Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:14])[CH3:13])[C@:7]([CH2:16][CH2:17][N:18]([CH3:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[N:28]([CH3:29])[C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=3[N:25]=1)([OH:15])[CH2:6][CH2:5]2.[C:35]1([N:41]=[C:42]=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[ClH:44]>C1(C)C=CC=CC=1.C(Cl)Cl.CCOCC.C(C(CCCC)C([O-])=O)C.[Sn+2].C(C(CCCC)C([O-])=O)C>[ClH:44].[ClH:44].[C:42](=[O:43])([O:15][C@:7]1([CH2:16][CH2:17][N:18]([CH3:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[N:28]([CH3:29])[C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=3[N:25]=2)[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[C@@H:8]1[CH:12]([CH3:14])[CH3:13])[NH:41][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)[C@H]1c2ccc(F)cc2CC[C@]1(O)CCN(C)CCCCCc1nc2ccccc2n1C
Reactant: O=C=Nc1ccccc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: Cl
Agent: [Sn+2]
Solvent: CCOCC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)[C@H]1c2ccc(F)cc2CC[C@@]1(CCN(C)CCCCCc1nc2ccccc2n1C)OC(=O)Nc1ccccc1
Yield: 65 %

Procedure:
A solution of 2.32 g (0.005 mol) of [1S,2S]-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-[2-[methyl-[5-(1-methyl-2-benzimidazolyl)pentyl]amino]ethyl]-2-naphthalenol and 0.6 g (0 005 mol) of phenyl isocyanate in 5 ml of toluene is treated with 7.5 mg of tin(II) 2-ethylhexanoate and heated to 100° for 15 hours. After concentration under reduced pressure the oily residue is chromatographed on 160 g of silica gel with methanol/methylene chloride (3:2) as the elution agent. The oily product obtained is dissolved in methylene chloride and treated with an excess of hydrogen chloride in ether. There are obtained 2.15 g (65%) of [1S,2S]-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-[2-[methyl-[5-(1-methyl-2-benzimidazolyl)pentyl]amino]ethyl]-2-naphthyl carbanilate dihydrochloride, m.p. 157°-160°, as a colourless crystalline powder.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([C:13]3[N:14]=[C:15]4[C:21]([C:22]([C:24]5([CH3:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)=[O:23])=[CH:20][N:19]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:16]4=[N:17][CH:18]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:41]I>CN(C)C=O>[CH:1]1([N:6]([CH3:41])[C:7]2[CH:8]=[C:9]([C:13]3[N:14]=[C:15]4[C:21]([C:22]([C:24]5([CH3:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)=[O:23])=[CH:20][N:19]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[C:16]4=[N:17][CH:18]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CI
Reactant: CC1(C(=O)c2cn(COCC[Si](C)(C)C)c3ncc(-c4cccc(NC5CCCC5)c4)nc23)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1cccc(-c2cnc3c(n2)c(C(=O)C2(C)CCCCC2)cn3COCC[Si](C)(C)C)c1)C1CCCC1
Reaction time: 14 h
Yield: 15 %

Procedure:
To a solution of [2-(3-Cyclopentylamino-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-(1-methyl-cyclohexyl)-methanone in dimethyl formamide was added sodium hydride (60% dispersion in mineral oil, 9 mg, 0.218 mmol) under argon. The reaction mixture was stirred at room temperature for 15 minutes before the addition of methyl iodide via syringe. The reaction was stirred for 14 h before quenching with water and extracting 3 times with dichloromethane. The combined organics were washed with water, dried over MgSO4, filtered and concentrated in vacuo. Preparative thin layer chromatography (25% EtOAc/hexanes) afforded 0.0152 g (15% yield) of [2-[3-(Cyclopentyl-methyl-amino)-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-(1-methyl-cyclohexyl)-methanone as a yellow oil. MS (E/I): 547 (M+H)
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CC#N>[Br-:23].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: CCCCCCCCCBr
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: CCCCCCCCC[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 45.5 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0561 g, 0.191 mmol) and 1-bromononane (0.055 mL, 0.288 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0435 g, 45.8%). EI-MS m/z 420 (M+) Rt (2.34 min).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:2]1.[H-].[Na+].[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.O>COCCOC>[O:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:13])[CH:7]([CH2:22][C:21]2[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:26])[F:27])=[CH:25][CH:24]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:2]1
Reactant: CCOC(=O)CC(=O)c1ccoc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccoc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
To a solution of ethyl 3-(3-furanyl)-3-oxopropionate (20 g, 110 mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60% in oil, 4.4 g, 110 mmol) under ice-cooling and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (26.2 g, 110 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution was stirred at room temperature for 3 hrs. The reaction solution was poured into water (300 ml) and extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give ethyl 3-(3-furanyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (28.8 g, 77%).
Reaction SMILES: [C:1]([CH:5]([O:30][SiH:31]([CH3:33])[CH3:32])[C:6]1[C:7]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:8]([C:18](OCC)=[O:19])[C:9]([CH:15]([CH3:17])[CH3:16])=[N:10][C:11]=1[CH:12]([CH3:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2].O>C1(C)C=CC=CC=1.O1CCCC1>[C:1]([CH:5]([O:30][SiH:31]([CH3:33])[CH3:32])[C:6]1[C:11]([CH:12]([CH3:13])[CH3:14])=[N:10][C:9]([CH:15]([CH3:17])[CH3:16])=[C:8]([CH2:18][OH:19])[C:7]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C(O[SiH](C)C)C(C)(C)C)c1-c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1nc(C(C)C)c(C(O[SiH](C)C)C(C)(C)C)c(-c2ccc(F)cc2)c1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
9.2 ml (32.2 mmol) of a 3.5 molar solution of sodium bis-(2-methoxyethoxy)-dihydroaluminate in toluene are added under nitrogen to a solution of 4.2 g (9.2 mmol) of the compound from Example 5 in 100 ml of dry tetrahydrofuran at 0° C. and the mixture is stirred overnight at room temperature. After cooling to 0° C., 100 ml of water are cautiously added dropwise and the mixture is extracted three times using 100 ml of ethyl acetate each time. The combined organic phases are washed once with saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue is chromatographed on a column (100 g of silica gel 70-230 mesh, φ3.5 cm, using ethyl acetate/petroleum ether 2:8).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([NH:19][NH2:20])=[O:18])[CH2:11][CH2:10]1.[CH2:21]1[CH2:26][CH2:25][CH:24]([CH2:27][N:28]=[C:29]=[O:30])[CH2:23][CH2:22]1.CCCCCC>C1(C)C=CC=CC=1>[CH:24]1([CH2:27][NH:28][C:29]([NH:20][NH:19][C:17](=[O:18])[CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:14][CH2:13]2)=[O:30])[CH2:25][CH2:26][CH2:21][CH2:22][CH2:23]1
Reactant: COc1ccccc1N1CCN(CCC(=O)NN)CC1
Reactant: O=C=NCC1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COc1ccccc1N1CCN(CCC(=O)NNC(=O)NCC2CCCCC2)CC1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
To a suspension of 3-[4-(2-methoxyphenyl)piperazino]propanohydrazide D2 (0.30 g, 1.07 mmol) in anhydrous toluene (5 mL), cyclohexanemethyl isocyanate (0.16 g, 0.165 mL, 1.16 mmol) was added and the mixture was heated at reflux until all solid dissolved. The solution was allowed to cool slowly to room temperature. Hexane was added and the resulting oil was extracted with ethyl acetate, the organic phase was washed with water, dried over MgSO4 and evaporated under reduced pressure to afford 0.40 mg (87%) N-(cyclohexylmethyl)-2-{3-[4-(2-methoxyphenyl)piperazino]propanoyl}-1-hydrazinecarboxamide D4 as a pale yellow oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1.S(Cl)([Cl:12])=O>>[ClH:12].[Cl:12][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1
Reactant: Cc1cc(CO)ccn1
Reactant: O=S(Cl)Cl
Product: Cc1cc(CCl)ccn1
Product: Cl

Procedure:
The title compound was prepared in accordance with the general method of example E from 4-(hydroxymethyl)-2-methylpyridine and thionylchloride.
Reaction SMILES: [C:1]1(=[O:7])[CH2:5][CH2:4][C:3](=O)[CH2:2]1.[CH3:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=O)[CH:16]=2)[NH:11][N:10]=1.N1CCCCC1.[NH2:26][C:27]([CH3:31])=[CH:28][C:29]#[N:30]>C(O)C>[CH3:31][C:27]1[NH:26][C:3]2[CH2:4][CH2:5][C:1](=[O:7])[C:2]=2[CH:18]([C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[CH3:8])[C:28]=1[C:29]#[N:30]
Reactant: CC(N)=CC#N
Reactant: O=C1CCC(=O)C1
Reactant: Cc1n[nH]c2ccc(C=O)cc12
Solvent: C1CCNCC1
Solvent: CCO
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C2=C(CCC2=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
91 mg (0.936 mmol) cyclopentane-1,3-dione, 150 mg (0.936 mmol) 3-methyl-1H-indazole-5-carbaldehyde (Example 1A) and piperidine (0.1 ml) in ethanol (8 ml) were heated to reflux for 1.5 h and then left standing without stirring at room temperature overnight. The mixture was then evaporated to dryness, the remaining solid was dissolved in acetic acid (8 ml), and 77 mg (0.936 mmol) 3-aminobut-2-enenitrile were added. The solution was heated to reflux for 2 h. After cooling, the mixture was evaporated to dryness again, and the remaining solid was purified by preparative RP-HPLC (acetonitrile/water gradient) to yield 34 mg (12% of th.) of the title compound.
Reaction SMILES: C1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9](C)C)CC1.[Cl:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].[C:23](=O)([O-])[O-].[Li+].[Li+]>>[Cl:13][C:14]1[CH:21]=[C:20]([N:6]2[C@H:7]([CH3:23])[CH2:8][C@H:4]([OH:12])[C@@H:5]2[CH3:9])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: O=C([O-])[O-]
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: [Li+]
Product: C[C@@H]1C[C@H](O)[C@H](C)N1c1ccc(C#N)c(Cl)c1

Procedure:
By an operation in the same manner as in Example 53 and using (2S,3S,5R)-2,5-dimethylpyrrolidin-3-ol 0.5 oxalate (144 mg), 2-chloro-4-fluorobenzonitrile (254 mg) and lithium carbonate (193 mg), the title compound was obtained as colorless oil (yield: 61 mg, yield: 27%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[NH:34][C:33](=[O:35])[C:20]3([CH2:25][CH2:24][N:23](CC4C=CC=CC=4)[CH2:22][CH2:21]3)[N:19]=[C:18]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:17]=2[CH:42]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[NH:34][C:33](=[O:35])[C:20]3([CH2:25][CH2:24][N:23]([C:2]([O:4][CH2:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=4)=[O:3])[CH2:22][CH2:21]3)[N:19]=[C:18]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:17]=2[CH:42]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC12CCN(Cc1ccccc1)CC2
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)N1CCC2(CC1)N=C(c1ccccc1)c1cc(Cl)ccc1NC2=O
Reaction time: 3 h

Procedure:
10 g (0.029 mole) of a 50% strength solution of benzyl chloroformate in toluene are added to a mixture of 4.0 g (0.0093 mole) of 7-chloro-5-phenyl-1'-benzyl-spiro[1H-1,4-benzodiazepine-3,4'-piperidin]-2-(3H)-one and 2.4 g (0.029 mole) of finely powdered NaHCO3 in 80 ml of absolute chloroform. The reaction mixture is boiled for 3 hours, with reflux cooling. It is then poured onto ice and the organic phase is separated off and washed twice with 10% strength NaHCO3 solution. After drying over Na2SO4, the mixture is filtered and the solvent is evaporated off. A pale brown-colored remains, and is crystallized with petroleum ether. The compound is filtered off with suction, washed with petroleum ether and dried at 60° C. in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:22](O)[CH2:23][OH:24].O>C1C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:24][CH2:23][CH2:22][O:7]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: Brc1ccc(C2OCCO2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Bromobenzaldehyde (3 g, 0.0162 moles) in benzene (60 mL) was treated with p-toluenesulfonic acid monohydrate (0.15 g, 0.79 mmoles) and ethylene glycol (5 mL, 0.0896 moles). The reaction was refluxed under nitrogen with azeotropic removal of water. After 3 hours, the reaction was cooled to room temperature and diluted with an equal volume of ethyl acetate. This solution was washed twice with aqueous bicarbonate, dried over magnesium sulfate and concentrated under reduced pressure. A colorless oil was recovered. Yield=2.83 g (92%). TLC (5% ethyl acetate in hexanes) showed clean product, Rf=0.17.
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][C:11]#[N:12].O=[C:14]1[CH2:19][CH2:18][S:17][CH2:16][CH:15]1[C:20](OC)=[O:21].C([O-])(=O)C.[NH4+].O>C(#N)C>[O:21]=[C:20]1[N:3]2[C:2]([NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=32)=[C:10]([C:11]#[N:12])[C:14]2[CH2:19][CH2:18][S:17][CH2:16][C:15]1=2
Reactant: N#CCc1nc2ccccc2[nH]1
Reactant: COC(=O)C1CSCCC1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: N#Cc1c2c(c(=O)n3c1[nH]c1ccccc13)CSCC2
Temperature: 140 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
A mixture of 1H-benzimidazol-2-ylacetonitrile (13 g), methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (15.3 g), and ammonium acetate (33 g) was heated and stirred at 140° C. for 1 hour. The reaction mixture was cooled to room temperature, water and acetonitrile were added, and the resulting precipitate was collected by filtration and dried under reduced pressure to obtain 12-oxo-3,4,6,12-tetrahydro-1H-thiopyrano[4′,3′:4,5]pyrido[1,2-a]benzimidazole-5-carbonitrile (16 g).
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH2:18][CH2:19][C:20]#[C:21][CH2:22][CH3:23].C([CH2:27][C:28]([NH:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=[O:34])=[O:29])(O)=O.Cl>C1(C)C=CC=CC=1>[CH2:18]([O:17][C:10]1[CH:11]=[C:12](/[CH:13]=[CH:27]/[C:28]([NH:30][C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33]([OH:35])=[O:34])=[O:29])[CH:15]=[CH:16][C:9]=1[O:8][CH3:7])[CH2:19][C:20]#[C:21][CH2:22][CH3:23]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: CCC#CCCOc1cc(C=O)ccc1OC
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCC#CCCOc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OC
Yield: 73.7 %

Procedure:
Piperidine (0.21 mL, 2.2 mmol) was added to a suspension of 4-methoxy-3-(hex-3-ynyloxy)benzaldehyde (0.50 g, 2.2 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.44 g, 2.0 mmol) in toluene (5 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recrystallised from EtOH providing (E)-2-[[3-(3-(hex-3-ynyloxy)-4-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.58 g, 75%) as a yellow crystalline solid; mp 163-165° C.; δH (400 MHz, DMSO-d6) 1.05 (t, J=7.6 Hz, 3H, CH3), 2.15 (q, J=7.6 Hz, 2H, CH3CH2), 2.62 (t, J=7.6 Hz, 1H, OCH2CH2C), 3.80 (s, 3H, OCH3), 4.09 (t, J=7.6 Hz, 2H, OCH2), 6.80 (d, J=15.6 Hz, 1H, CH═CHCO), 6.99 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.25 (d, J5′,6′=8.0 Hz, 1H, H6′), 7.40 (s, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.61 (d, J5,6=8.0 Hz, 1H, H6), 11.26 (s, 1H, NH), 13.58 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 11.8, 14.0, 19.3, 55.6, 67.0, 76.2, 83.0, 111.9, 112.0, 116.6, 120.0, 120.3, 122.6, 123.0, 127.3, 131.1, 134.0, 141.0, 141.6, 147.9, 150.8, 164.2, 169.4; HRMS (ESI) calculated for C23H23NO5 [M+H]+ 394.1649. found 394.1648; vmax 755, 1253, 1510, 1604, 1657, 3238, 3524 cm−1.
Reaction SMILES: CSC.B.[C:5]([CH2:8][C:9]1[C:10]([Cl:18])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])(O)=[O:6]>C1COCC1>[Cl:18][C:10]1[C:11]([CH2:12][OH:13])=[CH:15][CH:16]=[CH:17][C:9]=1[CH2:8][CH2:5][OH:6]
Reactant: O=C(O)Cc1cccc(C(=O)O)c1Cl
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCCc1cccc(CO)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of borane dimethyl sulfide complex (2M in THF, 220 mL) was added portionwise over 5 minutes to a suspension of 3-(carboxymethyl)-2-chlorobenzoic acid [Aromatic Intermediate 11, step c] (18.9 g) in dry THF (800 mL) at room temperature. The resulting effervescing suspension was stirred at room temperature for 30 minutes, then heated to reflux for 60 minutes, and allowed to cool to room temperature overnight. The mixture was quenched by the portionwise addition of methanol (100 mL) over 15 minutes and stirred until bubbling ceased. Concentrated aqueous HCl (25 mL) was added, the mixture was stirred for 30 min and concentrated under reduced pressure. The gummy residue was partitioned between ethyl acetate (500 mL) and aqueous HCl (2M, 200 mL). The phases were separated and the aqueous phase extracted with ethyl acetate (2×300 mL). The combined organic phases were washed with brine (300 mL), dried over magnesium sulphate, filtered and evaporated to give the subtitled compound as a yellow oil. Yield 17.8 g.
Reaction SMILES: CC[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH:11]([NH2:13])=O.[CH:14](O)=O>>[CH3:3][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([NH2:13])[CH3:14]
Reactant: NC=O
Reactant: CCC(=O)c1ccccc1
Reactant: O=CO
Product: Cc1ccccc1C(C)N
Temperature: 25 °C

Procedure:
26 ml of 2-methylacetophenone(0.2M), 32 ml of formamide and 7.5 ml of formic acid were mixed and reacted at 160° C. for 5 hours while distilling water off. The resultant was cooled to room temperature and extracted from ethyl ether. The extract was washed with water, concentrated under a reduced pressure, added with 20 ml of concentrated hydrochloric acid and heated under reflux for an hour. The reaction solution was cooled to room temperature, washed with ethyl ether and neutralized with aqueous NaOH solution. After extracting the resultant with ethyl ether, the extract was dried over anhydrous sodium sulfate and concentrated under a reduced pressure, to give 16.9 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:19]([OH:21])=[O:20])[CH:9]=[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[N:3]=1.S(Cl)(Cl)=O.[CH3:26]O>C(OCC)(=O)C>[CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:19]([O:21][CH3:26])=[O:20])[CH:9]=[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[N:3]=1
Reactant: CO
Reactant: Cc1nc2c(OCc3ccccc3)cc(C(=O)O)cc2[nH]1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(OCc2ccccc2)c2nc(C)[nH]c2c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 2-methyl-4-[(phenylmethyl)oxy]-1H-benzimidazole-6-carboxylic acid (10.0 g, 35.4 mmol, STEP 4 in Example 1), and thionyl chloride (5.2 mL, 7.1 mmol) in methanol (300 mL) was stirred at 80° C. for 3 hours. The mixture was diluted with ethyl acetate, and washed with saturated ammonium chloride aqueous solution. The organic layer was dried over magnesium sulfate, and concentrated in vacuum. The residue was diluted with methanol, filtered to remove the precipitate, and the filtrate was concentrated in vacuum. The resulted solid was washed with dichloromethane to give the title compound as a brown solid (29.8 g, crude), which was used in the next step without further purification. MS (ESI) m/z: 297 (M+H)+, 295 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:30]1[CH2:34][C@@H:33]([CH3:35])[C:32](=[O:36])[O:31]1)[CH2:10][C@@H:11]([CH:27]([CH3:29])[CH3:28])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42][CH2:41]1>>[OH:46][CH:43]1[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][NH:37][C:32](=[O:36])[C@H:33]([CH3:35])[CH2:34][C@H:30]([OH:31])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:10][C@@H:11]([CH:27]([CH3:29])[CH3:28])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH:14]=2)[CH2:41][CH2:42]1
Reactant: NCCN1CCC(O)CC1
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C2C[C@@H](C)C(=O)O2)C(C)C)ccc1OC
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCCN2CCC(O)CC2)C(C)C)ccc1OC

Procedure:
102 mg of 2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one (Example 105e) and 0.5 g of N-(2-aminoethyl)-4-hydroxypiperidine are stirred for 2 hours at 80° C. The reaction mixture is purified by means of FC (60 g of silica gel, dichloromethane/methanol=4:1). The title compound is obtained: Rf (dichloromethane/methanol=4:1)=0.16.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25][O:26][CH2:27][CH2:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][N:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:34][C:33]4[CH:32]=[N:31][C:30]([O:29][CH2:28][CH2:27][O:26][CH3:25])=[CH:37][CH:36]=4)[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COCCOc1ccc(C=O)cn1
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCNC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COCCOc1ccc(CN2CCC[C@@H](CN3CCN(C(=O)Nc4ccc(Cl)c(Cl)c4)CC3)C2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27 %

Procedure:
To a suspension of the hydrochloride salt of N-(3,4-dichlorophenyl)-4-[(3R)-piperidin-3-ylmethyl]piperazine-1-carboxamide (442 mg, 1.00 mmol) in dichloromethane (40 ml) was added 6-(2-methoxyethoxy)nicotinaldehyde (199 mg, 1.00 mmol) and the cloudy mixture stirred at room temperature for 10 minutes. Polymer supported sodium triacetoxyborohydride (555 mg, 1.50 mmol) was added and the reaction stirred at room temperature overnight. The mixture was filtered, the filtrate washed with water (20 ml), organic extract dried (Na2SO4), filtered and evaporated to an oil. Flash column chromatography (10 gram Isolute silica column eluting; CH2Cl2 to 10% MeOH/CH2Cl2) yielded N-(3,4-dichlorophenyl)-4-[((3R)-1-{[6-(2-methoxyethoxy)pyridin-3-yl]methyl}piperidin-3-yl)methyl]piperazine-1-carboxamide (145 mg, 27%) as a white foam.