Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)CCl.C(N(CC)CC)C.[C:31]12([CH2:41]O)[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]3)[CH2:32]1)[CH2:38]2>ClCCl.CN(C1C=CN=CC=1)C>[C:4]([O:3][C:1]([NH:8][C@H:9]([C:17]([O:19][CH2:41][C:31]12[CH2:40][CH:35]3[CH2:34][CH:33]([CH2:39][CH:37]([CH2:36]3)[CH2:38]1)[CH2:32]2)=[O:18])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:2])([CH3:5])([CH3:7])[CH3:6]
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)OCC12CC3CC(CC(C3)C1)C2
Reaction time: 8 h

Procedure:
To a solution of 500 mg (1.89 mmol) of N-Boc-L-phenylalanine in 25 ml of dichloromethane were added, at RT, 1192 mg (6.2 mmol) of EDC, 578 μl (4.1 mmol) of triethylamine, 345 mg (2.8 mmol) of DMAP and 345 mg (2.1 mmol) of 1-adamantylmethanol. The reaction mixture was stirred overnight, then diluted with 50 ml of dichloromethane, and was successively washed with 10% aqueous citric acid solution, water and saturated sodium chloride solution. The organic phase was dried over magnesium sulphate, then concentrated, and the residue was purified by preparative HPLC. 769 mg (90% of theory) of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[S:12]([N:15]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH:5]=[N:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([N:18]1[CH2:19][CH2:20][CH2:21][N:15]([S:12]([C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11]=2[C:2]([CH3:1])=[CH:3][N:4]=[CH:5]3)(=[O:14])=[O:13])[CH2:16][CH2:17]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cncc2cccc(S(=O)(=O)N3CCCNCC3)c12
Solvent: c1ccncc1
Product: CC(=O)N1CCCN(S(=O)(=O)c2cccc3cncc(C)c23)CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
To 30 ml of a suspension prepared by suspending 2.25 g of hexahydro-1-[(4-methyl-5-isoquinolinyl)sulfonyl]-1H-1,4-diazepine in pyridine was added 2.0 g of acetic anhydride, and the mixture was stirred at 60° C. for 30 minutes. This reaction mixture was concentrated, made basic with sodium hydrogencarbonate/H2O, and extracted with chloroform. The extract was dried and concentrated to provide 1.91 g of 1-acetyl-hexahydro-4-[(4-methyl-5-isoquinolinyl)sulfonyl]-1H-1,4-diazepine as oil.
Reaction SMILES: O[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[CH2:3][C:4](=[O:8])[CH:5]([CH3:7])[CH3:6].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:6][CH:5]([CH3:7])[C:4](=[O:8])[CH:3]=[CH:2][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: CC(C)C(=O)CC(O)c1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)C(=O)C=Cc1cccc([N+](=O)[O-])c1
Yield: 97.1 %

Procedure:
A mixture of 1-hydroxy-4-methyl-1-(3-nitrophenyl)pentan--3-one (3.32 g), p-toluenesulfonic acid monohydrate (0.03 g) and toluene (50 mL) was refluxed for 1 hour under Dean-Stark conditions. The mixture was diluted with ethyl acetate, washed (sat. sodium bicarbonate, water and brine) and the solvent removed. Chromatography (hexane/ethyl acetate, 3:1) yielded 4-methyl-1-(3-nitrophenyl)-1-penten-3-one (2.98 g) as a yellow solid. NMR: 1.11 (d,6, J=6.8, CH3), 3.02 (m,1, CH), 7.27 (d,1, J=16.2, CH), 7.73 (m,2, CH,Ar), 8.24 (m,2, Ar), 8.61 (m,1, Ar), MS: m/z=219(M).
Reaction SMILES: [CH2:1]([CH:4]([CH2:10][C:11](OCC)=[O:12])[C:5](OCC)=[O:6])[CH2:2][CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[Al]>C(OCC)C>[OH:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:10][CH2:11][OH:12]
Reactant: CCCC(CC(=O)OCC)C(=O)OCC
Agent: [Al+3]
Agent: [Al]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CCCC(CO)CCO
Yield: 66.8 %

Procedure:
A solution of diethyl 2-prop-1-ylsuccinate (23.47 g) in diethyl ether (100 ml) was added dropwise to a cooled and stirred suspension of lithium aluminium hydride (6.19 g) in dry diethyl ether (500 ml) under an atmosphere of nitrogen. When the addition was complete, the reaction mixture was stirred at room temperature for 1.5 hours, then enough water to hydrolyse both the excess reducing agent and the intermediate aluminium complexes was added. The resulting solids were filtered off and the filtrate was dried over magnesium sulphate and concentrated to give 3-hydroxymethylhexan-1-ol (9.58 g, 67%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([NH2:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:14][O:15][C:16](OC)([O:21]C)[C:17](OC)=O>>[C:16]([C:17]1[O:13][C:9]2[C:8]3[N:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:2]([Cl:1])=[CH:11][C:10]=2[N:12]=1)([O:15][CH3:14])=[O:21]
Reactant: Nc1cc(Cl)c2cccnc2c1O
Reactant: COC(=O)C(OC)(OC)OC
Product: COC(=O)c1nc2cc(Cl)c3cccnc3c2o1
Temperature: 100 °C
Yield: 0.1 %

Procedure:
A mixture of 5-chloro-7-amino-8-hydroxyquinoline (6 g, 30.8 mol) and methyl trimethoxyacetate (16.3 g, 123.2 mol) was heated at 100° C. overnight. The reaction was cooled in an ice bath and filtered. The precipitate was dissolved in acetone (250 ml). The resulting solution was treated with charcoal at reflux, filtered through a pad of silica gel and celite and partially concentrated. Crystals formed which were filtered and dried giving 4.1 g (51% yield) of solid. M.P. 217°-218° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[OH-].[Na+].[CH2:12](Br)[C:13]#[CH:14].C1(C)C(C)=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6])[C:13]#[CH:12]
Reactant: C#CCBr
Reactant: OCc1cccc(O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Solvent: C1CCOC1
Product: C#CCOc1cccc(CO)c1

Procedure:
To a solution of 3-hydroxybenzylalcohol (2.4 g, 20 mmol) in THF (50 mL) and water (2.5 mL) was first added powdered sodium hydroxide (1.5 g, 37.5 mmol) and then a solution of propargyl bromide, dissolved as an 80% weight solution in xylene (3.36 mL, 30 mmol). The reaction mixture was heated at reflux for 6 h. To the mixture was added 10% citric acid (2.5 mL) and the solvent was removed under vacuum. The residue was extracted with ethyl acetate (3×15 mL) and the combined organic layers were washed with saturated NaCl solution (10 mL), dried over MgSO4 and concentrated to give the 3-propargyloxybenzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].C(OC([NH:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][NH:31][CH2:30]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:28][C@H:29]1[C@@H:33]([CH3:34])[CH2:32][N:31]([C:3]2[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]3[CH:12]3[CH2:14][CH2:13]3)=[CH:5][C:4]=2[F:19])[CH2:30]1
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)C[C@H]1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.2 %

Procedure:
A mixture of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (1.8 g), anhydrous acetonitrile (18 ml), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (reference example 3; 1.81 g) and DBU (0.90 g) was refluxed for an hour. The resulting mixture was concentrated under reduced pressure, the resulting residue was dissolved in chloroform and washed with 10% aqueous citric acid solution. The chloroform layer was further washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in hot methanol (25 ml) and, after cooling, the resulting precipitate was collected by filtration. Then this precipitate was suspended in methanol (18 ml), to this solution was added concentrated hydrochloric acid (18 ml) dropwise and stirred at room temperature for 15 minutes. The reacting mixture was neutralized with concentrated aqueous ammonia, after cooling, the resulting precipitate was collected by filtration and washed with water, methanol and ether successively to give the title compound (1.67 g) as white powder, mp 240°-243° C. (decompd.).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH2:36]O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(Br)(Br)(Br)[Br:39]>ClCCl>[Br:39][CH2:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][CH2:27][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCCCOCCOCCCCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCOCCOCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
Triphenylphosphine (6.55 g) in dichloromethane (30 ml) was added dropwise to 3-[2-(4-phenylbutoxy)ethoxy]-1-propanol (5.0 g) and carbon tetrabromide (8.3 g) in dichloromethane (30 ml) at 0°. The mixture was stirred at room temperature for 1 h, evaporated onto silica, and purified by FCC eluting with cyclohexane - followed by System B (1:9) to give the title compound (5.4 g) as an oil. T.l.c. (System B 1:9) Rf 0.35
Reaction SMILES: [CH:1](Br)=[CH2:2].[Mg].[Cl:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:8][CH:7]=1.[Cl-].[NH4+]>O1CCCC1.O>[Cl:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)([OH:11])[CH:1]=[CH2:2])=[CH:8][CH:7]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cccnc1
Reactant: C=CBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(O)(c1ccc(Cl)cc1)c1cccnc1
Yield: 88.8 %

Procedure:
A solution of vinylbromide (38.4 g, 359 mmol) in 100 ml tetrahydrofuran was added to a mixture of magnesium (9.15 g, 377 mmol) in 40 ml tetrahydrofuran under a nitrogen atmosphere at 50° to 60° C. After reflux for 1 h 3-(4-chlorobenzoyl)pyridine (62.4 g, 287 mmol) in 250 ml tetrahydrofuran was added at 10° C. After stirring for 1 h a solution of 20 g ammonium chloride in 100 ml water was added and the mixture filtered. The organic phase was evaporated and the residue taken up in ether and treated with charcoal. After filtration the solvent was evaporated to give 62.6 g (89%) of a brownish oil which solidified. Recrystallisation from toluene gave a product having m.p. 82.5°-84° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[Cu][C:20]#[N:21].O.C(OCC)(=O)C>CN(C=O)C.C1(C)C=CC=CC=1>[C:20]([C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])#[N:21]
Reactant: N#C[Cu]
Reactant: O=C(c1ccccc1)c1ccc([N+](=O)[O-])c(Cl)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 67.5 °C
Reaction time: 0.08 h
Yield: 57.5 %

Procedure:
A stirred mixture of 3-chloro-4-nitrobenzophenone (5.00 g), (J. Org. Chem., 1962, 27, 1605-1608), and copper(I)cyanide (2.57 g) in DMF (50 ml) was heated at reflux for 16 hours. The hot reaction mixture was then poured into a stirred solution of ferric chloride (15.30 g) concentrated hydrochloric acid (5 ml) and water (200 ml). The mixture was heated at 65-70° C. for 30 minutes, cooled to ambient temperature treated with ethyl acetate (250 ml) and stirred vigorously for 5 minutes. The organic phase was separated and the aqueous layer extracted with another 250 ml portion of ethyl acetate. The combined organics were dried, filtered and evaporated to give a brown oil. Chromatography (eluent toluene) gave the title compound (2.77 g) as a yellow solid. M.p. 117-119° C.; EA C14H8N2O3 requires C, 66.67; H, 3.02; N, 11.11%; found: C, 66.83; H, 2.99; N, 11.12%.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH:13]3[NH:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:10][C:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH3:32][O+](C)C>>[C:1]1([N:7]2[C:11]([CH2:12][CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:32])=[N:19]3)=[CH:10][C:9]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[O+](C)C
Reactant: O=C1CCCCC(Cc2cc(-c3ccccc3)nn2-c2ccccc2)N1
Agent: F[B-](F)(F)F
Product: COC1=NC(Cc2cc(-c3ccccc3)nn2-c2ccccc2)CCCC1

Procedure:
The title product of Example 146 is reacted with trimethyloxonium tetrafluoroborate by the method of Example 3 to generate the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C([O-])([O-])=O.[K+].[K+].[C:15](Cl)(=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.CC(C)=O>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:15](=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1Br
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(C=Cc1ccccc1)Nc1ccccc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
To a mixture of 2-bromoaniline (0.976 g, 5.81 mmol, Sigma-Aldrich) and K2CO3 (1.16 g, 8.71 mmol) in water (5.5 mL) and acetone (4.5 mL) was added cinnamoyl chloride (1 g, 5.81 mmol, Sigma-Aldrich) and the reaction was stirred for 2 h at 0° C. The mixture was treated with ice cold water (25 mL) to obtain a brownish precipitate. The precipitate was filtered and dried under vacuum. The crude material was further treated with petroleum ether to give N-(2-bromophenyl)cinnamamide (1.1 g, 64%) as off-white solid. MS (ESI, pos. ion) m/z: 303.2 (M+1).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:24]([CH3:25])[C:13]2=[N:14][CH:15]=[C:16]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:17]=[C:12]2[N:11]=1)[CH3:2].CO.[BH4-].[Na+].[OH-].[Na+]>C1COCC1>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:24]([CH3:25])[C:13]2=[N:14][CH:15]=[C:16]([CH:18]([OH:23])[C:19]([F:22])([F:21])[F:20])[CH:17]=[C:12]2[N:11]=1)[CH3:2]
Reactant: CCSc1ccccc1-c1nc2cc(C(=O)C(F)(F)F)cnc2n1C
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCSc1ccccc1-c1nc2cc(C(O)C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of the crude 1-[2-(2-ethylsulfanyl-phenyl)-3-methyl-3H-imidazo[4,5-b]pyridin-6-yl]-2,2,2-trifluoro-ethanone from Production Example 110-a (773 mg), methanol (5 ml), and THF (20 ml), sodium borohydride (109 mg) was added under ice-cooling. The mixture was stirred at room temperature for 12 hours, and then 1M aqueous sodium hydroxide solution was poured, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 170 mg of 1-[2-(2-ethylsulfanyl-phenyl)-3-methyl-3H-imidazo[4,5-b]pyridin-6-yl]-2,2,2-trifluoro-ethanol (hereinafter referred to as Present Compound 265).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[NH2+]C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:34][N:35]1[CH2:38][CH:37]([CH2:39][NH2:40])[CH2:36]1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10](=[O:12])[NH:40][CH2:39][CH:37]1[CH2:38][N:35]([CH2:34][C:33]2[CH:41]=[CH:42][C:43]([Cl:44])=[C:31]([Cl:30])[CH:32]=2)[CH2:36]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)C1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C[NH2+]C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)NCC1CN(Cc2ccc(Cl)c(Cl)c2)C1
Reaction time: 0.08 h

Procedure:
A solution of tert-Butoxycarbonylamino-acetic acid (1.88 g, 10.7 mmol) in dichloromethane (15 ml) is treated with triethylamine (1.5 ml, 10.7 mmol) and [Dimethylamino-[1,2,3]-triazolo-[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluoro phosphate (4.06 g, 10.7 mmol) and stirred for 5 minutes. To the reaction mixture is added a solution of C-[1-(3,4-Dichloro-benzyl)-azetidin-3-yl]-methylamine (2.64 g, 10.7 mmol) in dichloromethane (15 ml) with stirring for a further 3 hours. The reaction mixture is partitioned between dichloromethane and saturated sodium bicarbonate solution, the organic phase is washed with brine, dried over magnesium sulphate and evaporated. The crude product is purified by chromatography over flash silica eluting with 7% methanol in dichloromethane to afford the title compound.
Reaction SMILES: [CH:1]1([CH2:9][OH:10])[CH:5]2[CH2:6][CH2:7][CH2:8][CH:4]2[CH2:3][NH:2]1.CCN(C(C)C)C(C)C.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33]([N:2]2[CH2:3][CH:4]3[CH2:8][CH2:7][CH2:6][CH:5]3[CH:1]2[CH2:9][OH:10])=[O:34])=[CH:25][CH:26]=1
Reactant: OCC1NCC2CCCC21
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)N2CC3CCCC3C2CO)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of the carbamate above in CH2Cl2 was added TFA (1:1 v/v). The reaction was stirred at rt for 30 min before being concentrated in vacuo. The crude residue was taken up in EtOAc, and washed with sat aqueous NaHCO3, brine, dried (MgSO4), and concentrated to afford (octahydrocyclopenta[c]pyrrol-1-yl)methanol as a pale yellow oil. To a solution of (octahydrocyclopenta[c]pyrrol-1-yl)methanol (1 eq) in DMF was added DIPEA (2 eq) followed by 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid (1.5 eq) and HATU (2 eq). The reaction was allowed to stir at rt for 15 h, and was then concentrated in vacuo to remove the DMF. The crude residue was taken up in EtOAc and washed with 1M HCl, sat aq. NaHCO3, brine, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hex) to give the title compound as a clear oil. MS (ESI) 361.1 (M+H)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](O)=O)[CH2:10][CH2:9]1)=O)(C)(C)C.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[NH2:38])[C:33]#[N:34]>CN(C=O)C.N1C=CC=CC=1>[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[NH:38][C:37]3[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=3[N:29]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: N#Cc1ccc(N)c(N)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N#Cc1ccc2[nH]c(C3CCNCC3)nc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 57.1 %

Procedure:
To a mixture of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (15 g, 69.7 mmol) in DMF (50 mL) and pyridine (50 mL) was added CDI (11.3 g, 69.7 mmol) at 45° C. and the mixture was stirred for another 2 h at this temperature. Then 3,4-diamino-benzonitrile (9.27 g, 69.7 mmol) was added and the mixture was stirred at RT overnight. Solvents were removed in vacuo and the residue was dissolved in HOAc (20 mL) and heated for 1 h at 100° C. Then the reaction mixture was concentrated and the residue was partitioned between DCM and aqueous of Na2CO3. The organic layer was dried over Na2SO4 and concentrated to give the crude product which was purified by column chromatography (ethyl acetate:petroleum ether=1:2) to give the compound 2-piperidin-4-yl-1H-benzoimidazole-5-carbonitrile (9 g, 70%) as pale solid.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[CH:30]=2)[CH:10]=1.[CH3:44][O:45][CH2:46][CH2:47][NH:48][C:49](=[O:54])[CH2:50][CH2:51][NH:52][CH3:53].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:44][O:45][CH2:46][CH2:47][NH:48][C:49](=[O:54])[CH2:50][CH2:51][N:52]([CH2:35][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=1)[C:28]([NH:27][C:16]1[CH:17]=[CH:18][C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:20][C:15]=1[C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][N:12]=1)[C:8]([NH:7][CH2:6][C:5]1[CH:39]=[CH:40][CH:41]=[C:3]([C:2]([F:43])([F:42])[F:1])[CH:4]=1)=[O:38])=[O:37])[CH3:53]
Reactant: CNCCC(=O)NCCOC
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CBr)c2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCNC(=O)CCN(C)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 28.1 %

Procedure:
Into a 8-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(3-(bromomethyl)benzamido)-5-(piperidin-1-yl)phenyl)-isonicotinamide 42a (250 mg, 0.31 mmol, 1.00 equiv, 80%) in N,N-dimethylformamide (6 mL), N-(2-methoxyethyl)-3-(methylamino)propanamide (185 mg, 1.04 mmol, 3.00 equiv, 90%), potassium carbonate (106 mg, 0.77 mmol, 2.00 equiv), and potassium iodide (32 mg, 0.19 mmol, 0.50 equiv). The resulting solution was stirred for 5 h at 60° C. The resulting solution was diluted with 100 mL of ethyl acetate. The resulting mixture was washed with 1×20 mL of 10% sodium bicarbonate. The resulting mixture was washed with 1×20 mL of brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with water:methanol (0.05% TFA) (10:90). The product was obtained as 63.7 mg (23%) of a yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.87 (d, J=6 Hz, 1H), 8.29 (m, 2H), 8.06 (m, 2H), 7.70 (m, 8H), 7.31 (d, J=9 Hz, 1H), 4.70 (s, 2H), 4.50 (m, 2H), 3.43 (m, 2H), 3.39 (m, 6H), 2.89 (s, 3H), 2.76 (m, 2H), 1.86 (m, 4H), 1.73 (m, 2H). MS (ES, m/z): 731 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6](=N)[C:7](Cl)(Cl)Cl)[CH2:2][CH2:3][CH3:4].[CH3:12][C:13](=CCC/C(=C/CO)/C)C.B(F)(F)F.C([O-])(O)=O.[Na+]>C1CCCCC1>[CH2:1]([O:5][CH2:6][CH2:7][CH2:12][CH3:13])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: CCCCOC(=N)C(Cl)(Cl)Cl
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCCCC1
Product: CCCCOCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound (13) is prepared as follows: To a solution of 18.9 g t.butyltrichloroacetimidate in 50 ml cyclohexane is added a solution of 12.1 g geraniol (10) in 50 ml cyclohexane. After external cooling in ice is added dropwise in 15 min 0.8 ml BF3 -etherate. The reaction mixture is stirred at room temperature for 2 hours. Then 1.0 g NaHCO3 is added and the mixture is stirred for 10 min. The precipitate is filtered off and washed with hexane. After separation, washing with 5% aqueous NaHCO3 -solution and water successively, drying and evaporation to dryness, the organic phase yields 17.3 g of a product. This product is purified by flash chromatography; the desired t.butylether (13) is obtained in a yield of 11.43 g (69%). Identification by NMR: 1H-NMR(CDCl3); δ: 5.33 (t.1H); 5.09 (t.1H); 3.92 (d.2H); 2.15-1.95 (4H); 1.67 (s. 3H); 1.66(s.-3H); 1.59 (s.3H); 1.23 (s.9H).