Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH:10][C@H:11]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]2)=[O:9])[CH2:3]1.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>ClCCl>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH:10][C@H:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)=[O:9])[CH2:3]1.[F:23][C:24]([F:29])([F:28])[C:25]([O-:27])=[O:26]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)CN2CCC(O)C2)C1
Solvent: ClCCl
Product: O=C(CN1CCC(O)C1)N[C@H]1CCNC1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-3-[2-(3-Hydroxypyrrolidin-1-yl)acetyl]amino-1-(tert-butoxycarbonyl)pyrrolidine (531 mg) prepared in Step A mentioned above was added with a 30% solution of trifluoroacetic acid in dichloromethane (8 ml), and the mixture was stirred at room temperature for 2 hours. The volatile components were evaporated under reduced pressure to obtain the title compound as trifluoroacetate (900 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][NH:5][C:6]1[NH:10][C:9]2[C:11]3[CH2:12][C:13]([CH3:23])([CH3:22])[O:14][C:15]=3[C:16]([C:18](OC)=[O:19])=[CH:17][C:8]=2[N:7]=1.[F:28][C:29]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:30]=1[NH2:31].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][NH:5][C:6]1[NH:10][C:9]2[C:11]3[CH2:12][C:13]([CH3:23])([CH3:22])[O:14][C:15]=3[C:16]([C:18]([NH:31][C:30]3[CH:32]=[C:33]([C:36]([F:37])([F:38])[F:39])[CH:34]=[CH:35][C:29]=3[F:28])=[O:19])=[CH:17][C:8]=2[N:7]=1
Reactant: COC(=O)c1cc2nc(NCc3ccccc3Cl)[nH]c2c2c1OC(C)(C)C2
Reactant: Nc1cc(C(F)(F)F)ccc1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3cc(C(F)(F)F)ccc3F)cc3nc(NCc4ccccc4Cl)[nH]c23)O1
Yield: 4.7 %

Procedure:
The title compound was prepared following the procedure described for Example-137 using methyl 2-((2-chlorobenzyl)amino)-7,7-dimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Intermediate-52, 0.200 g, 0.519 mmol), 2-fluoro-5-trifluoromethyl aniline (0.237 g, 1.0389 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL). The obtained crude was purified by column chromatography eluting with 0.5% DCM:MeOH to afford 0.013 g of the desired product. 1HNMR (DMSO-d6): δ 1.55 (s, 6H), 3.14 (s, 2H), 4.61 (m, 2H), 7.32 (m, 2H), 7.40 (m, 1H), 7.49-7.62 (m, 5H), 7.69 (m, 1H), 8.93 (d, J=6.3 Hz, 1H), 10.34 (bs, 1H), 11.00 (bs, 1H). [M+H]+: 533.08.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])[N:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6].[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:3][CH2:4][C:5]([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])[N:16]=[CH:15][N:14]=3)[CH2:9][CH2:8]2)=[O:6])=[O:30])=[CH:27][CH:26]=1
Reactant: CC(C)COc1cc(N2CCN(C(=O)CN)CC2)ncn1
Reactant: O=C(O)c1ccc(F)cc1
Agent: Cl
Product: CC(C)COc1cc(N2CCN(C(=O)CNC(=O)c3ccc(F)cc3)CC2)ncn1

Procedure:
The title compound was prepared according to the procedure described in Example 3 using 2-amino-1-(4-(6-isobutoxypyrimidin-4-yl)piperazin-1-yl)ethanone dihydrochloride and 4-fluorobenzoic acid.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].F[C:10](F)(F)C(O)=O.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[CH3:18][N:19]([CH:21]=[N:6][C:5]1[CH:7]=[CH:8][N:1]([CH3:10])[C:2](=[O:3])[N:4]=1)[CH3:20]
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1cc[nH]c(=O)n1
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1ccn(C)c(=O)n1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
Cytosine (3.0 g, 27 mmol) and dimethyl-formamide-dimethylacetal (40 mL) was added to 100 mL mad apple-type flask with a magnetic stirrer, heated at 120° C. with constant stirring. Then, trifluoroacetic acid (0.2 mL) was added and the mixture was allowed to stir for 18 hr. The reacting solution was cooled to room temperature, followed by cooling in ice bath. The white precipitation was filtrated, dissolved in dichloromethane and ethanol, and changed to powders by hexane. The solids were collected and dried under vacuum. Thus, 4-N—(N,N-dimethylaminomethylene)-1-methylcytosine was obtained as white solids (3.6 g, yield, 74%). 1H-NMR (400 MHz, DMSO-d6)
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[CH:16].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26].C(O)(=O)C>ClCCCl>[CH2:25]([N:27]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([C:15]#[CH:16])=[CH:18][CH:19]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: C#Cc1ccc(C=O)cc1
Reactant: CCNCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C#Cc1ccc(CN(CC)CC)cc1
Reaction time: 18 h
Yield: 63.3 %

Procedure:
Sodium triacetoxyborohydride (1.22 g, 5.76 mmol) was added to a solution of 4-ethynylbenzaldehyde (0.50 g, 3.84 mmol) in 1,2-dichloroethane (18.75 mL) at rt. Diethylamine (0.61 mL, 5.76 mmol) and acetic acid (0.12 mL, 1.92 mmol) were then added under N2 atmosphere to the mixture at rt and the reaction was stirred for 18 h. The reaction was quenched with sat. sodium bicarbonate solution (10 mL) and the mixture was stirred for 15 min. Dichloromethane (18.75 mL) was then added and the layers were separated. The aqueous layer was extracted using dichloromethane (10 mL), and the combined organic layers were washed with brine and dried over sodium sulfate. The solvent was then removed under vacuum at 40° C./200 mbar. The resultant oily residue was purified by silica gel column chromatography using dichloromethane: methanol (100 to 90:10) gradient to give the title compound as pale yellow thick oil (0.455 g, 63.2%). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=8.0 Hz, 2H), 7.76 (d, J=7.6 Hz, 2H), 3.78 (s, 2H), 3.08 (s, 1H), 2.72-2.66 (m, 4H), 1.13 (t, J=7.2 Hz, 6H); MS ESI 187.9 [M+H]+, calcd for [C13H17N+H]+ 187.14.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH:5]([CH3:19])[CH2:4][NH:3]1)=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[C:10]=3[Cl:18].[OH-:20].[K+]>>[C:2]([C:7]1[NH:8][C:9]2[C:14]([C:6]=1[CH:5]([CH3:19])[CH2:4][NH2:3])=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[C:10]=2[Cl:18])([OH:20])=[O:1]
Reactant: [OH-]
Reactant: COc1cc2c3c([nH]c2c(Cl)c1Cl)C(=O)NCC3C
Agent: [K+]
Product: COc1cc2c(C(C)CN)c(C(=O)O)[nH]c2c(Cl)c1Cl

Procedure:
Following the procedure of Example 2, 1.85 g (6.18 mmoles) of 1-oxo-4-methyl-6-methoxy-7,8-dichloro-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole were hydrolyzed with aqueous alcoholic KOH. The yield of crude amino acid, 2-carboxy-3-(1-amino-2-propyl)-5-methoxy-6,7-dichloroindole, thus formed was quantitative. The amino acid was decarboxylated without further purification, using the procedure of Example 2, with 3M hydrochloric acid for 48 hours to yield 3-(1-amino-2-propyl)-5-methoxy-6,7-dichloroindole.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C:9](=O)[CH:10]=[C:11]([CH3:16])[C:12](=[O:15])[C:13]=1[CH3:14].[NH2:18][C:19]1[CH:23]=[CH:22][NH:21][N:20]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH3:14][C:13]1[C:12](=[O:15])[C:11]([CH3:16])=[CH:10][C:9](=[N:18][C:19]2[CH:23]=[CH:22][NH:21][N:20]=2)[C:8]=1[CH3:7]
Reactant: CC1=CC(=O)C(C)=C(C)C1=O
Reactant: Nc1cc[nH]n1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CC1=CC(=Nc2cc[nH]n2)C(C)=C(C)C1=O
Temperature: 25 °C
Yield: 24.2 %

Procedure:
A 1.62 ml quantity of pyridine was dissolved in 60 ml of dichloroethane, and 0.55 ml of titanium tetrachloride was added thereto. The mixture was refluxed with heating for 15 minutes. Then, to the mixture were added 1.50 g of 2,3,5-trimethyl-1,4-benzoquinone and 0.83 g of 3-aminopyrazole, and the mixture was refluxed with heating for 2 hours. The reaction mixture was cooled to room temperature and filtered through a Celite pad and the insoluble materials were washed there with chloroform. The filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent: diethyl ether-hexane=1:1), giving 0.52 g of 2,3,6-trimethyl-4-(3-pyrazolylimino)-2,5-cyclohexadien-1-one (Compound 37a) as a yellow solid. Table 3 below shows the structure and properties of Compound 37a.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:7]=[CH:6][C:5]([C@H:8]3[CH2:12][CH2:11][CH2:10][C@H:9]3[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=2)=[CH:24][CH:23]=1
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(I)cc1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc([C@H]3CCC[C@H]3NS(=O)(=O)C(C)C)cc2)cc1
Yield: 89.2 %

Procedure:
The Suzuki coupling of (+,−) Cis propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (200 mg, 0.51 mmol, prepared in example 17) and 4-methoxyphenylboronic acid (93 mg, 0.61 mmol) was accomplished in a manner analogous to the procedure described in example 27. The reaction was worked up in a manner analogous to example 3. Purification by silica chromatography using a Chromatotron® was achieved eluting with methylene chloride to afford 170 mg (89%) of the title compound.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1.C(N(CC)CC)C.[C:20]([OH:24])([CH3:23])([CH3:22])[CH3:21]>ClC1C=CC=CC=1.O>[C:20]([O:24][C:1](=[O:2])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1cccc(N)n1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: Clc1ccccc1
Product: Cc1cccc(NC(=O)OC(C)(C)C)n1
Reaction time: 0.5 h
Yield: 92 %

Procedure:
556.0 g (500 mL) of monochlorobenzene were added to a reaction system followed by blowing in 107.8 g (1.09 moles) of phosgene over the course of 1 hour at −10° C. to −5° C. A mixed solution containing 54.07 g (0.5 moles) of 2-amino-6-picoline, 107 g (1.06 moles) of triethylamine, 92.7 g (1.25 moles) of t-butanol and 333 g (300 mL) of monochlorobenzene were dropped into this phosgene solution over the course of 4.5 hours while holding the internal temperature at −11° C. to −8° C. Following completion of dropping, the solution was stirred for 0.5 hours. Next, a mixed solution obtained by dissolving 120 g (1.19 moles) of triethylamine in 217.4 g (200 mL) of monochlorobenzene was dropped in over the course of 1 hour while holding the internal temperature at −10° C. to −5° C. Following completion of dropping, the solution was stirred for 0.2 hours. Next, 300 mL of water were added. The organic phase was washed with 150 mL of water. The organic phase was subjected to quantitative analysis by HPLC. The target (6-methyl-pyridin-2-yl)-carbamic acid tert-butyl ester was obtained at a yield of 92%. The yield of 1,3-bis-(6-methyl-pyridin-2-yl)-urea (urea compound) was 4%. 4% of the 2-amino-6-picoline used for the starting material remained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.CN(C=O)C.[CH3:32][C:33]([CH3:37])([CH3:36])[C:34]#[CH:35].C(OCC)(=O)C>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:32][C:33]([CH3:37])([CH3:36])[C:34]#[C:35][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[CH:26]=[N:25][CH:24]=[N:23][CH:22]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1ncc(Br)cc12
Reactant: C#CC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 90 °C

Procedure:
Combined (S)-3-bromo-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (120 mg, 0.293 mmol), tetrakis(triphenylphosphine)palladium (33.8 mg, 0.029 mmol), copper(i) iodide (11.14 mg, 0.059 mmol) and DMF (1950 μL, 0.293 mmol). Added 3,3-dimethylbut-1-yne (96 mg, 1.170 mmol) and DIPA (2085 μL, 14.63 mmol), flushed with argon, sealed and heated at 90° C. overnight. The reaction was diluted with water (25 mL) and poured into a separatory funnel containing ethyl acetate (25 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (12 g), 0-10% methanol in DCM with 0.1% ammonium hydroxide) to provide (S)-3-(3,3-dimethylbut-1-ynyl)-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a tan solid. Found MS: MH+=412.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH:12]=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]([S:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10](/[CH:12]=[N:20]/[S:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Reactant: CC(C)(C)S(N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(/C=N/S(=O)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To a solution of 3-formyl-azetidine-1-carboxylic acid tert-butyl ester (1.0 g, 5.4 mmol) and 2-methylpropane-2-sulfinamide (654 mg, 5.4 mmol) in dry CH2Cl2 (10 mL) was added anhydrous CuSO4 (1.9 g, 11.9 mmol). The heterogeneous reaction mixture was stirred at room temperature overnight then filtered over Celite, rinsing with CH2Cl2. The filtrate was concentrated and the resultant residue was absorbed onto SiO2 and purified by column chromatography with 20% to 40% EtOAc/hexanes to provide 1.26 g (81%) of 3-{[(E)-2-methyl-propane-2-sulfinylimino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH:9]1[C:13]2([CH3:30])[CH:14]([OH:29])[CH2:15][CH:16]3[C:21]4([CH3:27])[CH2:22][CH2:23][CH:24]([OH:26])[CH2:25][CH:20]4[CH2:19][CH:18]([OH:28])[CH:17]3[CH:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1.CC(OC)(C)C.Cl>N1C=CC=CC=1.O>[OH:28][C@@H:18]1[CH2:19][C@H:20]2[C@:21]([CH3:27])([CH2:22][CH2:23][C@@H:24]([O:26][S:37]([C:34]3[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=3)(=[O:39])=[O:38])[CH2:25]2)[C@@H:16]2[C@@H:17]1[C@H:12]1[C@:13]([CH3:30])([C@@H:14]([OH:29])[CH2:15]2)[C@@H:9]([C@H:2]([CH3:1])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])[CH2:10][CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCC(C)C1CCC2C3C(O)CC4CC(O)CCC4(C)C3CC(O)C12C
Agent: Cl
Solvent: O
Solvent: COC(C)(C)C
Solvent: c1ccncc1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: -8 °C

Procedure:
To a solution of cholic acid methyl ester (1000.0 g, 2.366 mol) in pyridine (2250 mL) at −10° C. was added a solution of p-toluenesulfonyl chloride (654.2 g, 2.431 mol) in pyridine (650 mL) dropwise over 2.5 hours while maintaining the reaction temperature at −10 to −6° C. The solution was mixed at −10° C. for an additional 12.5 hours, diluted with water (61.8 g) with continued cooling. The mixture at −7.5° C. was added over a period of 43 minutes to a mixture of MTBE (5 L) and 6N HCl (6.2 L). The layers were separated and the organic phase was washed with 7% NaHCO3 (2 L), followed by 2% NaCl (2 L), and finally with pH 7 phosphate buffer (2 L). The organic phase was filtered, concentrated under reduced pressure with MTBE (3×200 mL) to give 1608.93 g of a very viscous pale-straw colored oil (95.3% potency adjusted yield) that was used directly in the next step. 1H NMR (CDCl3, 400 MHz) δ 7.79 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.6 Hz, 2H), 4.40-4.31 (m, 1H), 3.97 (br s, 9H), 3.83 (br s, 1H), 3.68 (s, 3H), 2.60-2.50 (m, 1H), 2.45 (s, 3H), 2.43-1.34 (m, 25H), 0.99 (d, J=6.3 Hz, 3H), 0.88 (s, 3H), 0.69 (s, 3H). MS (ESI) Expected=576; base=594.2 (576+NH4+).
Reaction SMILES: [F:1][C:2]([F:55])([F:54])[C:3]1[CH:4]=[C:5]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][O:23][CH3:24])[CH2:17]2)[CH2:10][C@H:9]1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([N:33]=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH:27]=1)=[O:7].[H][H]>CO.[Pd]>[F:53][C:50]([F:51])([F:52])[C:48]1[CH:47]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:54])[F:55])[CH:49]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][O:23][CH3:24])[CH2:17]2)[CH2:10][C@H:9]1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([NH2:33])[CH:27]=1)=[O:7]
Reactant: [H][H]
Reactant: COC[C@@H]1CN(CCN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc(C)c(N=C(c4ccccc4)c4ccccc4)c3)C2)CCO1
Agent: [Pd]
Solvent: CO
Product: COC[C@@H]1CN(CCN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc(C)c(N)c3)C2)CCO1
Yield: 35.2 %

Procedure:
A solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-(diphenylmethyleneamino)-4-methylbenzyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]piperazine (65 mg) in methanol was subjected to hydrogenolysis (3 atm hydrogen pressure) using 10% palladium on carbon (6 mg, 50% wet) at 50° C. for 16 hours. After cooling, the mixture was filtered and the filtrate was evaporated in vacuo. Ethyl acetate and water were added to the residue and the organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (NH-DM1020, Fuji Silysis Chemical Ltd.) with a mixture of hexane and ethyl acetate (1:1) as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-amino-4-methylbenzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]-piperazine (18 mg). To a solution of the obtained compound in methanol was added 4N hydrogen chloride in ethyl acetate (0.05 ml) and the mixture was evaporated in vacuo to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-amino-4-methylbenzyl)-4-[2-((2S)-2-(methoxymethyl)morpholino]ethyl]-piperazine trihydrochloride (20 mg).
Reaction SMILES: [F:1][C:2]([P:8]([C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])(=[O:13])[O:9][CH2:10][C:11]#[CH:12])([F:7])[C:3]([F:6])([F:5])[F:4].[CH3:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>>[F:7][C:2]([P:8]([C:14]([F:19])([F:20])[C:15]([F:18])([F:17])[F:16])(=[O:9])[O-:13])([F:1])[C:3]([F:6])([F:5])[F:4].[CH2:10]([N+:24]1[CH:25]=[CH:26][N:22]([CH3:21])[CH:23]=1)[C:11]#[CH:12]
Reactant: C#CCOP(=O)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: Cn1ccnc1
Product: C#CC[n+]1ccn(C)c1
Product: O=P([O-])(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
Propargyl bis(pentafluoroethyl)phosphinate (11.18 g; 32.9 mmol) is slowly added dropwise to cooled (0° C.) N-methylimidazole (2.22 g; 27.1 mmol) in a 100 ml glass flask. In an exothermic reaction, an orange solid is formed, which is warmed and stirred at room temperature for 1.5 h. After drying in vacuo (10−3 mbar) at room temperature, 1-propargyl-3-methylimidazolium bis(pentafluoroethyl)phosphinate, [CH≡CCH2MIM][(C2F5)2P(O)O], (11.14 g; 26.3 mmol) is isolated as pale-orange solid in a yield of 99% and a purity of 97%. The coloured solid can be washed colourless with dichloromethane and n-hexane.
Reaction SMILES: [CH2:1]([O:3]C(C1C(OC)=C2C(NC3C=CC(OC4C=CC=CC=4)=CC=3)=C(C#N)C=NN2C=1)=O)C.[OH:33][C:34]([C:37]1[C:38](C)=[C:39]2[C:44]([NH:45][C:46]3[CH:51]=[CH:50][C:49]([O:52][C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)=[CH:48][CH:47]=3)=[C:43]([C:59]#[N:60])[CH:42]=[N:41][N:40]2[CH:61]=1)([CH3:36])[CH3:35].C(O)(C(F)(F)F)=O.O.C(O)(C(F)(F)F)=O.CC#N>>[OH:33][C:34]([C:37]1[C:38]([O:3][CH3:1])=[C:39]2[C:44]([NH:45][C:46]3[CH:47]=[CH:48][C:49]([O:52][C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)=[CH:50][CH:51]=3)=[C:43]([C:59]#[N:60])[CH:42]=[N:41][N:40]2[CH:61]=1)([CH3:36])[CH3:35]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1OC
Reactant: Cc1c(C(C)(C)O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: COc1c(C(C)(C)O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 0.13 h
Yield: 98 %

Procedure:
The title compound (170 mg, 98%) was prepared from 393 (180 mg, 0.42 mmol) by a route analogous to that used for the preparation of compound 396. It has a retention time of 6.49 min. (Column: HTS, 5 u, 4.6×50 mm; Gradient: 5-100% B in 8.0 min; A=0.1% TFA/H2O; B=0.1% TFA/CH3CN; Run time 10 min; Det: 215 nM; FR: 1.2 ml/min); MS Found: (M−H)+=413.3
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH2:28]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)[CH2:29][CH3:30]>C1COCC1>[CH2:28]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[CH:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:34][CH:33]=1)[CH2:29][CH3:30]
Reactant: CCCOc1ccc(C=O)cc1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCOc1ccc(C=CCCCC(=O)O)cc1
Yield: 75.5 %

Procedure:
This compound was synthesized from 4-carboxybutyltriphenylphosphonium bromide (8.87 g, 20 mmol) and p-propoxybenzaldehyde (3.28 g, 20 mmol, synthesized from p-hydroxybenzaldehyde and 1-iodopropane) in THF (100 mL) by a Wittig reaction. Crystallization (petroleum ether) afforded the product (3.75 g, 76%) as white crystals (mp, 49°-50° C.). IR: 3400-2500, 1725 cm-1 ; 1H-NMR: 1.00 (t, 3H), 1.75 (m, 4H), 2.35 (m, 4H), 3.90 (t, 2H), 5.55 (m, 1H), 6.35 (m, 1H), 7.00 (q, 4H), 11.30 (bs, 1H). Anal. Calcd. for C15H20O3 : C, 72.55, H, 8.12%; Found: C, 72.45, H, 8.13%. Z:E=35:65.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]=2[C:14]=1[F:15].CC[N:18]([CH2:21][CH3:22])CC.CN(C(ON1N=N[C:33]2[CH:34]=[CH:35][CH:36]=[N:37][C:32]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CC#N>[C:36]([C:35]1([C:2]2[CH:3]=[CH:4][C:5]([CH:21]([NH:18][C:11](=[O:13])[CH2:10][N:7]3[C:6]4[C:14]([F:15])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[N:9]=[CH:8]3)[CH3:22])=[CH:6][CH:14]=2)[CH2:34][CH2:33][CH2:32]1)#[N:37]
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Reactant: CCN(CC)CC
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC#N
Product: CC(NC(=O)Cn1cnc2ccc(F)c(F)c21)c1ccc(C2(C#N)CCC2)cc1

Procedure:
N-{1-[4-(1-Cyanocyclobutyl)phenyl]ethyl}-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide is synthesized according to example 5 by mixing (6,7-difluoro-1H-benzimidazol-1-yl)acetic acid (212 mg, 1.00 mmol) prepared according to scheme 2,1-[4-(1-aminoethyl)phenyl]cyclobutanecarbonitrile (200 mg, 1.00 mmol) prepared according to scheme 9, Et3N (304 mg, 3.00 mmol, 0.418 mL) and HATU (280 mg, 1.00 mmol) in MeCN (10.0 mL). The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Gemini (5μ) 21.2×50 mm, Mobile phase: A=water (10 mM NH4CO3) B=MeCN, (220 mg, 0.558 mmol, 56%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.39 (d, J=7.03 Hz, 3H) 1.91-2.05 (m, 1H) 2.16-2.34 (m, 1H) 2.53-2.64 (m, 2H) 2.66-2.78 (m, 2H) 4.87-5.01 (m, 1H) 5.07 (s, 2H) 7.11-7.31 (m, 1H) 7.33-7.49 (m, 5H) 8.19 (s, 1H) 8.84 (d, J=7.81 Hz, 1H); MS [M+H], calcd: 395.0, found: 395.2.