Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[C:11]1[C:19]([NH:21][C:22]1([C:28]([NH:30][C@H:31]([CH2:36][OH:37])[CH2:32][CH2:33][S:34][CH3:35])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:20]>CS(C)=O.C(Cl)Cl>[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[C:11]1[C:19]([NH:21][C:22]1([C:28]([NH:30][C@H:31]([CH:36]=[O:37])[CH2:32][CH2:33][S:34][CH3:35])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:20]
Reactant: CSCC[C@@H](CO)NC(=O)C1(NC(=O)c2cc3ccccc3s2)CCCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CSCC[C@@H](C=O)NC(=O)C1(NC(=O)c2cc3ccccc3s2)CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Under an argon gas atmosphere, 245 mg (1.9 mmol) of N,N-diisopropylethylamine was added dropwise to a solution of 297 mg (1.9 mmol) of sulfur trioxide-pyridine complex in 10 ml of dimethyl sulfoxide and 5 ml of anhydrous methylene chloride under ice-cooling, and the mixture was stirred for 15 minutes. Further, under ice-cooling, 100 mg (0.23 mmol) of N-[[1-[(2-benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-methioninol was added to the reaction solution, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was poured to ice-water and the mixture was extracted with ethyl acetate twice. The organic layer was washed with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine, and after it was dried with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. 20 ml of diisopropyl ether was added to the residue, and the mixture was stirred at room temperature for 18 hours. The obtained crystal was collected by filtration to quantitatively obtain the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:16]=1)[C:3](=[O:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].Cl[C:34]1[CH:44]=[CH:43][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:36][N:35]=1.C(N(CCCC)CCCC)CCC.O>CN1C(=O)CCC1>[C:8]([O:7][C:6]([NH:5][CH2:4][C:3]([N:2]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:34]4[CH:44]=[CH:43][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:36][N:35]=4)[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:1])=[O:13])=[O:12])([CH3:11])([CH3:9])[CH3:10]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: CN(Cc1cccc(-c2cnc(N3CCNCC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ccc(N2CCN(c3ncc(-c4cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c4)cn3)CC2)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
tert-Butyl (2-{methyl[3-(2-piperazin-1-ylpyrimidin-5-yl)benzyl]amino}-2-oxoethyl)carbamate (200 mg) and ethyl 6-chloronicotinate (169 mg) were dissolved in NMP (4 ml), and N,N-dibutylbutan-1-amine (252 mg) was added thereto, followed by stirring at 100° C. overnight. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with saturated brine and dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0% to 8% CHCl3/MeOH) to obtain ethyl 6-(4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)nicotinate (100 mg).
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH3:11])[CH:9]=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.Cl.[F:13][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=1)[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1.C([O-])(O)=O.[Na+]>C(#N)C>[F:13][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=1)[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:2]2[C:7]3=[C:8]([CH3:11])[CH:9]=[CH:10][N:6]3[N:5]=[CH:4][N:3]=2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Reactant: Cc1ccn2ncnc(Cl)c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccn2ncnc(Nc3ccc(OCc4cccc(F)c4)cc3)c12
Yield: 35.8 %

Procedure:
A solution of 4-chloro-5-methyl-pyrrolo[2,1-f][1,2,4]triazine (47 mg, 0.281 mmol) (Ref. WO 03/042172 A2) and 4-(3-fluoro-benzyloxy)-phenylamine hydrochloride (70 mg, 0.299 mmol) and NaHCO3 (600 mg, 7.14 mmol) in dry acetonitrile (2 ml) was heated at 80° C. for 8 hr. Filtration followed by removal of the solvent from the filtrate and purification by preparative HPLC afforded the title product (35 mg, 37%) as an oil. Analytical HPLC retention time=1.41 min. (YMC Xterra S7 C18, 3.0×50 mm column, 10–90% aqueous methanol over 2 minutes containing 0.1% TFA, 5 mL/min, monitoring at 220 nm) and a LC/MS M++1=331.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5](=[O:19])[CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:20][C:21]([CH:23]1[NH:28][CH2:27][CH2:26][N:25]([CH2:29][C:30]([NH:32][C:33]2[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:40])=[O:31])[CH2:24]1)=[O:22]>CN(C)C=O>[OH2:19].[NH2:20][C:21]([CH:23]1[N:28]([CH2:2][CH2:3][CH2:4][C:5](=[O:19])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:27][CH2:26][N:25]([CH2:29][C:30]([NH:32][C:33]2[C:34]([Cl:40])=[CH:35][CH:36]=[CH:37][C:38]=2[Cl:39])=[O:31])[CH2:24]1)=[O:22]
Reactant: NC(=O)C1CN(CC(=O)Nc2c(Cl)cccc2Cl)CCN1
Reactant: O=C(CCCCl)C(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: NC(=O)C1CN(CC(=O)Nc2c(Cl)cccc2Cl)CCN1CCCC(=O)C(c1ccccc1)c1ccccc1
Product: O
Temperature: 60 °C
Reaction time: 48 h
Yield: 3.7 %

Procedure:
A mixture of 4.45 parts of 5-chloro-1,1-diphenyl-2-pentanone, 9.94 parts of 3-(aminocarbonyl)-N-(2,6-dichlorophenyl)-1-piperazineacetamide and 90 parts of N,N-dimethylformamide was stirred for 48 hours at 60° C. and evaporated. The residue was taken up in water and alkalized with ammonia. The product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified twice by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was taken up in 2,2'-oxybispropane and allowed to stand for 10 days. The product was filtered off and dried at the air, yielding 0.32 parts (3.7%) of 3-(aminocarbonyl)-N-(2,6-dichlorophenyl)-4-(4-oxo-5,5-diphenylpentyl)-1-piperazineacetamide monohydrate; mp. 91.6° C. (compound 171).
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:24]=[C:23]([CH3:25])[C:10]([O:11][CH2:12][CH2:13][CH2:14][CH:15]([C:17]3[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=3)[OH:16])=[C:9]([CH3:26])[CH:8]=2)=[N:3]1.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[S:29]>C(#N)C.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:8]=[C:9]([CH3:26])[C:10]([O:11][CH2:12][CH2:13][CH2:14][CH:15]([C:17]3[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=3)[O:16][C:28]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[S:29])=[C:23]([CH3:25])[CH:24]=2)=[N:3]1
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCC(O)c1nccn1C
Reactant: S=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCC(OC(=S)Oc1ccccc1)c1nccn1C
Yield: 78.5 %

Procedure:
To a solution of 2-[4-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-1-hydroxy-butyl]-1-methylimidazole (690 mg, 1.94 mmol) in 30 ml of acetonitrile was added at 20° C. 473 mg (3.88 mmol) of DMAP and 403 mg (2.33 mmol) of phenyl chlorothioformate, and the mixture was stirred at 20° C. for 3 h. The solvent was concentrated in vacuo and the residue was partitioned between methylene chloride and an aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (20 cm column, ethyl acetate/hexane, 1/1-4/1) to afford 750 mg (78%) of 2-[4-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxyl]-1-phenoxythiocarbonyloxy-butyl]-1-methylimidazole, as a yellow oil.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:24]=[O:25])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:26]OS([O-])(=O)=O.C[S+](C)C.[OH-].[Na+]>ClCCl.O>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:24]1[CH2:26][O:25]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(C=O)cccc2c1Nc1ccccc1C
Reactant: COS(=O)(=O)[O-]
Agent: C[S+](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(C3CO3)cccc2c1Nc1ccccc1C
Reaction time: 2.5 h
Yield: 53.9 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)quinoline-8-carbaldehyde (0.5 q, 1.5 mmol) was dissolved in dichloromethane (5 ml) and trimethylsulphonium methylsulphate (0.34 g, 1.8 mmol) and 50% aqueous sodium hydroxide (0.75 ml) added. The mixture was stirred vigorously for 2.5 hours, when a further addition of trimethylsulphonium methylsulphate (0.23 g, 1.2 mmol) and 50% aqueous sodium hydroxide (0.5 ml) was made. After stirring for a further 2 hours the mixture was diluted with water and extracted with dichloromethane. The dried extracts were evaporated to an oil, which was purified by flash chromatography (silica gel, ethyl acetate/chloroform). The product crystallised on trituration with petroleum ether to give 3-butyryl-4-(2-methylphenylamino)-8-oxiranylquinoline (0.28 g, 54%), m.p. 114°-116°.
Reaction SMILES: [O:1]=[C:2]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=[O:18])[NH:10][C:9]2[CH:19]=[CH:20][CH:21]=[N:22][C:8]1=2)[CH2:3][CH2:4][C:5]#[CH:6].[CH2:23]=O.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>[Cu]Cl.O1CCOCC1>[O:1]=[C:2]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=[O:18])[NH:10][C:9]2[CH:19]=[CH:20][CH:21]=[N:22][C:8]1=2)[CH2:3][CH2:4][C:5]#[C:6][CH2:23][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CCNCC1
Reactant: C#CCCC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Reactant: C=O
Agent: Cl[Cu]
Solvent: C1COCCO1
Product: O=C1Nc2cccnc2N(C(=O)CCC#CCN2CCCCC2)c2ccccc21

Procedure:
A mixture consisting of 9.6 g (0.03 mol) of 5,11-dihydro-11-[1-oxo-4-pentynyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 1.08 g (0.036 mol) of paraformaldehyde, 3.06 g (0.036 mol) of piperidine, 0.2 g of copper(I) chloride and 150 ml of dioxan is refluxed for 1 hour. After the reaction has ended the insoluble constituents are filtered off and the filtrate is evaporated to dryness in vacuo. The crude product is purified by column chromatography on silica gel (mobile phase: ethyl acetate, ethyl acetate+10% methanol). After recrystallisation from ethyl acetate, 2.7 g (21% of theory) of the desired compound are obtained, m.p. 197° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][NH2:8])[CH3:2].[S:12](Cl)([OH:15])(=O)=[O:13].[CH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:10]([O:9][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][CH2:7][NH:8][S:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:15])=[O:13])[CH3:11]
Reactant: c1ccccc1
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(CCCN)OCC
Product: CCOC(CCCNS(=O)(=O)c1ccccc1)OCC
Yield: 86 %

Procedure:
42 g 4-amino butyraldehyde diethyl acetal and 88 g benzene sulfochloride are processed as explained in Preparation Example 1. The reaction mixture is not clear from the very beginning and vigorous stirring is therefore indispensable. Methylene chloride is used for the extraction of the sulfonamide acetal. Yield: 86% based on the amino acetal used. The product will crystallize when standing for an extended time at room temperature; melting point: 109°-111° C.; for further purification recrystallization from a 2:1 volume mixture of water and ethanol is possible.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[C:22]([NH:24][CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([O:29]C)=[O:28])=[O:23].O.CCOC(C)=O.Cl>CO.[OH-].[Na+]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[C:22]([NH:24][CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([OH:29])=[O:28])=[O:23]
Reactant: COC(=O)C(C)(C)CNC(=O)c1ncc2cc(NCc3ccc(OC)cc3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CNc2ccc3c(O)c(C(=O)NCC(C)(C)C(=O)O)ncc3c2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Methyl 3-(4-hydroxy-7-(4-methoxybenzylamino)isoquinoline-3-carboxamido)-2,2-dimethylpropanoate (15 mg, 0.03 mmol) was dissolved in MeOH (2 mL) and 2 N NaOH (2 mL). After stirring for 5 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-20% MeOH/CH2Cl2) to give the title compound in 13 mg. MS: (−) m/z 422.13 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:3](C(N)=O)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([NH:15][C:16]([C:18]2[C:19](=[O:31])[N:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:21]([CH3:24])[C:22]=2[CH3:23])=[O:17])=[CH:13][CH:14]=1.O.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C.CC#[N:53]>CCOC(C)=O>[NH2:53][C:3]1[C:2]([Cl:1])=[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[N:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3Cl)cn2)c(=O)n(-c2ccccc2)n1C
Reactant: CC#N
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3Cl)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
To a solution of 3-chloro-4-((6-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)pyridin-3-yl)oxy)picolinamide (290 mg, 0.6 mmol) in EtOAc (4 mL), CH3CN (4 mL), and H2O (2 mL) was added PhI(OAc)2 (234 mg, 0.72 mmol). The reaction was stirred at 0° C. for 30 minutes, then warmed up to rt and continued to stir for 12 hours. The mixture was filtered through a CELITE® pad, which was washed with DCM (30 mL). The filtrate was washed with water (20 mL), then concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=50/1) to give the title compound as a light beige solid (120 mg, 44.7%).
Reaction SMILES: C([O-])(=O)CCC.[C:7]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])(=[O:9])[CH3:8].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([O:33][C:34](=[O:39])[CH2:35][CH2:36][CH2:37]Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C.CCOC(C)=O.CCCCCCC>[C:7]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([O:15][CH2:37][CH2:36][CH2:35][C:34]([O:33][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:39])=[O:14])(=[O:9])[CH3:8]
Reactant: O=C(CCCBr)OCc1ccccc1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: CCCC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCCCCCC
Product: CC(=O)Oc1ccccc1C(=O)OCCCC(=O)OCc1ccccc1
Temperature: 90 °C

Procedure:
Benzyl 4-{[2-(acetyloxy)phenyl]carbonyloxy}butanoate was synthesized from benzyl-4-bromo)butanoate, 2-(acetyloxy)benzoic acid and potassium carbonate. To a solution of benzyl-4-bromobutanoate (0.5 g, 1.9 mmol) in acetonitrile (5 ml) at ambient temperature was added potassium carbonate (0.28 g, 2.0 mmol) and 2-(acetyloxy)benzoic acid (0.35 g, 1.9 mmol). The reaction was heated to 90° C. for 18 hours and monitored by TLC (4:1 heptane:EtOAc) The mixture was allowed to cool to room temperature and concentrated in vacuo. The crude product was partitioned between water and EtOAc and the organic phase was separated, dried over Na2SO4, filtered and concentrated in vacuo. The title compound was purified by silica column chromatography eluting with heptane:EtOAc (4:1, v:v) and isolated as a clear, colorless oil (0.556 g, 81% yield). 1H NMR (250 MHz, DMSO-d6) δ 7.29-7.41 (5H, m), 5.09 (2H, s), 4.01 (2H, t, 6.5 Hz), 2.44 (2H, t, 7.3 Hz), 1.97 (3H, s), 1.85 (2H, quin, 6.9 Hz).
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])C.[Li]CCCC.[CH3:13][C:14]1C[CH2:17][CH2:16][N:15]=1.C(OC(=O)C)C>C1COCC1>[N:4]1[CH2:1][CH2:3][CH2:7][C:5]=1[CH:6]=[C:14]([NH:15][CH2:16][CH3:17])[CH3:13]
Reactant: CC(C)NC(C)C
Reactant: CC1=NCCC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNC(C)=CC1=NCCC1
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (22.2 g, 219.3 mmol) in THF (200 mL) was dropwise added n-BuLi (2.89 M, 75.9 mL, 219.3 mmol) at −78° C. under nitrogen. Once all the n-BuLi was added, the temperature was adjusted to −5° C., and the reaction mixture was stirred for 30 min. Then a solution of 2-methyl-1-pyrroline (11.3 g, 135.7 mmol) in THF (15 mL) was added dropwise to the reaction mixture at −5° C., and then stirred. After 30 min, ethylacetate (9.20 g, 104.4 mmol) was added dropwise over 30 min. The reaction mixture was stirred as the temperature was allowed to gradually rise to room temperature, and was continuously stirred at room temperature overnight. THF solvent was removed under reduced pressure, then 80 mL of methanol was added dropwise to the residue. After removing all of the volatile solvent, diethyl ether (100 mL) was added to the residue, and the mixture was filtered. Concentration of the filtrate under reduced pressure, followed by column chromatography, provided the desired product.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:29][CH2:30][O:31][CH2:32][CH3:33]>C(#N)C.CC(C)=O>[CH2:30]([O:31][CH2:32][CH2:33][N:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)[O:18][CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)[CH3:29]
Reactant: CCOCCBr
Reactant: CN1CCC(OC(c2cccc(I)c2)c2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC#N
Product: CCOCCn1c(C(OC2CCN(C)CC2)c2cccc(I)c2)nc2ccccc21
Temperature: 60 °C

Procedure:
A solution of 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (example 51, 260 mg) in anhydrous acetonitrile (10 mL) is treated with 60% sodium hydride (47 mg) for 30 min at room temperature. 1-Bromo-2-ethoxyethane (84 μL) is then introduced. After warming at 60° C. for 8 h, dilution with water and extraction with diethylether, the organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 98/2/0.5 to 95/5/0.5) to afford the pure base that is then converted into its dioxalate salt in acetone to give 1-(2-ethoxyethyl)-2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, dioxalate, melting at 88° C.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[CH:11]=[CH:12][C:13]([C:15](=O)[CH:16]([NH:24][C:25](=O)[CH2:26][CH2:27][O:28][CH3:29])[C:17]4[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=4)=[CH:14][C:9]=3[N:8]([CH3:32])[C:7]2=[O:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C([O-])=O.[NH4+:41].CO>C(OCC)(=O)C>[CH:1]1([N:6]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]4[NH:41][C:25]([CH2:26][CH2:27][O:28][CH3:29])=[N:24][C:16]=4[C:17]4[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=4)=[CH:14][C:9]=3[N:8]([CH3:32])[C:7]2=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [NH4+]
Reactant: COCCC(=O)NC(C(=O)c1ccc2c(c1)n(C)c(=O)n2C1CCCC1)c1cccc(C)c1
Agent: O=C([O-])C(F)(F)F
Solvent: CO
Solvent: CCOC(C)=O
Product: COCCc1nc(-c2cccc(C)c2)c(-c2ccc3c(c2)n(C)c(=O)n3C2CCCC2)[nH]1
Yield: 85.8 %

Procedure:
N-[2-(1-Cyclopentyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-2-oxo-1-m-toly-ethyl]-3-methoxy-propionamide (294 mg, 0.65 mmol) was stirred with ammonium trifluoroacetate (857 mg, 6.5 mmol) and the mixture was heated to 150 deg C. in an oil bath. Occasionally, the sides of the flask were rinced down with methanol to insure all reactants were heated uniformly. A TLC (ethyl acetate) of the reaction mixture after 1 hour of heating showed complete reaction. The oil bath was removed, and hot water was added to the reaction mixture as it cooled. When the mixture reached room temperature, no precipitate formed, so the aqueous mixture was extracted with ethyl acetate (2×20 mL). The combined organic phase was washed with water and dried over anhydrous sodium sulfate to afford 240 mg of a tan solid. MS (M+1)=431.3.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8]2[CH:11]=[CH:12][C:3]=1[CH:4](Br)[O:5][CH2:6][O:7]2.[C-:14]#[N:15].[K+].O>C(O)C>[F:1][C:2]1[C:9]([F:10])=[C:8]2[CH:11]=[CH:12][C:3]=1[CH:4]([C:14]#[N:15])[O:5][CH2:6][O:7]2
Reactant: Fc1c2ccc(c1F)C(Br)OCO2
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CC1OCOc2ccc1c(F)c2F
Temperature: 70 °C
Reaction time: 5 h
Yield: 95.2 %

Procedure:
2,3-Difluoromethylenedioxybenzyl bromide (40.4 g) was dissolved in ethanol and potassium cyanide (11.3 g) was added. The mixture was stirred at 70° C. for 5 hours. Water and a further portion of potassium cyanide (2 g) were added and the mixture was stirred at 70° C. for a further 3 hours. Most of the solvent was removed in vacuo and water was added to the residue, which was extracted with diethyl ether, washed with water, dried and concentrated to yield the title compound as a yellow oil, (30.2 g), NMR (CDCl3): 3.80(s,2H), 7.10(m,3H).
Reaction SMILES: C(OC([N:8]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:9][CH2:10][CH2:11][S:12][C:13]1[N:17]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[N:14]=1)=O)(C)(C)C.[ClH:38]>C(OCC)(=O)C>[Cl-:38].[C:22]([O:21][C:19]([CH2:18][N:17]1[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[N:14]=[C:13]1[S:12][CH2:11][CH2:10][CH2:9][NH2+:8][CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: Cl
Reactant: CC(C)(C)OC(=O)Cn1c(SCCCN(CCc2ccccc2)C(=O)OC(C)(C)C)nc2ccccc21
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cn1c(SCCC[NH2+]CCc2ccccc2)nc2ccccc21
Product: [Cl-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl {2-[3-(tert-butoxycarbonyl-phenethyl-amino)-propylsulfanyl]-benzoimidazol-1-yl}-acetate (Precursor J-01b, 199 mg, 0.38 mmol) is dissolved in a 1M HCl solution in ethyl acetate (1.89 ml). The resulting solution is stirred at rt for 1 h. The solvent is evaporated and the crude solid is dissolved in dichloromethane, the resulting organic phase is washed with a saturated aqueous NaHCO3 solution and with water. Evaporation of the solvent in vacuo and chromatography of the residue on silica-gel (dichloromethane/MeOH, 92:8) yields the title compound (107 mg) in 61% as a white solid: tR=2.62 min (LC-2), ESI-MS (pos.): m/z 510.49 [M+H]+.