. N-chlorosuccinimide (4.00 g) was further added thereto, and the mixture was further stirred under heating at 60° C. for 2 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=33:1) to give 4-chloro-5-ethyl-2-thiophenecarboxaldehyde (3.1 g) as colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[C:13]1([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1>CCOCC>[C:13]1([C:19]2[CH:20]=[CH:21][C:22]([C:23](=[O:24])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[CH:26][CH:27]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: O=C(O)c1ccc(C2=CCCCC2)cc1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(c1ccc(C2=CCCCC2)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
40 g of 2-bromopyridine in 50 ml of absolute ether are added dropwise slowly at -60° C with stirring and in a nitrogen atmosphere to 175 ml of a 1.5 N solution of butyl-lithium in ether, followed, 15 minutes after the completion of the addition, by a solution of 15 g of p-(1-cyclohexenyl)-benzoic acid in 250 ml of absolute ether. The cooling bath is then removed, the reaction mixture is allowed to warm up to room temperature and it is stirred for 2 hours at room temperature. Working up is carried out by pouring the reacton solution onto a mixture of ice and ammonium chloride and partitioning it between ether and water. The ether phase is separated off and washed successively with water, 0.1 N sodium hydroxide solution and water, dried over sodium sulphate and evaporated under reduced pessure. Distillation under reduced pressure of the evaporation residue yields, in the fraction boiling at 200° C (0.9 mm Hg), crude 2-{[p-(1-cyclohexenyl)-phenyl]-oxomethyl}-pyridine of the formula ##STR3## of melting point 58°-60° C.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][C:5]([NH2:18])=[C:4]([N+:19]([O-])=O)[CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH2:19])[C:5]([NH2:18])=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1cc(OCCCN2CCCCC2)c(F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)c(OCCCN2CCCCC2)cc1N
Yield: 100.1 %

Procedure:
200 mg of 4-fluoro-2-nitro-5-(3-piperidin-1-ylpropoxy)-phenylamine in solution in 15 mL of methanol are hydrogenated under 1 bar of hydrogen pressure in the presence of 20 mg of palladium-on-charcoal at 25° C. for 10 hours. The reaction crude is filtered through celite and the filtrate is concentrated under vacuum in a rotary evaporator. 180 mg of 4-fluoro-5-(3-piperidin-1-ylpropoxy)benzene-1,2-diamine are obtained in the form of a black oil. The product is used without any other purification.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][NH:11][CH2:10]3)=[CH:5][CH:4]=1.Br[CH2:18][CH2:19][CH2:20][Cl:21]>O1CCCC1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>[Cl:21][CH2:20][CH2:19][CH2:18][N:11]1[CH2:12][C@H:13]2[C@:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=3)([CH2:14]2)[CH2:10]1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: ClCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc([C@]23C[C@H]2CN(CCCCl)C3)cc1
Temperature: 25 °C

Procedure:
To a solution of (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (1.00 g) in dry tetrahydrofuran (5 mL), diisopropylethylamine (2.4 mL) and 1-bromo-3-chloropropane (3.7 mL) were added and the resulting mixture was heated at reflux for 3 hours. After cooling at room temperature it was diluted with ethyl acetate (30 mL) washed twice with a saturated solution of NH4Cl in water (20 mL) and once with a saturated solution of NaHCO3 in water (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with cyclohexane/EtOAc 7:3 to give the title compound as a colourless oil (1.26 g).
Reaction SMILES: Cl.[N:2]1[C:8]2=[CH:9][CH2:10][S:11][C:7]2=[CH:6][CH:5]=[CH:4][N:3]=1.N1C(C)=CC(C)=CC=1C.NC(N)=[O:23]>C(Cl)Cl.C1COCC1>[O:23]=[C:6]1[C:7]2[S:11][CH:10]=[CH:9][C:8]=2[N:2]=[N:3][CH:4]=[CH:5]1
Reactant: C1=CN=NC2=CCSC2=C1
Reactant: NC(N)=O
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=c1ccnnc2ccsc12

Procedure:
The synthesis of I, J analogs of the benzodiazepines scaffold is illustrated in the following pathway. In both approaches chiral amino acid are introduced into the synthesis raising the diversity around the α carbon. Thieno diazepine I is prepared from 2-amino-3-acyl)-thiophenes 5, which reacts with pre formed Boc amino acid chloride (amino acid, BTC, collidine, THF or DCM). Deprotection of 8 (4N HCl) with concomitant ring closure leads to 2-oxothienodiazepine I. Thiophenodiazepine J can be prepared starting from 2-amino-3-carboxy-thiophenes A, which after pre activation to the thienooxzaine dione (BTC, collidine, THF or DCM)) reacts with amino ketone to obtain 9, ring closure afford 5-oxothienodiazepine.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH2:10])=[CH:8][C:7]([CH:11]2[CH2:14][C:13]([O:17][CH3:18])([O:15][CH3:16])[CH2:12]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26](O)([C:28]([F:31])([F:30])[F:29])=[O:27].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CCOC(C)=O>[C:1]([N:5]1[C:9]([NH:10][C:26](=[O:27])[C:28]([F:31])([F:30])[F:29])=[CH:8][C:7]([CH:11]2[CH2:12][C:13]([O:15][CH3:16])([O:17][CH3:18])[CH2:14]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: COC1(OC)CC(c2cc(N)n(C(C)(C)C)n2)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC1(OC)CC(c2cc(NC(=O)C(F)(F)F)n(C(C)(C)C)n2)C1
Reaction time: 72 h
Yield: 59.6 %

Procedure:
To a stirring solution of 2-tert-butyl-5-(3,3-dimethoxy-cyclobutyl)-2H-pyrazol-3-ylamine (5.0 g, 19.7 mmol) in EtOAc (40 mL) was added triethylamine (27 mL, 197 mmol), TFA (2.3 mL, 29.6 mmol), followed by a solution of 1-propanephosphonic acid cyclic anhydride (25 mL, 50 wt % sol. in EtOAc, 39.4 mmol). After 72 hr, the reaction was diluted with EtOAc and washed with aqueous NaOH (1 N). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of this material was accomplished by MPLC, using a Biotage® column (35 L), eluting with 25% EtOAc/hexanes. The product-containing fractions were collected and concentrated to yield the title compound (4.1 g, 60% yield) as a colorless oil. 400 MHz 1H NMR (CDCl3) d 8.00 (bs, 1H), 6.26 (s, 1H), 3.22 (dddd, J=8.7, 8.7, 8.7, 8.7, Hz, 1H), 3.18 (s, 3H), 3.15 (s, 3H), 2.61-2.55 (m, 2H), 2.25-2.19 (m, 2H), 1.59 (s, 9H). LRMS m/z (APCI+) 350 (M+1).