Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:28]=[CH:27][C:11]3[N:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:14][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[C:29]1([C:35]2[C:36]3[C:41]([C:42]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[C:43]4[C:48]=2[CH:47]=[C:46](B(O)O)[CH:45]=[CH:44]4)=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C1(C)C=CC=CC=1>[C:21]1([N:12]2[C:11]3[CH:27]=[CH:28][C:8]([C:5]4[CH:6]=[CH:7][C:2]([C:39]5[CH:38]=[CH:37][C:36]6[C:41](=[C:42]([C:52]7[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=7)[C:43]7[C:48]([C:35]=6[C:29]6[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=6)=[CH:47][CH:46]=[CH:45][CH:44]=7)[CH:40]=5)=[CH:3][CH:4]=4)=[CH:9][C:10]=3[N:14]=[C:13]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Reactant: Clc1ccc(-c2ccc3c(c2)nc(-c2ccccc2)n3-c2ccccc2)cc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: c1ccc(-c2c3ccccc3c(-c3ccccc3)c3cc(-c4ccc(-c5ccc6c(c5)nc(-c5ccccc5)n6-c5ccccc5)cc4)ccc23)cc1
Temperature: 80 °C
Reaction time: 10 h
Yield: 74.1 %

Procedure:
2.3 g (6.0 mmol) of 5-(4-chlorophenyl)-1,2-diphenyl-1H-benzimidazole, 2.5 g (6.6 mmol) of 9,10-diphenylanthracene-2-boronic acid, tris(dibenzylideneacetone)dipalladium (0) (0.14 g, 0.15 mmol), and cesium carbonate (4.7 g, 14 mmol) were suspended into 20 mL of anhydrous dioxane, a solution of tricyclohexylphosphine/toluene (25 mass %, 0.49 ml, 0.43 mmol) was added, and the whole was stirred at 80° C. for 10 hours. The reaction mixture was diluted with 200 mL of toluene and 100 mL of water, and was filtered through Celite 545 for removing Pd black. An organic layer was fractionated from the filtrate, washed with 50 mL of a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate, and the solvent was distilled off, with the result that red oil was obtained. The oil was purified by means of silica gel column chromatography to obtain 3.0 g of a greenish white solid (75% yield). Mass spectral analysis confirmed that the solid was a target product. The solid had an m/e of 674 with respect to a molecular weight of 674.27.
Reaction SMILES: C[Al](C)C.[CH:5]([NH2:8])([CH3:7])[CH3:6].CO[C:11](=[O:32])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:21]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[N:22][O:23][CH:24]=2)=[N:14][CH:13]=1.O>O1CCOCC1>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:21]2[C:20]([CH2:19][O:18][C:15]3[CH:16]=[CH:17][C:12]([C:11]([NH:8][CH:5]([CH3:7])[CH3:6])=[O:32])=[CH:13][N:14]=3)=[CH:24][O:23][N:22]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Reactant: CC(C)N
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Product: CC(C)NC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55.6 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 1.17 mL, 2.3 mmol) was added dropwise (exothermic) to a solution of isopropylamine (2.3 mmol) in dioxane (15 mL) and the resulting mixture was stirred at room temperature for 1.5 h. Then 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.58 mmol) was added. The resulting mixture was then heated at 85° C. for 2 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=2:1 to 1:1) afforded the title compound (120 mg, 56%) which was obtained as a white solid. MS: m/e=372.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25](O)=[O:26])[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.Cl.[CH3:36][NH:37][CH3:38]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]([N:37]([CH3:38])[CH3:36])=[O:26])[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1
Reactant: CNC
Reactant: CC1Cc2ccc(-c3ccnc(C(=O)O)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Product: CC1Cc2ccc(-c3ccnc(C(=O)N(C)C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50B, Step 2 starting from 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid and dimethylamine hydrochloride. LCMS (M+H)+: m/z=487.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([CH2:19]O)=[CH:17][N:18]=3)[N:15]=2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].C([N:23](CC)CC)C.N([Na])=[N+]=[N-].CP(C)C.C1COCC1>C(Cl)Cl.O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([CH2:19][NH2:23])=[CH:17][N:18]=3)[N:15]=2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: OCc1cnc2ccc(-c3cc(F)c(F)c(F)c3)nn12
Reactant: CCN(CC)CC
Agent: CP(C)C
Agent: [N-]=[N+]=N[Na]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NCc1cnc2ccc(-c3cc(F)c(F)c(F)c3)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of (6-(3,4,5-trifluorophenyl)imidazo[1,2-b]pyridazin-3-yl)methanol (0.442 g, 1.6 mmol) in CH2Cl2 (5 mL) was added Mesyl-Cl (0.37 ml, 4.7 mmol) and triethylamine (0.66 ml, 4.7 mmol)-slight exotherm, place flask in water bath- and the mixture stirred at rt 1 h. The mixture was concentrated in vacuo (without heating the flask) and the residue dissolved in DMF (2 mL) and azidosodium (0.23 g, 3.5 mmol) was added in one portion. After 45 minutes, additional azidosodium (0.40 g, 6.0 mmol) was added and the mixture stirred 1 h longer. The mixture was diluted with EtOAc, washed with water, brine, (back extract aq layer) and dry organic layer over Na2SO4, filter and evaporate. The azide intermediate was dissolved in THF (4 mL) and trimethylphosphine 1M in THF (2.4 ml, 2.4 mmol) was added. The reaction mixture was stir at rt until the bubbling stops, plus an additional 2 minutes, then water (1 mL) was added. The mixture was diluted with EtOAc, washed with NaHCO3 solution, sat. NaHCO3, (back extract aq layer), then dry organic layer over Na2SO4, filter and evaporate. The residue was purified via flash chromatography using al % NH4OH in MeOH in CH2Cl2 gradient to afford the title compound as a tan solid.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.I(O)(=O)(=O)=[O:15].S(OS([O-])=O)([O-])=O.[Na+].[Na+]>C(#N)C.C(Cl)Cl.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[CH:1]1([S:4]([C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)=[O:15])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(SC2CC2)cc1
Reactant: [O-][I+3]([O-])([O-])O
Agent: Cl[Fe](Cl)Cl
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(S(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.3 %

Procedure:
350 mg of 1-(cyclopropylsulfanyl)-4-nitrobenzene is dissolved in 5 ml of acetonitrile and mixed with 10 mg of iron(III)-chloride hexahydrate. After 10 minutes of stirring at room temperature, 450 mg of periodic acid is added thereto while being cooled. The mixture is stirred for 30 minutes at room temperature, cooled in an ice bath and mixed drop by drop with semi-saturated sodium disulfite solution. It is diluted with methylene chloride, washed with water, sodium bicarbonate solution and saturated sodium chloride solution, and concentrated by evaporation. After purification by flash chromatography, 270 mg of (RS)-1-(cyclopropylsulfinyl)-4-nitrobenzene is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]=[N:13][S:14][CH:15]=2)=[O:10])=[CH:4][CH:3]=1.[N:16]([C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1)=[C:17]=[S:18]>C(#N)C>[F:26][C:25]([F:27])([F:28])[C:23]1[CH:24]=[C:19]([NH:16][C:17](=[S:18])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]3[N:12]=[N:13][S:14][CH:15]=3)=[O:10])=[CH:6][CH:7]=2)[CH:20]=[C:21]([C:29]([F:31])([F:32])[F:30])[CH:22]=1
Reactant: FC(F)(F)c1cc(N=C=S)cc(C(F)(F)F)c1
Reactant: Nc1ccc(NC(=O)c2csnn2)cc1
Solvent: CC#N
Product: O=C(Nc1ccc(NC(=S)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1)c1csnn1
Temperature: 25 °C

Procedure:
To a solution of [1,2,3]-thiadiazole-4-carboxylic acid (4-amino-phenyl) amide (2.0 g) in acetonitrile (50 mL) is added 1-isothiocyanato-3,5-bis-trifluoromethyl-benzene (2.5 g) in acetonitrile (50 mL) dropwise but rapidly and the reaction is stirred at room temperature. After ninety minutes, the solvent is removed under reduced pressure and the resulting brown solid is recrystallized from ethyl acetate/hexanes to give the pure product. [M+H]492.
Reaction SMILES: [F-].[K+].Br[C:4]1[N:21]([CH2:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]2)[C:7]2[C:8]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=3)=[N:9][C:10]([C:12]#[N:13])=[CH:11][C:6]=2[N:5]=1.[NH:30]1[C:35](=[O:36])[CH2:34][NH:33][C@H:32]2[CH2:37][CH2:38][CH2:39][C@H:31]12.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CS(C)=O>[Cl:20][C:18]1[CH:19]=[C:14]([C:8]2[C:7]3[N:21]([CH2:22][C@H:23]4[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]4)[C:4]([N:33]4[CH2:34][C:35](=[O:36])[NH:30][C@H:31]5[CH2:39][CH2:38][CH2:37][C@H:32]45)=[N:5][C:6]=3[CH:11]=[C:10]([C:12]#[N:13])[N:9]=2)[CH:15]=[N:16][CH:17]=1
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: O=C1CN[C@H]2CCC[C@@H]2N1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CC[C@H](Cn2c(N3CC(=O)N[C@H]4CCC[C@@H]43)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 100 °C

Procedure:
A vial was charged with potassium fluoride (163 mg, 2.81 mmol), 2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1, 250 mg, 0.562 mmol), (4aS,7aS)-octahydro-2H-cyclopenta[b]pyrazin-2-one (189 mg, 1.349 mmol), DMSO (1730 μl) and DIEA (491 μl, 2.81 mmol). The vial was capped and heated to 100° C. overnight. The mixture was then cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (0-20% MeOH in DCM) afforded 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(4aS,7aS)-3-oxooctahydro-1H-cyclopenta[b]pyrazin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C27H30ClN7O [M+H]+ 504. found 504.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][N:10]=[CH:9]2)=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].[Br:17]Br.C([O-])(=O)C.[Na+]>>[NH2:1][C:2]1[C:3]([C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([N:8]2[CH:9]=[N:10][N:11]=[CH:12]2)=[CH:6][C:7]=1[Br:17]
Reactant: BrBr
Reactant: Nc1ccc(-n2cnnc2)cc1C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Nc1c(Br)cc(-n2cnnc2)cc1C(F)(F)F

Procedure:
The following compound, m.p. 202°-3°, was prepared similarly to the previous Preparation using 4-(4-amino-3-trifluoromethylphenyl)-1,2,4-triazole, bromine, and sodium acetate (in place of hydrogen bromide and acetic acid) as the starting materials: ##STR146##
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][CH:13]([CH2:23][O:24]CC2C=CC=CC=2)[CH2:14][O:15]CC2C=CC=CC=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(O)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][CH:13]([CH2:23][OH:24])[CH2:14][OH:15])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@H](OC(COCc2ccccc2)COCc2ccccc2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)[C@H]1CC[C@H](OC(CO)CO)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an argon purged solution of cis/trans-4-(2-benzyloxy-1-benzyloxymethyl-ethoxy)-cyclohexanecarboxylic acid ethyl ester (2.30 g, 5.39 mmol) in acetic acid (54 ml) was added palladium on charcoal 10% (0.57 g). The reaction mixture was purged with hydrogen gas and stirred at room temperature for 3 h under an atmosphere of hydrogen gas. The catalyst was removed by filtration over Decalite. The filtrate was concentrated in vacuo. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.74 g, 56%) as colorless oil. MS m/e: 247 (M+H+)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH2:20][CH2:21][NH2:22])[CH:16]=[CH:17][C:18]=1[Cl:19].[BH4-].[Na+].[OH-].[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][NH:22][CH2:21][CH2:20][C:15]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([Cl:12])[CH:14]=1
Reactant: O=Cc1cc2ccccc2o1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Clc1ccc(CCNCc2cc3ccccc3o2)cc1Cl
Temperature: 25 °C

Procedure:
A solution of 150 mg (1.03 mmol) of benzofuran-2-carbaldehyde and 195 mg (1.03 mmol) of 2-(3,4-dichloro-phenyl)-ethylamine in methanol (4 ml) was heated to reflux for 3 h. Then the reaction mixture was allowed to cool to RT and 58 mg (1.54 mmol) of sodium borohydride were added. The mixture was heated to reflux over night. After cooling to RT, 0.1 N sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography (silica gel; dichloromethane and dichloromethane/methanol 95:5). The title compound was isolated as yellow oil (249 mg, 76%). MS (ISP) 320.2 (M+H)+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Br:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[C:8]([F:14])[CH:7]=1>ClC1C=CC=CC=1>[Br:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:11]=[C:1]=[O:2])=[C:8]([F:14])[CH:7]=1
Reactant: NCc1ccc(Br)cc1F
Reactant: O=C(Cl)Cl
Solvent: Clc1ccccc1
Product: O=C=NCc1ccc(Br)cc1F
Reaction time: 2 h
Yield: 69.1 %

Procedure:
Chlorobenzene (30 ml) is introduced into the reaction vessel at 60° C. and saturated with phosgene. A solution of 4-bromo-2-fluorobenzylamine (20.4 g, 0.10 mol) in chlorobenzene (40 ml) is added dropwise at 60° C. over 3 hours. At the same time, phosgene is passed in. Stirring of the batch is continued for 2 hours at 60° C., and the mixture is subsequently refluxed to remove the gases phosgene and hydrogen chloride. The batch is worked up by distillation. 15.9 g of 4-bromo-2-fluorobenzyl isocyanate (boiling point 109° C. at 4 mbar) are obtained. Yield: 69.1% of theory.
Reaction SMILES: [Mg].[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.[CH3:11][N:12]([CH3:25])[C:13]1(C#N)[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1.[Cl-].[NH4+]>C(OCC)C>[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][C:13]1([N:12]([CH3:25])[CH3:11])[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Reactant: Fc1ccccc1CCl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C1(Cc2ccccc2F)CCC2(CC1)OCCO2
Reaction time: 1 h

Procedure:
1.16 g magnesium were stirred into 20 ml analytical grade diethyl ether under a nitrogen atmosphere and approximately one third of the solution of 6.19 g 2-fluorobenzyl chloride in 25 ml analytical grade diethyl ether was added. The remainder of the solution was rapidly added dropwise after the Grignard formation had started, and when the addition had ended the mixture was subsequently stirred for one hour, a solution of 5.00 g 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile in 25 ml analytical grade diethyl ether was then added dropwise and the reaction mixture was stirred overnight. For working up, 36 ml ammonium chloride solution (20 per cent by weight) were added, while cooling with ice, the phases were separated, the aqueous phase was extracted twice with 50 ml diethyl ether each time and the combined organic phases were washed successively with 20 ml water and 20 ml saturated sodium chloride solution. The crude [8-(2-fluorobenzyl)-1,4-dioxaspiro[4.5]dec-8-yl]dimethylamine obtained (7.34 g) was stirred, without further purification, with a mixture of 18 ml conc. hydrochloric acid (32 per cent by weight) and 10 ml water for 24 hours at room temperature. The reaction mixture was then first washed three times with 50 ml diethyl ether each time and then adjusted to pH 9 by addition of aqueous ammonia (25 per cent by weight), while cooling with ice, and extracted three times with 50 ml methylene chloride each time, the combined methylene chloride extracts were dried over sodium sulfate, filtered and concentrated and the residue was largely freed from solvent residues in vacuo. 5.80 g 4-dimethylamino-4-(2-fluorobenzyl)cyclohexanone were obtained as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3]/[CH:4]=[C:5](/[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)\[C:6]1[NH:7][CH:8]=[C:9](CC2C=CC=CC=2)[N:10]=1.N.[Na].[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH3:26][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[C:6]1[NH:10][CH:9]=[CH:8][N:7]=1
Reactant: COc1ccc(/C(=C/CN(C)C)c2nc(Cc3ccccc3)c[nH]2)cc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: COc1ccc(C(CCN(C)C)c2ncc[nH]2)cc1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
A solution of (E) and (Z)-N,N-dimethyl-3-(4-methoxyphenyl)-3-[(1-phenylmethyl)imidazol-2-yl]-2-propen-1-amine (1.0 g) in dry toluene (20 ml) was added to liquid ammonia (20 ml) with stirring at -78°. Sodium was added until the mixture was deep blue (ca. 0.23 g required). After stirring at -78° for 2 h. ammonium chloride (1 g) was added, the mixture allowed to warm to room temperature and the residue partitioned between 2 N sodium carbonate (50 ml) and ethyl acetate (3×50 ml). The organic solution was dried (Na2SO4) and concentrated to give the title compound as a white solid (0.67 g) which crystallised from ether with m.p. 131°-133°, ωmax (CHBr3) 3440 (NH), 2770, 2820 (Me2NCH2 --).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[CH2:17]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1(c2ccncc2)CCCC1
Reactant: BrCc1ccccc1
Solvent: CC#N
Product: CCOC(=O)C1(C2CCN(Cc3ccccc3)CC2)CCCC1

Procedure:
Ethyl 1-pyridin-4-ylcyclopentanecarboxylate and benzyl bromide were reacted in acetonitrile under heating. The residue obtained by subjecting the reaction solution to evaporation under reduced pressure, triethylamine and platinum oxide were reacted in ethanol under a hydrogen atmosphere to obtain ethyl 1-(1-benzylpiperidin-4-yl)cyclopentanecarboxylate.
Reaction SMILES: C(O)=O.[CH3:4][O:5][C:6]1[CH:53]=[CH:52][CH:51]=[CH:50][C:7]=1[CH2:8][O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]2[O:33][CH2:34][C:35]2[O:36][C:37]3[C:43]([O:44][CH2:45][CH2:46][CH2:47][O:48][CH3:49])=[CH:42][CH:41]=[CH:40][C:38]=3[CH:39]=2)=[CH:16][CH:15]=1.C(N(CC)CC)C>CC(C)=O.[Pd]>[CH3:4][O:5][C:6]1[CH:53]=[CH:52][CH:51]=[CH:50][C:7]=1[CH2:8][O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]2[O:33][CH2:34][CH:35]2[CH2:39][C:38]3[CH:40]=[CH:41][CH:42]=[C:43]([O:44][CH2:45][CH2:46][CH2:47][O:48][CH3:49])[C:37]=3[O:36]2)=[CH:16][CH:15]=1
Reactant: COCCCOc1cccc2cc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)oc12
Agent: [Pd]
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COCCCOc1cccc2c1OC(COC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc3ccccc3OC)cc1)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.035 ml of formic acid are added to the suspension of 0.20 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[7-(3-methoxypropoxy)benzofuran-2-ylmethoxy]piperidine-1-carboxylate (Example 7a) and 0.20 g of 10% Pd/C in 3 ml of acetone. After 15 minutes, 0.16 ml of triethylamine is added in portions. The reaction mixture is stirred at room temperature over 20 hours and clarified by filtration, and the filtrate is concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.34 (1:2 EtOAc-heptane); Rt=6.24.
Reaction SMILES: [C:1]([NH:7][NH2:8])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[O:9]=[C:10]=[N:11][C@H:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]([CH3:15])[CH3:14]>O1CCOCC1>[C:1]([NH:7][NH:8][C:10]([NH:11][C@H:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]([CH3:14])[CH3:15])=[O:9])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: COC(=O)[C@@H](N=C=O)C(C)C
Reactant: C=CCCC(=O)NN
Solvent: C1COCCO1
Product: C=CCCC(=O)NNC(=O)N[C@H](C(=O)OC)C(C)C
Reaction time: 3 h

Procedure:
To a 1.6 M solution of pent-4-enohydrazide (from Step 2) in dioxane, 1 eq. of methyl N-(oxomethylene)-L-valinate, (prepared as described in J. Het. Chem. 1990, 739) was added. After sting at RT for 3 h, volatiles were removed in vacuo, to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 9.55 (d, J 2.1, 1H), 7.86 (d, J 2.2, 1H), 6.48 (d, J 8.1, 1H), 5.86-5.76 (m, 1H), 5.04 (dd, J 17.2, 1.5, 1H), 4.96 (d, J 18.2, 10.3, 1H), 4.09 (dd, J 8.7, 5.7, 1H), 3.64 (s, 3H), 2.32-2.24 (m, 2H), 2.22-2.15 (m, 2H), 2.08-1.90 (m, 1H), 0.94 (d, J 3.9, 3H), 0.92 (d, J 3.9, 3H). MS (ES+) C12H21N3O4 requires: 271 found: 272 (M+H+).
Reaction SMILES: P(Br)(Br)[Br:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[C:8]([Cl:14])[CH:7]=1.[OH-].[Na+]>ClC(Cl)C>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][Br:2])=[C:8]([Cl:14])[CH:7]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(Br)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: Clc1cc(Br)ccc1CBr
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
Phosphorus tribromide (40.5 mL, 0.431 mol) was added dropwise to a solution of (4-bromo-2-chlorophenyl)-methanol (15, 86.1 g, 0.386 mol) in dichloroethane (430 mL) at 0° C. The reaction mixture was stirred for 10 minutes at this temperature then for 0.5 h at 10° C. The mixture was cooled to 0° C. and a sodium hydroxide solution (600 mL, 2N) was added dropwise. The two layers were separated and the aqueous layer was extracted with dichloroethane (200 mL). The combined organic layers were washed with water (200 mL), dried over sodium sulfate and evaporated in vacuo. The crude product (91 g) was distilled under reduced pressure (7 mmHg), to give 4-bromo-1-bromomethyl-2-chlorobenzene (62.5 g, 0.22 mol, 57%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:18]([O-])=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Pt]>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH2:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cc([N+](=O)[O-])ccc2C1
Agent: [Pt]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Yield: 58.3 %

Procedure:
The 6-nitro-3,4-dihydro-1H-isoquinoline2-carboxylic acid tert-butyl ester (82 mg, 0.29 mmol) in THF (2 mL) was hydrogenated with 5% Pt-C (50% water wet, 10 mg) at 50 psi for 5 hrs. The catalyst was filtered off, the solvent was removed under vacuum and the residue chromatographed on silica with ethyl acetate/hexanes to give 42 mg (57%) of the title product.