Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:28])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([NH2:27])[C:22](=[O:26])[N:23]([CH3:25])[CH3:24])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C(N(CC)C(C)C)(C)C.[C:38]1([CH3:48])[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>C(Cl)Cl.CCCCCC.C(OCC)(=O)C>[CH3:3][O:4][C:5](=[O:28])[CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([C:22](=[O:26])[N:23]([CH3:24])[CH3:25])[NH:27][S:44]([C:41]3[CH:42]=[CH:43][C:38]([CH3:48])=[CH:39][CH:40]=3)(=[O:46])=[O:45])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCc1ccc(-c2ccc(CC(N)C(=O)N(C)C)cc2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: COC(=O)CCc1ccc(-c2ccc(CC(NS(=O)(=O)c3ccc(C)cc3)C(=O)N(C)C)cc2)cc1
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
Hydrochloride compound 53 (2.1 g, 5.37 mmol) was dissolved in CH2Cl2 (35 mL) and cooled to 0-5° C. N,N-Diisopropylethylamine (1.87 mL, 11.0 mmol) was added to the above solution followed by addition of p-toluenesulfonyl chloride (0.85 g, 4.46 mmol) in small portions. The reaction mixture was then warmed up to room temperature and stirred overnight. The solvent was removed under reduced pressure and the residual oil was taken up in EtOAc (50 mL). The organic layer was washed with 2.0 M HCl (1×10 mL), saturated NaHCO3 (1×10 mL), and brine (1×25 mL). The resulting EtOAc layer was dried and concentrated under reduced pressure to yield an oil. Flash chromatography (30-50% ethyl acetate in hexane containing 1% acetic acid) yielded the desired sulfonamide 54 (1.1 g, 40%). 1H NMR (DMSO-d6): 8.10 (d, J=9.6 Hz, 1H), 7.55 (d, J=8.0 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 4.33 (m, 1H), 3.59 (s, 3H), 2.81-2.90 (m, 3H), 2.75 (s, 3H), 2.62-2.68 (m, 3H), 2.53 (s, 3H), 2.26(s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][C:10]=1[I:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21].O>CCCCCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:24][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:11][C:10]=1[I:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)c(I)c1
Reactant: CC(C)(C)N
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)NS(=O)(=O)c1ccc(OCc2ccccc2)c(I)c1
Temperature: 37.5 °C
Reaction time: 17 h
Yield: 94 %

Procedure:
A 3-neck, 3 L, round-bottom flask was equipped with an over-head stirrer, thermometer, and a pressure-equalizing dropping-funnel was charged with the solution of 4-benzyloxy-3-iodo-benzenesulfonyl chloride. The flask immersed in a cold water bath (Tint=22° C.) and tert-butylamine (90.1 g, 0.710 mol, 2.1 eq) was added drop-wise (Tint no change). The resulting reaction mixture was stirred overnight at the ambient water-bath temperature. After 17 h, the reaction mixture was worked-up and the organic layer was separated and concentrated to approx. ⅓ (˜500 mL) of its original volume at which point the product started to precipitate. The reaction mixture was warmed to 35-40° C. at atmospheric pressure till the solids had re-dissolved. The solution was then allowed to cool, with gentle stirring, to room temperature. Within 2 days a white precipitate had formed. The suspension was stirred vigorously while hexane (1.5 L) was slowly added, then stirred overnight, and then cooled in an ice-bath for 1-2 h The precipitate was collected by filtration and washed with hexane, dried, first under suction to give 4-benzyloxy-N-tert-butyl-3-iodo-benzenesulfonamide (238, 94%).
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]#[C:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:13]=2)[N:8](S(C2C=CC=CC=2)(=O)=O)[CH:7]=1.[OH-].[Na+]>CCO>[O:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[CH:13]=[C:14]2[C:6]([C:5]#[C:4][C:3]([OH:37])=[O:2])=[CH:7][NH:8][C:9]2=[N:10][CH:11]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)C#Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(-c3ccccc3Oc3ccccc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C#Cc1c[nH]c2ncc(-c3ccccc3Oc3ccccc3)cc12
Temperature: 90 °C
Yield: 110 %

Procedure:
A mixture of ester 14 (30 mg, 0.059 mmol), EtOH (593 μL) and 10% aq. NaOH (296 μL) was heated at 90° C. for 1 h. The reaction mixture was cooled, concentrated and acidified to pH 5 with 1N HCl. The mixture was then extracted with ethyl acetate (4×10 mL). The combined organic extracts were dried (MgSO4) and concentrated to give the crude product 15 (23 mg, 110%) which was used for the subsequent reactions without further purification.
Reaction SMILES: C([O:3][C:4](=[O:46])[CH2:5][CH2:6][CH2:7][N:8]([C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[CH:39]=1)[CH2:9][C:10]1[CH:37]=[CH:36][C:13]2[N:14]=[C:15]([NH:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[N:16]([CH2:17][C:18]3[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([CH3:25])[N:19]=3)[C:12]=2[CH:11]=1)C.[Li+].[OH-].O>O1CCCC1.O>[CH3:44][C:42]1[CH:43]=[C:38]([N:8]([CH2:9][C:10]2[CH:37]=[CH:36][C:13]3[N:14]=[C:15]([NH:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[N:16]([CH2:17][C:18]4[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([CH3:25])[N:19]=4)[C:12]=3[CH:11]=2)[CH2:7][CH2:6][CH2:5][C:4]([OH:46])=[O:3])[CH:39]=[C:40]([CH3:45])[CH:41]=1
Reactant: CCOC(=O)CCCN(Cc1ccc2nc(NCCCN3CCOCC3)n(Cc3nc(C)ccc3O)c2c1)c1cc(C)cc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)cc(N(CCCC(=O)O)Cc2ccc3nc(NCCCN4CCOCC4)n(Cc4nc(C)ccc4O)c3c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56 %

Procedure:
A mixture of 4-{(3,5-dimethyl-phenyl)-[3-(3-hydroxy-6-methyl-pyridin-2-ylmethyl)-2-(3-morpholin-4-yl-propylamino)-3H-benzoimidazol-5-ylmethyl]-amino}-butyric acid ethyl ester (Compound 71), prepared as described for compounds n-4, (0.000175 mol) and LiOH/H2O (0.00035 mol) in tetrahydrofuran (8 ml) and H2O (8 ml) was stirred at room temperature for 12 hours. The tetrahydrofuran was evaporated and a 1N solution of NaOH in water was added. The solution was extracted with CH2Cl2/CH3OH (95/5). The organic layer was separated, dried (over MgSO4), filtered and the solvent was evaporated. The residue was taken up in H2O. The precipitate was filtered off and dried, yielding 0.059 g of 4-{(3,5-dimethyl-phenyl)-[3-(3-hydroxy-6-methyl-pyridin-2-ylmethyl)-2-(3-morpholin-4-yl-propylamino)-3H-benzoimidazol-5-ylmethyl]-amino}-butyric acid (Compound 62, 56%, melting point: 121° C.).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:18][C:17]3[CH2:16][NH:15][CH2:14][CH2:13][C:12]=3[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[CH2:22]([CH:16]1[NH:15][CH2:14][CH2:13][C:12]2[CH2:11][N:10]([S:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=3)(=[O:8])=[O:9])[CH2:18][C:17]1=2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)N2CC3=C(CNCC3)C2)cc1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2CC3=C(C2)C(Cc2ccccc2)NCC3)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
1.8 g of N8 -(p-toluenesulfonyl)-3,8-diazabicyclo[4.3.0]non-1(6)-ene, prepared in preparation 8, was dissolved in 30 ml of methanol. 6 ml of 50% aqueous sodium hydroxide solution and 1.5 ml of benzyl bromide were added to the solution and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to remove methanol and then extracted with methylene chloride (30 ml×3). It was dried (Na2SO4) and concentrated and then dried under reduced pressure. 2 g of the title compound was obtained (yield 85%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([C:24]1[S:28][C:27]([CH2:29][NH:30][C:31](=[O:51])[C@H:32]([CH:38]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[NH:33][C:34]([O:36][CH3:37])=[O:35])=[CH:26][CH:25]=1)[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:71](O)[CH:72]([CH3:74])[CH3:73].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][C@H:10]([C:24]1[S:28][C:27]([CH2:29][NH:30][C:31](=[O:51])[C@H:32]([CH:38]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[NH:33][C:34]([O:36][CH3:37])=[O:35])=[CH:26][CH:25]=1)[N:11]([CH2:71][CH:72]([CH3:74])[CH3:73])[S:12]([C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)(=[O:13])=[O:14])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)CO
Reactant: COC(=O)N[C@H](C(=O)NCc1ccc([C@@H](CO[Si](C)(C)C(C)(C)C)NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)s1)C(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)NCc1ccc([C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(C)C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)s1)C(c1ccccc1)c1ccccc1

Procedure:
A solution of N-({5-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-{[(4-nitrophenyl)sulfonyl]amino}ethyl]thiophen-2-yl}methyl)-Nα-(methoxycarbonyl)-β-phenyl-L-phenyl alaninamide (60 mg, 0.080 mmol), Ph3P (105 mg, 0.398 mmol), isobutanol (0.037 mL, 0.398 mmol) and DIAD (0.077 mL, 0.398 mmol) in THF (0.4 mL) stirred at 40° C. under N2 atmosphere, for 18 hours. Ethyl acetate and water were added and the phases were separated. The organic phase was washed with brine, dried, and concentrated under reduce pressure. The concentrate was purified on silica gel using 5%-65% ethyl acetate in hexane to afford the title compound with impurities. MS: m/z=810.3 ((MH+)).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.[Cl-:10].[Na+].S(=O)(=O)(O)O.I([O-])(=O)(=O)=O.[Na+]>C(#N)C.O>[Cl:10][C:2]1[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=1[CH3:9]
Reactant: Cc1cc(C)cc(C)c1
Reactant: [Cl-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: Cc1cc(C)c(Cl)c(C)c1
Temperature: 80 °C
Yield: 40 %

Procedure:
Mesitylene (1 mmol) was treated with sodium chloride (1.2 mmol) in acetonitrile: water (2:1, 6 ml). 20% Sulfuric acid (5 ml) and sodium periodate (20 mol %) was added to the reaction mixture. The mixture was heated at 80° C. under inert atmosphere for 6 h. The product was purified by column chromatography to give chloromesitylene (40%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18](CC3C=CC=CC=3)[CH2:17][CH2:16]2)[C:12]([O:28][CH3:29])=[CH:11][C:10]=1[C:30]([OH:33])([CH3:32])[CH3:31])C1C=CC=CC=1>CCO>[OH:33][C:30]([C:10]1[CH:11]=[C:12]([O:28][CH3:29])[C:13]([N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)=[CH:14][C:9]=1[OH:8])([CH3:31])[CH3:32]
Reactant: COc1cc(C(C)(C)O)c(OCc2ccccc2)cc1N1CCN(Cc2ccccc2)CC1
Solvent: CCO
Product: COc1cc(C(C)(C)O)c(O)cc1N1CCNCC1
Reaction time: 12 h
Yield: 91.8 %

Procedure:
A mixture of 2-[2-Benzyloxy-4-(4-benzyl-piperazin-1-yl)-5-methoxy-phenyl]-propan-2-ol (2.01 g, 4.5 mmol) 10% Pd/C (0.28 g) in EtOH (60 mL) was hydrogenated at 50 psi at room temperature for 12 hours. The reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure to yield 1.1 g (92%) of 2-(1-Hydroxy-1-methyl-ethyl)-4-methoxy-5-piperazin-1-yl-phenol.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[C:9]1([CH2:15][C:16](Cl)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN1C(=O)CCC1>[Cl:8][C:5]1[N:4]=[N:3][C:2]([NH:1][C:16](=[O:17])[CH2:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:6]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CN1CCCC1=O
Product: O=C(Cc1ccccc1)Nc1ccc(Cl)nn1
Temperature: 19 °C
Reaction time: 1.5 h
Yield: 88.3 %

Procedure:
To a solution of 3-amino-6-chloropyridazine (11.14 g, 86.0 mmol) in NMP (279 mL) at 19° C. was added phenylacetyl chloride (18.2 mL, 137.6 mmol) dropwise over 5 minutes with the internal temperature of the solution maintained Ti≦28° C. The resulting mixture was stirred at 19° C. for 90 minutes and poured into ice water (557 mL). The white precipitate was collected by suction filtration, rinsed with water (2×110 mL) and diethyl ether (110 mL). The product was dried overnight under high vacuum to afford N-(6-chloropyridazin-3-yl)-2-phenylacetamide (xxx, 18.8 g). 1H NMR (300 MHz, DMSO-d6) δ 11.57 (s, 1H), 8.40 (d, J=9.636 Hz, 1H), 7.90 (d, J=9.516 Hz, 1H), 7.36 (m, 5H) 3.82 (s, 2H)
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH:10]1N=CN(C(N2C=NC=C2)=O)C=1.CO>C(Cl)Cl.CCCCC>[Br:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCCCC
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(Br)o1
Reaction time: 8 h

Procedure:
To a slurry of 15.00 g (0.0785 mol) of 5-bromofuranoic acid in 500 ml of methylene chloride, was added 12.73 g (0.0785 mol) of N,N-carbonyldiimidazole. After reacting at room temperature overnight, 6.4 ml (0.157 mol) of methanol was added and the resultant mixture was stirred for approximately one hour and then washed sequentially with a 0.5M sodium hydroxide solution (twice) and a 1M hydrochloric acid solution. The organic portion was dried over sodium sulfate, filtered and then concentrated in vacuo to provide a residue. This residue was slurried in pentane to provide a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[CH2:5][CH2:6][C:7]([OH:9])=O.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=1>C1COCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][C:7]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)=[O:9])[CH:10]=[CH:11][C:12]=1[OH:13]
Reactant: O=C(O)CCc1ccc(O)c(O)c1
Reactant: COC(=O)c1ccc(N)cc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc(NC(=O)CCc2ccc(O)c(O)c2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 22 %

Procedure:
To a solution of 3,4-dihydroxyhydrocinnamic acid (723 mg, 3.97 mmol) in anhydrous THF (20 mL) were added N-methylmorpholine (0.44 mL, 3.97 mmol) and isobutylchloroformate (0.52 mL,3.97 mmol) at 0° C. After 45 min, at 0° C., a solution of methyl 4-aminobenzoate (500 mg, 3.31 mmol) in anhydrous THF (4 mL) was added to the reaction mixture. After 5 min the temperature was allowed to warm up to rt and stir overnight. After extraction with EtOAc (100 mL), washing with HCl (0.1N, 50 mL) and a saturated aqueous solution of NaHCO3 (50 mL), the organic layer was dryed over sodium sulfate and evaporated under vacuo to give a yellow oil. Purification by flash chromatography using DCM/MeOH (95/5) as eluant gave the title compound as a colourless oil (22%) in a 94.8% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:3]=1[C:4]#[N:5].Cl[C:13]1[CH:14]=[C:15]2[N:22]([CH3:23])[C:21]([CH3:25])([CH3:24])[CH2:20][N:16]2[C:17](=[O:19])[N:18]=1>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:13]2[CH:14]=[C:15]3[N:22]([CH3:23])[C:21]([CH3:25])([CH3:24])[CH2:20][N:16]3[C:17](=[O:19])[N:18]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(CO)ccc1F
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCc3ccc(F)c(C#N)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 2-fluoro-5-(hydroxymethyl)benzonitrile and 7-chloro-1,2,2-trimethyl-2,3-dihydroi-midazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=S)[NH:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]2=3)=[CH:4][CH:3]=1.[C:21]([NH:24][NH2:25])(=O)[CH3:22]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12]3=[N:25][N:24]=[C:21]([CH3:22])[N:11]3[C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]2=3)=[CH:4][CH:3]=1
Reactant: CC(=O)NN
Reactant: O=C1CC(=S)Nc2ccccc2N1c1ccc(Cl)cc1
Solvent: CCCCO
Product: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(=O)C2
Yield: 40.1 %

Procedure:
A solution of 1-(4-chlorophenyl)-4-thioxo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (1.0 g, 3.3 mmol) and acetohydrazide (1.23 g, 16.6 mmol) in n-butanol (20 ml) was refluxed for 24 h under N2 atmosphere. The solvent was evaporated in vacuo and partitioned between DCM (100 mL) and water (50 mL). The organic phase was dried over Na2SO4 and the solvent was evaporated in vacuo to afford a residue. The residue was purified by column chromatography (silica-gel, DCM:MEOH=30:1) to give 6-(4-chlorophenyl)-1-methyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-one (430.0 mg, 40%). LRMS (M+H+) m/z: calcd 324.08. found 324. 1H NMR (300 MHz, CD3OD): δ 2.72 (s, 3H), 3.94 (q, J=14.1 Hz, 2H), 7.15-7.24 (m, 3H), 7.40-7.52 (m, 4H), 7.70-7.73 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:10]([CH:11]([C:13](=[O:16])[CH2:14][CH3:15])[CH3:12])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[BH4-].[Na+]>CO>[OH:16][CH:13]([CH2:14][CH3:15])[CH:11]([N:10]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])=[C:2]1[CH3:1])[CH3:12]
Reactant: CCC(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2cccnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To tert-butyl 2-methyl-1-(3-oxopentan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (100 mg, 0.32 mmol) in CH3OH (2 ml) were added NaBH4 (35.9 mg, 0.95 mmol) at 0° C. The mixture was allowed to warm 25° C. with stir for 2 h. After the reaction completed, the solution was concentrated under vacuum and the solid was partitioned between EtOAc and H2O. The organic was separated, dried over Na2SO4 and evaporated under reduced pressure to give tert-butyl 1-(3-hydroxypentan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate as a white oil. (50 mg yield 50%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(C(O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:26](CC)CC.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>O1CCOCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:26])([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)O)CC1
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N)(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 4-benzyl-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (0.65 mmol) in 1,4-dioxane (2 mL) are added Et3N (0.71 mmol) and DPPA (0.71 mmol) at room temperature. After warming to 100° C. and stirring for 2 h, the reaction mixture is diluted with AcOEt. The organic layer is washed with sat. aq. NaHCO3 and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is dissolved in THF (4 mL) and 6N aq. NaOH (0.22 mL) is added at room temperature. After stirring for 4 h, the reaction mixture is diluted with CH2Cl2, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give the title compound; 1H NMR (CDCl3), δ: 1.18 (2H, bs), 1.28-1.37 (2H, m), 1.46 (9H, s), 1.51-1.64 (2H, m), 2.66 (2H, s), 3.20 (2H, dd), 3.74 (2H, bd), 7.13-7.19 (2H, m), 7.21-7.34 (3H, m).
Reaction SMILES: C([O:4][C@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([CH2:15][O:16]C(=O)C)[O:8][C@@H:7]([O:20]C(=O)C)[C@@H:6]1[NH:24][C:25](=[O:27])[CH3:26])(=O)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[OH:20][CH:7]1[O:8][C@H:9]([CH2:15][OH:16])[C@H:10]([OH:11])[C@H:5]([OH:4])[C@H:6]1[NH:24][C:25]([CH3:26])=[O:27]
Reactant: CC(=O)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O
Temperature: 0 °C
Yield: 179.1 %

Procedure:
Commercially available acetic acid (2S,3R,4R,5R,6R)-4,5-diacetoxy-6-acetoxymethyl-3-acetylamino-tetrahydro-pyran-2-yl ester (10.0 g, 26 mmol) was dissolved in 116 mL of abs. CH2Cl2 and treated with trimethylsilyl triflate (14.27 g, 64 mmol). The reaction was allowed to proceed over night at 45° C. After cooling to 0° C., triethylamine (4.88 mL, 35 mmol) was added, the mixture diluted with CH2Cl2 and washed with NaHCO3-solution and water. Drying over Na2SO4 and evaporation of the solvent yielded 10.3 g of the title compound as brownish oil which was used without further purification for the next step, MS (ISP): 330.0 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:18]=[CH:17][C:10]3[NH:11][C:12]([C:14](O)=[O:15])=[N:13][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)(Cl)=O>>[N:1]1([CH2:6][C:7]2[CH:18]=[CH:17][C:10]3[N:11]4[C:14](=[O:15])[C:12]5=[N:11][C:10]6[CH:17]=[CH:18][C:7]([CH2:6][N:1]7[CH:5]=[CH:4][N:3]=[CH:2]7)=[CH:8][C:9]=6[N:13]5[C:14](=[O:15])[C:12]4=[N:13][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1nc2cc(Cn3ccnc3)ccc2[nH]1
Solvent: O=S(Cl)Cl
Product: O=c1c2nc3ccc(Cn4ccnc4)cc3n2c(=O)c2nc3cc(Cn4ccnc4)ccc3n12
Reaction time: 3 h

Procedure:
A mixture of 2.3 parts of 5-(1H-imidazol-1-ylmethyl)-1H-benzimidazole-2-carboxylic acid and 80 parts of thionyl chloride was stirred for 3 hours at reflux temperature. The reaction mixture was evaporated to dry, yielding 4.3 parts of 3,9-bis(1H-imidazol-1-yl-methyl)-6H,13H-pyrazino[1,2-a:4,5-a']bisbenzimidazole6,13-dione which were poured into a solution of 3.8 parts of sodium methoxide in 40 parts of methanol. The whole was stirred for 1 hour at room temperature. The whole was neutralised with 10 parts of acetic acid and concentrated to dry. The concentrate was taken up in a sodium hydrogen carbonate solution 10% and the product was extracted with a mixture of dichloromethane and methanol (90:10 by volume). The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanone. The product was filtered off and dried, yielding 0.7 parts (26.9%) of methyl 5-(1H-imidazol-1-ylmethyl)-1H-benzimidazole-2-carboxylate; mp. 228° C. (compound 267).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[N+:26]([O-])=O)(=[O:15])=[O:14])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.O.NN>[Ni].CO>[NH2:26][C:17]1[CH:18]=[C:19]([C:22]([F:24])([F:23])[F:25])[CH:20]=[CH:21][C:16]=1[S:13]([NH:12][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2)(=[O:14])=[O:15]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1ccc(Cl)c2cccnc12
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1ccc(Cl)c2cccnc12
Yield: 26.7 %

Procedure:
In the similar fashion using route 6 general procedure 14, N-(5-chloroquinolin-8-yl)-2-nitro-4-trifluoromethylbenzenesulfonamide (Intermediate 156) (120 mg, 0.28 mmol), Raney nickel (24 mg, 20% wt), hydrazine hydrate (40 μl, 0.84 mmol), MeOH (3 ml) gave the title compound (30 mg, 27%) after purification by column chromatography with DCM/MeOH (199:1) as the eluent.