Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C@H:5]1[C@@H:10]([OH:11])[CH2:9][CH2:8][CH2:7][NH:6]1)=[O:4].C(N(C(C)C)C(C)C)C.[Cl:21][C:22]1[C:29]([CH3:30])=[C:28]([N:31]=[C:32]=[O:33])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25].NC(N)=O.N1CC(=O)NC1=O>C(Cl)Cl>[Cl:21][C:22]1[C:29]([CH3:30])=[C:28]([N:31]2[C:3](=[O:4])[CH:5]3[CH:10]([OH:11])[CH2:9][CH2:8][CH2:7][N:6]3[C:32]2=[O:33])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: Cc1c(N=C=O)ccc(C#N)c1Cl
Reactant: COC(=O)[C@@H]1NCCC[C@@H]1O
Agent: NC(N)=O
Agent: O=C1CNC(=O)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(N2C(=O)C3C(O)CCCN3C2=O)ccc(C#N)c1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 58.3 %

Procedure:
To a suspension of compound 53B (0.20 g, 0.77 mmol) in CH2Cl2 (3 mL) cooled to 0° C. was added i-Pr2EtN (0.178 mL, 1.00 mmol). After stirring at 0° C. for 20 min, compound 23E (0.095 g, 0.59 mmol) in CH2Cl2 (1 mL) solution was added, along with 4 Å molecular sieves (0.5 g), and the resulting mixture stirred at rt until urea formation was completed (˜2 h). The mixture was then stirred at rt until hydantoin formation was complete (˜15 h). The reaction mixture was loaded on a silica gel column, eluted with 40% EtOAc/hexane, and 5% MeOH in EtOAc/hexane (1:1) to afford 0.11 g of the title compound as an off-white powder. HPLC: 99% at 1.67-1.79 min; Conditions: Phenom. Luna C18 (4.6×50 mm); Eluted with 0% to 100% B; 4 min gradient (A=90% H2O—10% ACN—0.1% H3PO4 and B=10% H2O—90% ACN—0.1% H3PO4), Flow rate at 4 mL/min., UV detection at 220 nm). The compound was further loaded on a Chiral AD column, eluted with 25% isopropanol in hexane isocratic to afford 50 mg each of enantiomer 53a (isomer A; retention time=14.2 min; 100% e.e.) and enantiomer 53b (isomer B; retention time=20 min; 100% e.e.) of the title compound as white powders. Chiral HPLC Conditions: (CHIRALPAK® AD column 4.6×250 mm; 25% isopropanol in hexane over 30 min at flow rate 1.0 mL/min, UV detection at 220 nm); MS (ES) m/z 320 [M+1]+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]=[O:20])=[C:11]2Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]=[O:20])=[C:11]2[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1c(Cl)n(S(=O)(=O)c2ccccc2)c2ccccc12
Reactant: C1CNCCN1
Product: O=Cc1c(N2CCNCC2)n(S(=O)(=O)c2ccccc2)c2ccccc12
Yield: 45 %

Procedure:
1-Benzenesulfonyl-2-chloro-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 1-benzenesulfonyl-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde (45% yield). ESI/MS 370 (M+H); RT 2.59 min.
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].CC([Si](C)(C)O[C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1)(C)C.[Bi](Br)(Br)Br.C([SiH](CC)CC)C>C(#N)C>[CH2:1]([O:4][C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1)[CH2:2][CH3:3]
Reactant: CCOC(=O)[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Reactant: CCC=O
Agent: Br[Bi](Br)Br
Agent: CC[SiH](CC)CC
Solvent: CC#N
Product: CCCO[C@H]1CC[C@H](C(=O)OCC)CC1
Reaction time: 1.5 h

Procedure:
Propionaldehyde (6.4 g) in acetonitrile (50 mL) was added over 30 minutes to a solution of cis/trans ethyl 4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexanecarboxylate (D1, 25.2 g), bismuth tribromide (4.4 g) and triethylsilane (17.5 mL) in acetonitrile (300 mL) and the mixture was stirred for a further 1.5 hours. The solvent was partially removed then the residue was treated with ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried with anhydrous sodium sulphate and the solvent was removed to give the title compounds contaminated with silicone residues (39.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[CH:7]=[CH:6]2.[Br:14]N1C(=O)CCC1=O>C(#N)C>[Br:14][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH3:13])=[N:9]2
Reactant: COc1ccc2nc(C)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ccc2nc(C)ccc2c1Br
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.4 %

Procedure:
A solution of 6-methoxy-2-methylquinoline (177 g, 1.02 mol) in acetonitrile (1.77 L) was cooled to 0-3° C. followed by portion-wise addition of N-bromo-succinimide (200 g, 1.12 mol) over a period of 30 minutes while maintaining the same temperature. The resulted brown slurry was warmed to ambient temperature and stirred for an additional 6 hours. The reaction was then quenched by a 10% NaHSO3 solution (211 mL). The reaction mixture was concentrated to a volume of 600 mL then slowly poured into 0.1 N NaOH (2.5 L). The slurry (pH=9) was stirred at room temperature for 1 hour then filtered, washed with water (2×1 L) and dried in a vacuum oven to give 253 g (98.6%) of the title compound as a brown solid. Rf=0.39 (3:7) ethyl acetate:heptane; 1H NMR (DMSO) δ 8.30 (d, J=6.5 Hz, 1H), 7.98 (d, J=6.9 Hz, 1H), 7.70 (d, J=7.0 Hz, 1H), 7.47 (d, J=6.5 Hz, 1H), 4.02 (s, 3H), 2.66 (s, 3H);
Reaction SMILES: [O:1]1[C:6]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:8]([O:10]CC)=[O:9])=[CH:5][S:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[O:1]1[C:6]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:8]([OH:10])=[O:9])=[CH:5][S:4][CH2:3][CH2:2]1
Reactant: CCCCCCON=C(C(=O)OCC)C1=CSCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCON=C(C(=O)O)C1=CSCCO1
Temperature: 25 °C
Reaction time: 43 h
Yield: 25.4 %

Procedure:
Ethyl 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-hexyloxyiminoacetate (mixture of syn isomer and anti isomer, 186.8 g.), 1 N aqueous solution of sodium hydroxide (472 ml.) and methanol (1.8 l.) were stirred at room temperature for 35 minutes and the insoluble substance was removed by filtration. The filtrate was stirred at room temperature for 43 hours and treated in a similar manner to that of Exampl I-(iii) to give 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-hexyloxyiminoacetic acid (syn isomer, 43 g.)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:23]=1[S:31](Cl)(=[O:33])=[O:32]>>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:23]=1[S:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:33])=[O:32]
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Reactant: CCOC(=O)c1cc(N)ccc1Oc1cncc(Cl)c1
Product: CCOC(=O)c1cc(NS(=O)(=O)c2cc([N+](=O)[O-])ccc2C)ccc1Oc1cncc(Cl)c1
Yield: 89 %

Procedure:
The title compound was prepared using the procedure described in Example 3, beginning with 0.1 g of the aniline of Example 1 and 2-methyl-5-nitrobenzenesulfonyl chloride and adding poly(4-vinylpyridine) (250 mg, 60 mesh) to the reaction mixture. After workup, 0.15 g (89%) of the title sulfonamide was obtained.
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:12][C:11]2[C:13]3[C:18]([C:19](=[O:22])[C:20](=[O:21])[C:10]=2[S:9][CH2:8]1)=[CH:17][CH:16]=[CH:15][CH:14]=3)(=O)=O.[N:23]1([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C>CS(C)=O>[O:21]=[C:20]1[C:10]2[S:9][CH2:8][CH:7]([CH2:6][N:26]3[CH2:25][CH2:24][N:23]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:28][CH2:27]3)[O:12][C:11]=2[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]1=[O:22]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CS(=O)(=O)OCC1CSC2=C(O1)c1ccccc1C(=O)C2=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(CC2CSC3=C(O2)c2ccccc2C(=O)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 8.5 %

Procedure:
To a solution of (5,6-dioxo-2,3,5,6-tetrahydronaphtho[1,2-b][1,4]oxathiin-2-yl)methyl methanesulfonate (0.15 g, 0.44 mmol) in DMSO (1.5 mL) was added ethyl piperazine-1-carboxylate (0.065 mL, 0.88 mmol) and triethylamine (0.12 mL, 0.88 mmol). The reaction mixture was shaken at 50° C. for 2 hours. The crude product was purified by reverse phase HPLC to give the desired product as a purple solid (0.015 g, 5%). M.p.=185-187° C.; 300 MHz 1H NMR (CDCl3) δ: 8.04 (d, J=7.2 Hz, 1H), 7.66 (m, 2H), 7.48 (t, J=7.2 Hz, 1H), 4.66 (m, 1H), 4.15 (m, 2H), 3.51 (m, 4H), 3.23 (m, 1H), 3.03 (m, 1H), 2.83 (m, 2H), 2.54 (m, 4H), 1.27 (m, 3H); LCMS: 403 [M+H].
Reaction SMILES: Cl.N1C=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]=1[NH2:30].COC(OC)(OC)CCC>C1(C)C=CC=CC=1>[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:15]2[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:16]=2[N:30]=[C:3]1[CH2:4][CH2:5][CH3:6]
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCCCCCl)c1C
Reactant: c1ccncc1
Agent: CCCC(OC)(OC)OC
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCCCCCl
Yield: 219.3 %

Procedure:
Under a nitrogen atmosphere, pyridine hydrochloride (4.2 g, 36.4 mmol) was added in small amounts to a solution of N4-(5-chloropentyl)-5,6-dimethyl-2-phenoxypyridine-3,4-diamine (32.4 g, 97.0 mmol) in toluene (500 mL). Trimethylorthobutyrate (17 mL, 107 mmol) was then added, and the reaction was heated at reflux for two hours. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (500 mL). The solution was washed with water (3×80 mL) and brine (1×40 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford an oil, which was dissolved in hexanes (20 mL) and concentrated under reduced pressure to provide an off-white solid. The crude solid was purified by column chromatography on silica gel (eluting with 2:1 hexane:ethyl acetate) to provide 30.8 g of 1-(5-chloropentyl)-6,7-dimethyl-4-phenoxy-2-propyl-1H-imidazo[4,5-c]pyridine as white crystals.
Reaction SMILES: [O:1]1[CH:3]([CH3:4])[CH:2]1[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:21]([CH3:22])[C:20](=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:24][CH3:25])[CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1.[CH2:26]([NH:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=1)[CH2:27][CH3:28]>>[OH:1][CH:3]([CH2:4][N:29]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=1)[CH2:26][CH2:27][CH3:28])[CH2:2][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:21]([CH3:22])[C:20](=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:24][CH3:25])[CH:18]=3)[N:13]=2)=[CH:10][CH:11]=1
Reactant: CCCNCCc1ccc(OC)c(OC)c1
Reactant: COc1ccc2nc(-c3ccc(OC4OC4C)cc3)n(C)c(=O)c2c1
Product: CCCN(CCc1ccc(OC)c(OC)c1)CC(O)COc1ccc(-c2nc3ccc(OC)cc3c(=O)n2C)cc1

Procedure:
This compound was prepared analogous to Example 2 from 2-[4-(1,2-epoxy-propoxy)-phenyl]-3-methyl-6-methoxy-3,4-dihydro-quinazolin-4-one and N-propyl-2-(3,4-dimethoxyphenyl)-ethylamine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C>[CH3:21][C:5]1[CH:4]=[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:2]2[N:7]([N:32]=[N:33][N:34]=2)[C:6]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c2nnnn2c1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 150 °C
Reaction time: 48 h
Yield: 47.1 %

Procedure:
A solution of 0.20 g (0.44 mmol) of [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) in 2.0 ml of DMF was treated with 0.099 g (1.52 mmol) of a sodium azide and the reaction mixture was heated up to 150° C. After 48 hours, it was poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 98:2 to 4:1) to give 0.095 g (47%) of the title compound as colorless oil. MS: 459.4 (MH−).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:22](O)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])=[O:4].[NH2:32][C@H:33]([C:37]([NH:39][C@H:40]([C:46]([N:48]1CC[CH2:61][C@H:49]1[C:50]([NH:52][CH2:53][C:54]([O:56]C(C)(C)C)=[O:55])=[O:51])=[O:47])[CH2:41][CH2:42][C:43](=[O:45])[NH2:44])=[O:38])[CH:34]([CH3:36])[CH3:35].[CH2:64](Cl)[CH2:65]Cl.Cl.O1CCOCC1>CC(N(C)C)=O.O>[NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:22]([NH:32][C@H:33]([C:37]([NH:39][C@H:40]([C:46]([N:48]1[CH2:65][CH2:64][CH2:61][C@H:49]1[C:50]([NH:52][CH2:53][C:54]([OH:56])=[O:55])=[O:51])=[O:47])[CH2:41][CH2:42][C:43](=[O:45])[NH2:44])=[O:38])[CH:34]([CH3:35])[CH3:36])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH:11]([CH3:12])[CH3:13])=[O:8])=[O:4]
Reactant: ClCCCl
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(C)C)C(=O)O
Reactant: CC(C)[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)NCC(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)CNC(=O)CN)C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)NCC(=O)O)C(C)C
Temperature: -5 °C

Procedure:
Boc-Gly-Gly-Val-Leu-OH (1.0 eq.) (SEQ ID NO 17), H-Val-Gln-Pro-Gly-OtBu (SEQ ID NO 18) (1.0 eq.) and Hobt (1.1 eq.) were dissolved in DMA at room temperature until a clear solution was obtained. The solution was cooled to about −5° C. and EDC (1.1 eq.) was added to the solution to initiate the coupling. The mixture was stirred at −5° C. until completion of the coupling (progress of reaction was followed by HPLC). The reaction mixture was diluted by addition of water what made the peptide precipitate. The solid was filtered, washed with an aqueous solution of KHSO4, with an aqueous solution of NaHCO3 and finally with water. The solid was dried under reduced pressure. To remove the Boc group, the protected octapeptide was dissolved in AcOH and HCl 4M in dioxane (12 eq.) was added. The mixture was stirred at 25° C. for about 2 h. The final peptide was recovered by precipitation in IPE at 25° C. The solid was filtered, washed several times with IPE and finally with MeCN. After drying under vacuum at 40° C., 80% of HCl.H-Gly-Gly-Val-Leu-Val-Gln-Pro-Gly-OH (SEQ ID NO 1) was recovered. The peptide was solubilised in a 0.05M ammonium acetate buffer solution at 25° C., adjusted to 4.5≦pH<5.0 with a 25% NH3 solution, and then diluted with MeCN. This solution was filtered and purified as described in example 9.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(C(O)=O)[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C1(P([N:33]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.O.CCO[C:40](C)=[O:41]>C1(C)C=CC=CC=1>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([N:33]=[C:40]=[O:41])[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CN1CCC(C(=O)O)(c2ccc(F)cc2)CC1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CCC(N=C=O)(c2ccc(F)cc2)CC1

Procedure:
4-(4-fluorophenyl)-1-methyl-4-piperidinecarboxylic acid hydrochloride (273 mg) was dissolved in dry toluene (10 mL) and, under a Nitrogen athmosphere and at r.t., TEA (0.33 mL) and diphenylphosphoryl azide (0.34 mL) were added. The mixture was refluxed for 4 h. Then water and AcOEt were added; the organic phase was separated and washed with brine, dried and evaporated under vacuum to give a crude which was purified by flash chromatography (elution with DCM:MeOH 9:1) to afford the title compound (47 mg) as white foam.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([N:11]=O)[CH2:7][CH2:6]1.[C:14]([NH:17][C:18]1[C:26]([Cl:27])=[CH:25][C:21]([C:22](Cl)=[O:23])=[C:20]([O:28][CH3:29])[CH:19]=1)(=[O:16])[CH3:15].C(N(CC)CC)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:14]([NH:17][C:18]1[C:26]([Cl:27])=[CH:25][C:21]([C:22]([NH:11][N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH:2]([CH3:13])[CH3:1])[CH2:6][CH2:7]2)=[O:23])=[C:20]([O:28][CH3:29])[CH:19]=1)(=[O:16])[CH3:15]
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)Cl
Reactant: CC(C)CCN1CCN(N=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NN1CCN(CCC(C)C)CC1
Reaction time: 1 h
Yield: 56.6 %

Procedure:
N-(3-methyl-butyl)-N'-nitroso-piperazine (2.5 g.) was added to 4-acetylamino-5-chloro-2-methoxy-benzoyl chloride (prepared from 3.5 g. of corresponding acid and thionylchloride) and triethylamine (5 ml.) in anhydrous toluene (250 ml.). After 1 hour, 10% sodium hydroxide (5 ml.) was added and the toluene layer separated, dried and evaporated to give 4-acetylamino-5-chloro-2-methoxy-N-[4-(3-methylbutyl)-1-piperazinyl]benzamide (3 g., 52%), m.p. 128°-30° (ex-ethylacetate/light petroleum.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH:5]=1.[Li+].[BH4-]>C1COCC1>[F:15][C:14]([F:16])([F:17])[CH2:13][O:12][C:6]1[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[CH:8][C:7]=1[C:10]#[N:11]
Reactant: COC(=O)c1ccc(C#N)c(OCC(F)(F)F)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(CO)cc1OCC(F)(F)F
Temperature: 70 °C

Procedure:
4-Cyano-3-(2,2,2-trifluoro-ethoxy)-benzoic acid methyl ester from step 1 (1.6 g, 6.2 mmol ) was dissolved in THF (62 ml). LiBH4 in THF (2M, 6.2 ml, 12.4 mmol) was added. The reaction mixture was heated to 70° C. for 3 hours. The reaction was quenched carefully with 3N HCl and then extracted with EtOAc (3×10 mL). The organic layers were combined, washed with brine, dried (MgSO4) filtered and concentrated to yield the desired product.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][CH3:7])[C:3](Cl)=[O:4].Cl.[CH:10]1([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][C:24]([NH2:26])=[CH:25][C:20]=3[N:19]=[C:18]2[C:27]([CH3:31])([CH3:30])[CH2:28][CH3:29])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CN(C1C=CN=CC=1)C.C(#N)C.CCOC(C)=O>[CH:10]1([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][C:24]([NH:26][C:3](=[O:4])[C:2]([CH3:8])([CH3:1])[CH2:6][CH3:7])=[CH:25][C:20]=3[N:19]=[C:18]2[C:27]([CH3:30])([CH3:31])[CH2:28][CH3:29])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CCC(C)(C)c1nc2cc(N)ccc2n1CC1CCCCC1
Reactant: CCC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCC(C)(C)C(=O)Nc1ccc2c(c1)nc(C(C)(C)CC)n2CC1CCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.5 %

Procedure:
2,2-Dimethylbutyryl chloride (24.6 mg, 0.18 mmol) was added to a mixture of 1-(cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazol-5-amine hydrochloride (65.0 mg, 0.15 mmol) (for preparation see in Example 7, step B) and DMAP (73.3 mg, 0.60 mmol) in acetonitrile (5 mL) at 0° C. The mixture was stirred for 6 h at room temperature, diluted with EtOAc (50 mL), washed with saturated NaHCO3 aqueous solution (10 mL), saturated NaCl aqueous solution (10 mL) and dried over Na2SO4. After filtration and evaporation, the residue was purified by MPLC (EtOAc as eluent on silica gel) to give the desired title compound as a syrup (51.6 mg, 87%). 1H NMR (400 MHz, CD3OD): δ 0.84 (t, J=7.52 Hz, 3H), 0.91 (t, J=7.52 Hz, 3H), 1.25 (m, 5H), 1.28 (s, 6H), 1.64 (m, 3H), 1.67 (s, 6H), 1.72 (q, J=7.49 Hz, 2H), 1.78 (m, 2H), 2.02 (q, J=7.49 Hz, 2H), 2.13 (m, 1H), 4.45 (d, J=7.62 Hz, 2H), 7.64 (dd, J=8.98, 1.76 Hz, 1H), 7.85 (d, J=9.18 Hz, 1H), 8.34 (s, 1H). MS (ESI) (M+H)+: 398.3. Anal. Calcd for C25H39N3O+1.50 TFA+0.70H2O (581.25): C, 57.86; H, 7.27; N, 7.23. Found: C, 57.90; H, 7.19; N, 7.34.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[N:10][C:11](Cl)=[N:12][CH:13]=1.[CH3:15][S:16][C:17]1[C:25]2[C:20](=[CH:21][C:22]([C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])=[CH:23][CH:24]=2)[NH:19][CH:18]=1>CN(C=O)C.C(OCC)(=O)C>[Br:7][C:8]1[CH:9]=[N:10][C:11]([N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[C:22]([C:26]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[O:27])[CH:21]=3)[C:17]([S:16][CH3:15])=[CH:18]2)=[N:12][CH:13]=1
Reactant: CSc1c[nH]c2cc(C(=O)N3CCOCC3)ccc12
Reactant: Clc1ncc(Br)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Temperature: 120 °C
Reaction time: 16 h

Procedure:
Potassium tert-butoxide (9.75 g, 86.95 mmol, 1.5 eq) and 5-bromo-2-chloropyrimidine (11.21 g, 57.97 mmol, 1.0 eq) were added to (3-(methylthio)-1H-indol-6-yl)(morpholino)methanone (16.0 g, 57.97 mmol, 1.0 eq) in DMF (100 mL). The mixture was stirred at 120° C. for 16 h, then cooled to room temperature, diluted with ethyl acetate (100 mL), and filtered through a pad of celite. The filtrate was washed with water (2×100 mL) and brine (50 mL), and dried over sodium sulphate. The solvents were distilled off and the residue was purified by silica gel column chromatography [100-200 mesh; ethyl acetate/petrolether=1:1]. Yield: 8.0 g (32% over two steps).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[CH:21][S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[CH:27](=O)[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[CH:21][S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:27]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cscn3)CC2)c1[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-c2nc3c(N4CCN(Cc5cscn5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 85 °C
Yield: 48.7 %

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-(thiazol-4-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.045 g, 0.11 mmol), EtOH (2.6 mL) and DMF (0.35 mL), p-anisaldehyde (0.017 g, 0.12 mmol) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.33 mL, 0.33 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v 96:4) to give the title compound as a white solid (0.026 g, 49%); 1H-NMR (500 Mz, DMSO-d6): δ 2.64-2.72 (m, 4H, piperazine N(CH2)2), 3.61-3.70 (m, 4H, piperazine N(CH2)2), 3.77 (br s, 2H, NCH2), 3.84 (s, 3H, OMe), 7.10 (d; J=9.0 Hz, 2H, ArH, C6H4), 7.58 (d, J=2.0 Hz, 1H, thiazole 5-H), 8.14 (d, J=7.0 Hz, 2H, ArH, C6H4), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 9.07 (d, J=2.0 Hz, 1H, thiazole 2-H), 13.33 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 3.07 min—485/487 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 485.0759, calculated for C21H22BrN6OS (M+H)+: 485.0742.