Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2.[Br:23]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:23][C:21]1[CH:20]=[CH:19][C:3]2[N:4]([CH:7]3[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]3)[CH2:5][CH2:6][S:1][C:2]=2[CH:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCSc3ccccc32)C1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CCSc3cc(Br)ccc32)C1
Reaction time: 1 h
Yield: 120.5 %

Procedure:
A solution of tert-butyl 3-(2H-benzo[b][1,4]thiazin-4(3H)-yl)pyrrolidine-1-carboxylate (0.41 g, 1.302 mmol) in DMF (5 mL), was cooled to 0° C. and treated dropwise with N-bromosuccinimide (0.17 g, 0.977 mmol) in DMF (5 mL) for 15 minutes. The reaction was kept at 0° C. and was stirred for 1 hour at this temperature. At this time, N-bromosuccinimide (0.023 g, 0.130 mmol) in DMF (1 mL) was added dropwise to the reaction, which was then stirred for 1 hour at 0° C. The solution was treated again with N-bromosuccinimide (0.023 g, 0.130 mmol) in DMF (1 mL) and was stirred for 1 hour at 0° C. The solution was diluted in water (100 mL) and extracted with EtOAc (2×100 mL). The aqueous phase was washed once with EtOAc (50 mL). The organic solutions were combined, washed with water (100 mL) and brine (50 mL), and dried (Na2SO4). The crude material was filtered through a silica pad (20% EtOAc/hexanes) and concentrated to give clear oil (0.47 g, 90%). 1H NMR (CDCl3) δ 7.18 (d, J=2.4 Hz, 1H), 7.07 (d, J=8.7 Hz, 1H), 6.62 (d, J=8.7 Hz, 1H), 4.34-4.28 (m, 1H), 3.71-3.23 (m, 6H), 3.03-3.04 (m, 2H), 2.19-1.95 (m, 2H), 1.47 (s, 9H); ESI-MS (m/z, %): 423, 421 (M+Na, 8), 401, 399 (MH+, 2), 343, 345 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:48]=[CH:47][C:5]([O:6][CH2:7][C:8]2[N:9]([CH3:46])[C:10]3[C:15]([C:16]=2[C:17]([CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:23][CH2:22]2)=[O:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:9]([CH3:46])[C:10]3[C:15]([C:16]=2[C:17]([CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:47][CH:48]=1
Reactant: Cn1c(COc2ccc(Cl)cc2)c(C(=O)CCC2CCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)c2ccccc21
Solvent: O=CO
Solvent: ClCCl
Product: Cn1c(COc2ccc(Cl)cc2)c(C(=O)CCC2CCNCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Under an argon atmosphere 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[2-(1-tritylpiperidin-4-yl)ethyl]carbonyl]-1H-indole (0.2723 g, 0.417 mmol) was dissolved in 2.1 ml of methylene chloride. To this solution formic acid (0.079 ml, 0.096 g, 2.084 mmol) was added and the resulting mixture was stirred at room temperature for about 2.5 hours. The progress of the reaction was monitored by thin layer chromatography.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:14])[CH2:4][C:5]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:32]1[CH:37]=[CH:36][CH2:35][CH2:34][CH2:33]1.C(OCC)(=O)C>C(Cl)Cl>[Br:1][CH2:2][CH:3]([O:14][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][O:32]1)[CH2:4][C:5]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6]
Reactant: C1=COCCC1
Reactant: CCOC(=O)CNC(=O)CC(O)CBr
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(=O)CC(CBr)OC1CCCCO1
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of 1 g ethyl 2-(4-bromo-3-hydroxybutanamido)acetate in 30 ml methylene chloride are added 100 mg pyridinium p-toluenesulphonate and 1 ml dihydropyran. Stirring is continued for 3 h at ambient temperature, the solvent is evaporated in vacuo and the residue chromatographed on silica, eluting with ether. A pale straw-coloured oil is obtained in 91% yield, Rf 0.5 (silica gel plates, thickness 0.25 mm eluent ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2Cl)=[CH:4][CH:3]=1.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1.ClCCl>C(OCC)(=O)C.ClCCl>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[NH:19][CH:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24][CH2:25]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: Fc1ccc(Cn2c(Cl)nc3ccccc32)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 4 h

Procedure:
Combine 1-(4-fluorobenzyl)-2-chloro-1H-benzimidazole (22.1 g, 84 mmol) and ethyl 4-aminopiperidine-1-carboxylate (27.7 g, 161 mmol) and heat to 170° C. After 4 hours, partition the reaction mixture between aqueous 2.5 M sodium hydroxide solution and chloroform. Separate the layers and extract the aqueous layer twice with chloroform. Combine the organic layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on a short column of silica gel eluting sequentially with dichloromethane and then 15% ethyl acetate/dichloromethane. Evaporate the product containing fractions, triturate with hexane, filter, and dry to give (1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)-(1-ethoxycarbonyl-piperidin-4-yl)amine as a solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([OH:33])[CH:27]=1)[C:10]([O:12][CH2:13][C@H:14]([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18])[CH3:15])=[O:11])=O)(C)(C)C.Cl.O1CCOCC1.[CH3:41][S:42]([OH:45])(=[O:44])=[O:43]>>[S:42]([OH:45])(=[O:44])(=[O:43])[CH3:41].[NH2:8][C@@H:9]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([OH:33])[CH:27]=1)[C:10]([O:12][CH2:13][C@H:14]([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18])[CH3:15])=[O:11]
Reactant: C[C@H](COC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C)OC(=O)c1ccccc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](COC(=O)[C@@H](N)Cc1ccc(O)c(O)c1)OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (2R)-2-phenylcarbonyloxypropyl (2S)-2-(tert-butoxycarbonyl)amino-3-(3,4-dihydroxyphenyl)propanoate is (10.5 g, 21.1 mmol) in 34 mL (6.0 eq) of 4.0 N HCl/1,4-dioxane was stirred at room temperature for 1 h. Methanesulfonic acid (1.48 mL, 22.8 mmol) was slowly added to the reaction mixture while stirred at room temperature. The solution was concentrated under vacuum to afford the anhydrous mesylate salt 1 as a brown solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26].O>CN(C)C=O>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCNCC
Reactant: CC(=O)O[C@H]1CC[C@H](c2ccc(CCl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)Cc1ccc([C@H]2CC[C@H](OC(C)=O)CC2)cc1
Temperature: 50 °C

Procedure:
A solution of 1 g (3.75 mmol) of trans-O-acetyl-4-(4-chloromethylphenyl)-cyclohexanol in 10 ml of dimethylformamide is mixed with 0.52 g (3.75 mmol) of potassium carbonate and 0.27 g (3.75 mmol) of diethylamine. This mixture is heated to 50° C. for 6 hours with stirring, then water is added and the mixture is extracted with methylene chloride. The organic phase is dried, evaporated down in vacuo and the residue remaining is purified by column chromatography (aluminium oxide basic, activity stage III, ICN; petroleum ether/ethyl acetate=15:1). Colourless oil.
Reaction SMILES: C(O)C.[H-].[Na+].[CH:6]1([C:10](=[O:12])[CH3:11])[CH2:9][CH2:8][CH2:7]1.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].S(=O)(=O)(O)O.O>>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[O:19])[CH:11]=[C:10]([CH:6]1[CH2:9][CH2:8][CH2:7]1)[OH:12])[CH3:18]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)C1CCC1
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=O)C=C(O)C1CCC1
Reaction time: 8 h

Procedure:
Ethanol (4.39 mL, 75.2 mmol) was added dropwise to a suspension of sodium hydride (0.607 g, 15.2 mmol, 60% in mineral oil) in a flask that was held in an ice bath. Ten minutes after complete addition, a mixture of 1-cyclobutylethanone (1.5 mL, 14 mmol, Aldrich) and diethyl oxalate (2.01 g, 13.8 mmol, Aldrich) was added dropwise. After stirring overnight, 4.0M sulfuric acid in water (0.00759 L, 30.4 mmol) was added. The product was extracted into diethyl ether. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The material was used without further purification in Step B.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:18][CH2:19][NH2:20])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)Cl>[Cl:21][CH2:22][C:23]([NH:20][CH2:19][CH2:18][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:10]([O:9][CH3:8])[CH:11]=1)=[O:24]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(CCN)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)CCl)cc1OC

Procedure:
4.5 ml of triethylamine were added to a solution of 5.11 g of 2-(3,4-dimethoxyphenyl)ethylamine dissolved in 35 ml of methylene chloride, and the mixture was stirred, whilst ice-cooling. 2.4 ml of chloroacetyl chloride were then added dropwise to the mixture over a period of 5 minutes, after which the mixture was stirred for 15 minutes, whilst ice-cooling. The reaction mixture was then concentrated by evaporation under reduced pressure, and ethyl acetate was added to the resulting residue. The ethyl acetate solution was washed, in turn, with water, with a 5% w/v aqueous solution of sodium bicarbonate, with 10% w/v aqueous hydrochloric acid and with a saturated aqueous solution of sodium chloride. It was then dried, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate and hexane, to give 5.77 g of the title compound as pale yellow-brown, feather-like crystals melting at 92-94° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[N:11][CH:12]=1.Br[CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[CH:8]=[C:9]([O:13][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=[N:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CN1CCC[C@H]1c1cncc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCC[C@H]1c1cncc(OCCNC(=O)OC(C)(C)C)c1
Yield: 34.3 %

Procedure:
(S)-5-(1-Methylpyrrolidin-2-yl)pyridin-3-ol (preparation 10) (175 mg, 0.98 mmol), tert-butyl 2-bromoethylcarbamate (550 mg, 2.45 mmol) and potassium carbonate (676 mg, 4.9 mmol) in DMF (7 mL) were heated at 90° C. for 16 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, dried over MgSO4 and evaporated. The crude product was purified by flash chromatography (5%→10% MeOH in DCM) to give the title compound as a yellow oil (108 mg, 34%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](Cl)=[N:6][CH:7]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>CCCCO.CCOC(C)=O>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1c(Cl)ncc(Br)c1=O
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Cn1c(Nc2ccccc2)ncc(Br)c1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
A mixture of 5-bromo-2-chloro-3-methylpyrimidin-4(3H)-one (0.510 g, 2.282 mmol), aniline (0.271 ml, 2.967 mmol) and NaHCO3 (0.767 g, 9.129 mmol) in n-BuOH (15 mL) was stirred at 60° C. for 16 hours. The reaction mixture was cooled to room temperature and then diluted with EtOAc. The EtOAc layer was washed with H2O and saturated aqueous NaCl. The aqueous phase was re-extracted with EtOAc (1×). The combined EtOAc layers were dried (Na2SO4), filtered and concentrated to yield the desired product (0.636 g, 99%) as a pale yellow solid that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.95 (br s, 1H), 7.94 (s, 1H), 7.47 (m, 2H), 7.35 (m, 2H), 7.14 (m, 1H), 3.53 (s, 3H). LRMS (ESI pos) m/e 280, 281 (M+, Br pattern).
Reaction SMILES: S[C:2]1[N:11]([CH2:12][CH:13]=[CH2:14])[C:10](=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[CH2:17][S:18][C:19]#[N:20].[H-].[Na+]>C(COC)OC>[S:18]([CH2:17][C:2]1[N:11]([CH2:12][CH:13]=[CH2:14])[C:10](=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[C:19]#[N:20]
Reactant: C=CCn1c(S)nc2ccccc2c1=O
Reactant: N#CSCCl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C=CCn1c(CSC#N)nc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5.8 g (0.03 mole) 2-mercapto-3-allyl-4(3H)-quinazolinone (the product of Example 5) in 200 ml dimethoxyethane, 5.4 g (0.05 mole) chloromethyl thiocyanate and 2.4 g (0.05 mole) 50% sodium hydride were added. The resulting mixture was stirred overnight at ambient temperature, refluxed at 50° C. for 8 hours, stirred overnight, refluxed at 50° C. for 8 hours and stirred overnight. The reaction mixture was washed with water, extracted with methylene chloride, dried over magnesium sulfate and stripped. The oily residue was triturated with ether, to give the above-identified product, as a solid, melting point 73°-76° C.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[CH2:9][CH2:8][C:7]2[S:10][CH:11]=[CH:12][C:6]=2[CH2:5]1>CC(O)=O.O>[Br:1][C:11]1[S:10][C:7]2[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][C:6]=2[CH:12]=1
Reactant: BrBr
Reactant: CN1CCc2sccc2C1
Solvent: CC(=O)O
Solvent: O
Product: CN1CCc2sc(Br)cc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
Bromine (0.3 mL) in HOAc (10 mL) was slowly added over 5 min to a mixture of 5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1.0 g, 6.5 mmol) in acetic acid (10 mL) and water (10 mL) at 0° C. The resulting mixture was stirred at 0° C. for 1 h. Work-up: the reaction mixture was partitioned between ethyl acetate (300 mL) and water (200 mL). The organic layer was separated, washed with saturated aqueous NaHCO3 (300 mL) and brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The residue was recrystallized from 1:4 EtOAc/petroleum ether (150 mL) to afford the title compound as white solid (660 mg, 43%). 1H NMR (DMSO-d6, 400 MHz): δ 6.91 (s, 1H), 3.33 (s, 2H), 2.73-2.71 (m, 2H), 2.52-2.51 (m, 2H), 2.33 (s, 3H). LCMS: 233 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:8][C@H:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)[CH3:10])=[O:7].[F:21][C:22]([F:32])([F:31])[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br.C([O-])([O-])=O.[Na+].[Na+]>>[F:21][C:22]([F:31])([F:32])[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:8][C@H:9]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=1)[CH3:10])=[O:7]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2)cc1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2Cc2cccc(C(F)(F)F)c2)cc1
Yield: 89.5 %

Procedure:
The title compound (D32) (70 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((S)-1-((R)-pyrrolidine-2-carboxamido)ethyl)benzoate (D14) (50 mg, 0.18 mmol) and 3-(trifluoromethyl)benzyl bromide (0.055 ml, 0.36 mmol). (Na2CO3: 2.5 eq; reaction time: 5 hrs; 70° C.)
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([CH3:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5].[N:13]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[CH3:5][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:12])[CH2:3][CH2:2][N:16]1[CH2:15][CH2:14][N:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17]1
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(C)(CCBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCN(CCC(C)(C)c2ccccc2)CC1
Yield: 81.8 %

Procedure:
A solution of 1-bromo-3-methyl-3-phenylbutane (0.73 g), ethyl piperazinecarboxylate (0.51 g) and anhydrous potassium carbonate (0.50 g) in tetrahydrofuran (5 ml) was refluxed under heating for 36 hours. To the reaction solution was added water and the solution was extracted with ethyl acetate. After washing with a saturated aqueous solution of sodium chloride, the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (15 g) and elution with a hexane-ethyl acetate (2:1) mixture gave 0.80 g of ethyl 4-(3-methyl-3-phenylbutyl)piperazine-1-carboxylate.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[C:19]([O:20][CH3:21])=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([F:22])[CH:13]=1.[CH3:23]N(C)C=O.[H-].[Na+].CI>>[F:22][C:14]1[CH:13]=[C:12]([O:11][CH2:10][C:2]2[N:3]([CH3:23])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[C:19]([O:20][CH3:21])=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: COc1cc(C=O)c(F)cc1OCc1nc2ccccc2[nH]1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COc1cc(C=O)c(F)cc1OCc1nc2ccccc2n1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.9 %

Procedure:
4-(1H-Benzimidazol-2-ylmethoxy)-2-fluoro-5-methoxy-benzaldehyde (142) (0.600 g, 2.0 mmol) was dissolved in N,N-dimethylformamide (15 mL, 190 mmol). After the addition of sodium hydride (60% dispersion in oil, 0.072 g, 3.0 mmol) the reaction was stirred for 15 minutes at room temperature. Methyl iodide (140 μL, 2.2 mmol) was added dropwise to the mixture. The reaction was stirred overnight at room temperature under an atmosphere of nitrogen. The solvent was evaporated to dryness under reduced pressure. Ethyl acetate was added and the organic portion was washed with water, dried over anhydrous sodium sulfate and concentrated. Purification with silica gel flash chromatography with a gradient of ethyl acetate in hexanes gave the desired compound as a white powder (143, 0.345 g, 55%). MS (ESI) [M+H+]+=315.2.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][N:10]([CH:15]([CH3:18])[CH2:16][OH:17])[C:11](=[O:14])[CH2:12]Br)=[CH:7][CH:6]=1>C1COCC1>[CH3:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][N:10]2[C@@H:15]([CH3:18])[CH2:16][O:17][CH2:12][C:11]2=[O:14])=[CH:7][CH:6]=1
Reactant: COc1ccc(CN(C(=O)CBr)C(C)CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)COC[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 10000 mL 4-necked, round bottomed flask purged and maintained with an inert atmosphere of nitrogen was placed a suspension of sodium hydride (125.6 g, 3.14 mol, 60%) in THF (5000 mL) and cooled to 25° C., followed by the addition of a solution of N-(4-methoxybenzyl)-2-bromo-N-(1-hydroxypropan-2-yl)acetamide (498 g, 1.57 mol) in THF (500 mL) dropwise over 30 minutes at 25° C. The resulting solution was allowed to stir overnight at 25° C. Upon completion, the reaction mixture was quenched by adding 1000 mL of ethanol and 250 mL of water. The resulting solution was further diluted with 1500 mL of dichloromethane and then washed three times with 2000 mL of water. The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum to afford the title compound as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:14][CH2:15][N:16]3[C:17](=[O:26])[C:18]4[C:19](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:21])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: c1cc(N2CCNCC2)ccn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(c2ccncc2)CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 73.8 %

Procedure:
A mixture of 1-pyridin-4-yl-piperazine [Org. Lett. 4 (2002) 737-740] (1.0 g, 6.12 mmol), N-(2-bromoethyl)-phthalimide (1.71 g, 6.74 mmol), potassium carbonate (0.85 g, 6.12 mmol), potassium iodide (1.02 g, 6.12 mmol) and dimethyl formamide (10 mL) was stirred at 70° C. for 24 h, then concentrated. The residue was dissolved in water, extracted with dichloromethane, the organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography using Kieselgel 60 (0.040-0.063 mm) (Merck) as adsorbent, and chloroform:methanol:NH4OH=10:1:0.1 as eluent to yield 1.52 g (74%) of the title compound, as a white solid.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[NH2:38])/[CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13]3[N:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:12]=3[CH2:11][N:10]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:9]=2[CH:37]=1.C([O:42][C:43]([CH3:48])([CH3:47])[C:44](Cl)=O)(=O)C>N1C=CC=CC=1>[F:36][C:33]([F:35])([F:34])[O:32][C:29]1[CH:30]=[CH:31][C:26]([S:23]([N:10]2[C:9]3[CH:37]=[C:5]([CH2:4][C:3]4[N:38]=[C:44]([C:43]([OH:42])([CH3:48])[CH3:47])[O:1][N:2]=4)[CH:6]=[CH:7][C:8]=3[NH:14][C:13]3[N:15]=[C:16]([C:19]([F:21])([F:22])[F:20])[CH:17]=[CH:18][C:12]=3[CH2:11]2)(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: N/C(Cc1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2)=N\O
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(O)c1nc(Cc2ccc3c(c2)N(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)Cc2ccc(C(F)(F)F)nc2N3)no1
Temperature: 82 °C
Reaction time: 2 h

Procedure:
To a solution of (1Z)-N′-hydroxy-2-[6-{[4-(trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]ethanimidamide (92 mg, 0.163 mmol, the product of Step A) in pyridine was added 2-acetoxyisobutyryl chloride (0.268 g, 1.63 mmol). The resulting mixture was heated at 80-84° C. for 1.5 hr, until LC-MS indicated the reaction was complete, and then the solution was concentrated to remove pyridine. The bright orange residue was dissolved in 5 mL of MeOH and K2CO3 was added. The mixture was stirred for 2 hr at 50° C., then another 0.5 g of K2CO3 was added and the solution was stirred for another 2 hr. The solution was filtered to remove solids and the filtrate was concentrated to remove MeOH. The residue was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate (3:1-2:1) to give the title compound; Mass Spectrum: m/e=630 (M+1).