Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][O:64][CH2:65][C@H:66]1[CH2:70][CH2:69][CH2:68][NH:67]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:67]1[CH2:68][CH2:69][CH2:70][C@@H:66]1[CH2:65][O:64][CH3:63])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: COC[C@H]1CCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC[C@H]1CCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (2R)-2-methoxymethyl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][N:7]1[CH2:10][C@H:9]([NH:11][S:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[CH:20][CH:21]=3)[CH:16]=2)(=[O:14])=[O:13])[C:8]1=[O:27])#[N:2].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][N:7]1[CH2:10][C@H:9]([N:11]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[CH:20][CH:21]=3)[CH:16]=2)(=[O:14])=[O:13])[C:8]1=[O:27])#[N:2]
Reactant: BrCc1ccccc1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CN(Cc4cccc(C#N)c4)C3=O)cc2c1
Product: COc1ccc2ccc(S(=O)(=O)N(Cc3ccccc3)[C@H]3CN(Cc4cccc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 25, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxoazetidin-3-(S)-yl]amide, prepared as described in Example 65, part D, and benzyl bromide. The crude product is purified by column chromatography eluting with gradient of 30% EtOAc/hexanes to 40% EtOAc/hexanes to afford the title compound as a white foam.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8]1[C:13]([C:14]([OH:16])=[O:15])=[C:12]([NH:17][C:18](=[O:24])[C@H:19]([CH:21]([CH3:23])[CH3:22])[NH2:20])[CH:11]=[CH:10][CH:9]=1.[CH:25]1[C:37]2[CH:36]([CH2:38][O:39][C:40](Cl)=[O:41])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]=2[CH:28]=[CH:27][CH:26]=1.Cl>O1CCOCC1.O>[CH:25]1[C:37]2[CH:36]([CH2:38][O:39][C:40]([NH:20][C@H:19]([C:18]([NH:17][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([CH3:7])[C:13]=3[C:14]([OH:16])=[O:15])=[O:24])[CH:21]([CH3:22])[CH3:23])=[O:41])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]=2[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cccc(NC(=O)[C@@H](N)C(C)C)c1C(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(NC(=O)[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(C)C)c1C(=O)O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 73 %

Procedure:
284 mg of sodium carbonate and 336 mg of 6-methyl-2-(L-valylamino)benzoic acid were dissolved in a mixture consisting of 17 ml of 1,4-dioxane and 12 ml of water, followed by adding dropwise a solution of 345 mg of 9-fluorenylmethoxycarbonyl chloride in 7 ml of 1,4-dioxane under ice-cooling. After stirring for 3.5 hours at room temperature, the reaction mixture was poured into water, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by a silica gel column chromatography (eluting solution: hexane-ethyl acetate-acetic acid) to give 460 mg of 2-{[N-(9-fluorenylmethoxy-carbonyl)-L-valyl]amino}-6-methylbenzoic acid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([Cl:28])[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1(SC)C=CC=CC=1>>[Cl:28][C:17]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[N:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:18]=1
Reactant: COc1ccc(-n2nc(Cl)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Solvent: CSc1ccccc1
Product: COc1ccc(-n2nc(Cl)cc2-c2ccc(O)cc2)cc1
Yield: 21.3 %

Procedure:
A solution of 4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenyl benzyl ether (2.79 g) and thioanisole (3.56 g) intrifluoroacetic acid (25 ml) was stirred at ambient temperature overnight. The mixture was concentrated in vacuo. The residue was recrystallized from AcOEt (15 ml) and n-hexane (12 ml) to give 1st crop of FR282117 (1.48 g). The mother liqour was washed with H2O, saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt/n-hexane=30%. The pure fractions were collected and concentrated in vacuo. The residual crystals were collected and washed with IPE to give 2nd crop of 4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol(457.2 mg) white powder
Reaction SMILES: C([O:4][C@H:5]1[C@@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@@H:37]([CH2:47][O:48]CC=C)[O:36][C@@H:7]([O:8][CH2:9][CH:10]([CH2:12][CH2:13][CH2:14][C@H:15]([C@@H:17]2[C@:34]3([CH3:35])[C@H:20]([C@H:21]4[C@H:31]([CH2:32][CH2:33]3)[C@:29]3([CH3:30])[CH:24]([CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:23][CH2:22]4)[CH2:19][CH2:18]2)[CH3:16])[CH3:11])[C@@H:6]1[O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)C=C.II.O>O1CCCC1.C(Cl)(Cl)Cl.[Ir]>[CH2:53]([O:52][C@@H:6]1[C@@H:5]([OH:4])[C@@H:38]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C@@H:37]([CH2:47][OH:48])[O:36][C@H:7]1[O:8][CH2:9][CH:10]([CH2:12][CH2:13][CH2:14][C@H:15]([C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[CH:24]([CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:23][CH2:22]3)[CH2:19][CH2:18]1)[CH3:16])[CH3:11])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: C=CCOC[C@H]1O[C@@H](OCC(C)CCC[C@@H](C)[C@H]2CC[C@H]3[C@@H]4CCC5CCCC[C@]5(C)[C@H]4CC[C@]23C)[C@H](OCc2ccccc2)[C@@H](OCC=C)[C@H]1OCc1ccccc1
Agent: [Ir]
Agent: II
Solvent: O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C)CO[C@@H]1O[C@H](CO)[C@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1
Yield: 88.2 %

Procedure:
Iridium complex (1,5-cyclooctadiene bis(methyldiphenylphosphine)iridium hexafluorophosphate, 136 mg, 0.12 mmol) was suspended in tetrahydrofuran (5 mL), and activated by stirring under H2 flow. To this solution Compound 25 (940 mg, 1.16 mmol) dissolved in tetrahydrofuran (5 mL) was added, and the mixture was stirred at room temperature for 1 hour under argon gas flow. Iodine (588 mg), water (30 mL) and tetrahydrofuran (15 mL) were added thereto, and the mixture was further stirred at room temperature for 1.5 hours. The reaction mixture was diluted with chloroform, and washed successively with saturated sodium thiosulfate solution, saturated aqueous sodium hydrogencarbonate, and saturated brine. The chloroform layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:acetone=6:1) to obtain Compound 26 (748 mg, 88.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24]O>C1COCC1>[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: CN(C)CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(N)cc1

Procedure:
Following the procedure described in part E of Example 1 (R), (S)-α-[[2-[((1,1-dimethylethyl)dimethylsilyl)oxy]-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-4-methoxybenzeneacetic acid was condensed with 4-[2-(dimethylamino)ethoxy]aniline to generate the title compound. The 4-[2-(dimethylamino)ethoxy]aniline was prepared by treating commercial 4-aminophenol with DEAD, φ3P, and 2-(dimethylamino)ethanol in THF.
Reaction SMILES: [NH2:1]C1C(I)=C(C(O)=O)C(I)=C(C(O)=O)C=1I.CCC[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[N:1]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: CCCCCCCCCCCC
Reactant: Nc1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Product: c1ccc2ncccc2c1
Yield: 95.6 %

Procedure:
According to the procedure described in Example 1, the reaction is carried out with the same amounts of 5-amino-2,4,6-triiodo-1,3-benzenedicarboxylic acid using n-dodecane instead of meta-xylene, with quinoline, giving a yield of 95.6%.
Reaction SMILES: [CH3:1][C:2](=[O:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].II.Cl>O1CCOCC1.[Zn]>[OH:8][C:2]([CH3:1])([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCCCCC(C)=O
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: C1COCCO1
Product: CCCCCC(C)(O)CC(=O)OCC

Procedure:
To a solution of 2-heptanone (10.1 mL) in 1,4-dioxane (150 mL) were added ethyl bromoacetate (9.6 mL), zinc (8.5 g) and iodine (3.7 g) at room temperature and the solution was sonicated. After 2 Hours, 1N hydrochloric acid was added dropwise to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue purified by flush column chromatography (n-hexane:ethyl acetate=15:1), to give the title compound (13.9 g) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]([CH2:19][CH3:20])[CH3:18])=[O:16])[CH2:10]2)=[N:6][C:7]=1[NH2:8].[CH:21]1([C:24]2[N:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][N:25]=2)[CH2:23][CH2:22]1.[S].C(O)(=O)C>C(O)C>[CH:21]1([C:24]2[N:29]=[C:28]([C:30]3[NH:8][C:7]4=[N:6][C:5]([N:9]5[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]([CH2:19][CH3:20])[CH3:18])=[O:16])[CH2:10]5)=[CH:4][CH:3]=[C:2]4[N:1]=3)[CH:27]=[CH:26][N:25]=2)[CH2:23][CH2:22]1
Reactant: O=Cc1ccnc(C2CC2)n1
Reactant: CCN(C)C(=O)[C@@H]1CCCN(c2ccc(N)c(N)n2)C1
Agent: [S]
Solvent: CC(=O)O
Solvent: CCO
Product: CCN(C)C(=O)[C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1
Temperature: 80 °C
Yield: 13.7 %

Procedure:
To a solution of (R)-1-(5,6-diaminopyridin-2-yl)-N-ethyl-N-methylpiperidine-3-carboxamide (200 mg, 0.722 mmol) in ethanol (10 mL) was added 2-cyclopropylpyrimidine-4-carbaldehyde (106 mg, 0.722 mmol), sulfur powder (69 mg, 2.16 mmol), and acetic acid (0.2 mL). The reaction mixture was heated to 80° C. for 18 h. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was concentrated under reduced pressure. The crude material was purified via preparative HPLC to afford the title compound (40 mg, 13.5%). 1H NMR (300 MHz, CDCl3) δ 1.09-1.18 (m, 3H), 1.19-1.31 (m, 4H), 1.65-1.73 (m, 1H), 1.84 (d, 1H), 1.88-1.98 (m, 2H), 2.31 (d, 1H), 2.69-2.87 (m, 1H), 2.99 (br s, 1H), 3.03 (br s, 1H), 3.11 (br s, 1H), 3.14-3.27 (m, 1H), 3.37-3.57 (m, 2H), 4.37 (d, 1H), 4.45-4.59 (m, 1H), 6.76 (d, 1H), 7.79-7.96 (m, 1H), 8.67 (d, 1H), 10.25 (br s, 1H). MS (ES+APCI) (M+H) 406.3; LCMS retention time 3.055 min (Method U1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[S:8][C:7]([CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.O1CCCC1>[Si:18]([O:1][CH2:2][CH2:3][C:4]1[S:8][C:7]([CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(O)Cc1ccc(CCO)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(CC(=O)O)s1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 22.9 %

Procedure:
To a solution of 2-[5-(2-hydroxyethyl)-2-thienyl]acetic acid (1.35 g, 7.26 mmol) and imidazole (1.04 g, 15.25) in N,N-dimethylformamide (18 mL) was added tert-butyldimethylsilyl chloride (2.29 g, 15.25 mmol) over 20 minutes. The resultant solution was stirred at room temperature for one hour. Tetrahydrofuran (18 mL) was then added and reaction solution cooled to 0° C. A solution of potassium carbonate (1.04 g, 7.6 mmol) in water (18 mL) was added and the solution stirred for 20 minutes. The reaction solution was then partitioned between ethyl acetate and brine. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with 0-50% ethyl acetate in iso-hexane to give the title compound as a yellow oil (500 mg, 23%).
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=O.[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCCCCC.C(OCC)(=O)C>[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:1][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:3])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1OCc2ccccc21
Reactant: NCCCCc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CN1CCCCc1ccccc1
Temperature: 150 °C
Reaction time: 16 h
Yield: 10.4 %

Procedure:
A mixture of phthalide (0.268 g, 2 mmol) and 4-phenyl-butylamine (0.316 mL, 2 mmol) was stirred at 150° C. for 16 h. Workup and silica gel column chromatography (2:1 hexane-ethyl acetate) afforded 2-(4-phenyl-butyl)-2,3-dihydro-isoindol-1-one (0.055 g, 11%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.70 (m, 4H), 2.71 (t, 2H), 3.66 (t, 2H), 4.31 (s, 2H), 7.14-7.56 (m, 8H), 7.82 (s, 1H).
Reaction SMILES: [OH-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][OH:14])=[CH:11][C:6]=2[CH:5]=[CH:4]1.C(O)(=O)C(O)=O.Cl[CH2:22][CH2:23][CH2:24][N:25]1[CH2:28][CH:27]([O:29][C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:26]1.O>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[S:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][O:14][CH2:22][CH2:23][CH2:24][N:25]3[CH2:26][CH:27]([O:29][C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:28]3)=[CH:11][C:6]=2[CH:5]=[CH:4]1
Reactant: OCCc1ccc2sccc2c1
Reactant: ClCCCN1CC(OC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)C(=O)O
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(C(OC2CN(CCCOCCc3ccc4sccc4c3)C2)(c2ccccc2)c2ccccc2)cc1
Yield: 36.7 %

Procedure:
In a mixture of 0.4 mL of toluene and 7 mL of a 50% (W/V) aqueous sodium hydroxide solution was suspended 0.54 g of 2-(1-benzothiophen-5-yl)-1-ethanol, followed by adding thereto 1.45 g of 1-(3-chloropropyl)-3-(trityloxy)azetidine oxalate and 0.03 g of tetra-n-butylammonium bromide, and the resulting mixture was refluxed for 7 hours. After the reaction mixture was cooled, water and toluene were added thereto and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform:methanol=75:1) to obtain 0.59 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-(trityloxy)azetidine as a light-yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:13][C@H:14]([C:19]([NH:21][CH2:22][C:23]#[N:24])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35](C2C=CC(B(O)O)=CC=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:23]([CH2:22][NH:21][C:19]([C@@H:14]([NH:13][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:2]2[CH:7]=[CH:6][C:5]([CH:37]3[CH2:36][NH:35][CH2:34][CH2:33][N:32]3[C:30]([O:29][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:31])=[CH:4][CH:3]=2)=[CH:3][CH:4]=1)[C:9]([F:12])([F:11])[F:10])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:20])#[N:24]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Reactant: CC(C)C[C@H](NC(c1ccc(Br)cc1)C(F)(F)F)C(=O)NCC#N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC(C)C[C@H](NC(c1ccc(-c2ccc(C3CNCCN3C(=O)OC(C)(C)C)cc2)cc1)C(F)(F)F)C(=O)NCC#N
Temperature: 85 °C

Procedure:
To N2-[1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N1-(cyanomethyl)-L-leucinamide (242 mg, 0.60 mmol), and 4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenylboronic acid (220 mg, 0.72 mmol) in DME (3 mL) under dry nitrogen was added 2M aqueous sodium carbonate (0.9 mL, 1.8 mmol) followed by the catalyst PdCl2(dppf) (63 mg, 0.077 mmol). The reaction was heated to 85° C. for 18 hours. Water was added and the product was extracted with EtOAc, the organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by chromatography using EtOAc in hexane to afford tert-butyl (4′-{1-[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)amino]-2,2,2-trifluoroethyl}-1,1′-biphenyl-4-yl)-1-piperazinecarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:37]=[CH:36][C:26]2[C:27]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[N:28][O:29][C:25]=2[CH:24]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:33]4[CH2:32][CH2:31][CH:30]([C:27]5[C:26]6[CH:36]=[CH:37][C:23]([F:22])=[CH:24][C:25]=6[O:29][N:28]=5)[CH2:35][CH2:34]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 6-fluoro-3-piperidine-4-yl-benzo[d]isoxazole (Table No.1, SM 8) in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=506.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1.C(O)=O.N>O>[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([CH2:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=2)[CH2:12]1
Reactant: O=Cc1cccc(O)c1
Reactant: CC1CCCNC1
Agent: N
Solvent: O
Solvent: O=CO
Product: CC1CCCN(Cc2cccc(O)c2)C1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
24.4 g (0.2 mol) of 3-hydroxybenzaldehyde are mixed with 40 ml (about 0.4 mol) of 3-methylpiperidine and 20 ml (about 0.52 mol) of 100% formic acid with cooling and then stirred for 2 hours at 120° C. When the reaction mixture has cooled to room temperature, it is poured into water and rendered alkaline with ammonia, and the precipitated solid is filtered off and recrystallised from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH:8][C:9]2[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C(N)(=O)C.Br[CH2:31][C:32]([N:34]([CH:43]([CH3:45])[CH3:44])[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)=[O:33]>CN(C=O)C>[CH:43]([N:34]([C:35]1[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)[C:32](=[O:33])[CH2:31][NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=1)([CH3:44])[CH3:45]
Reactant: COc1ccc(CNc2ccccc2N)cc1
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cc1
Agent: CC(N)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ccccc2NCC(=O)N(c2ccc(OC)cc2)C(C)C)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
To a solution of N-(4-methoxybenzyl)-benzene-1,2-diamine (2.42 g, 10.6 mmol) in DMF (40 mL) was added potassium carbonate (1.47 g,10.6 mmol), potassium iodide (176 mg, 1.06 mmol), and 2-Bromo-N-isopropyl-N-(4-methoxy-phenyl)-acetamide acetamide (3.03 g, 10.6 mmol). The resultant reaction mixture was stirred overnight at 60° C. The solvent was removed in vacuo and the crude material dissoved in EtOAc (150 mL), washed with water (2×50 mL) and brine (50 mL), dried with MgSO4, filtered and concentrated to a brown oil. The precipitate which formed upon the addition of ether (70 mL) was filtered to give the title compound (1.39 g, 3.21 mmol) as a yellow solid. The remaining filtrate was concentrated under reduced pressure to a brown oil which was purified by flash chromatography on silica gel (40 g) eluted with EtOAc/Hexanes (1:4, 900 mL).
Reaction SMILES: [CH3:1]CN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:24]1([N:28]2[CH2:33][CH2:32][N:31]([C:34]([C@@H:36]3[CH2:38][C@H:37]3[C:39]3[CH:47]=[CH:46][C:42]([C:43]([NH2:45])=[O:44])=[CH:41][CH:40]=3)=[O:35])[CH2:30][C@H:29]2[CH3:48])[CH2:27][CH2:26][CH2:25]1>CN(C=O)C>[CH:24]1([N:28]2[CH2:33][CH2:32][N:31]([C:34]([C@@H:36]3[CH2:38][C@H:37]3[C:39]3[CH:40]=[CH:41][C:42]([C:43]([NH2:45])=[O:44])=[CH:46][CH:47]=3)=[O:35])[CH2:30][C:29]2([CH3:1])[CH3:48])[CH2:25][CH2:26][CH2:27]1
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@@H]1CN(C(=O)[C@@H]2C[C@H]2c2ccc(C(N)=O)cc2)CCN1C1CCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1(C)CN(C(=O)[C@@H]2C[C@H]2c2ccc(C(N)=O)cc2)CCN1C1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.7 %

Procedure:
Intermediate 14 (282 mg, 1.38 mmol) was dissolved in DMF (15 mL). DIPEA (1.201 mL, 6.88 mmol) was added, followed by HOBT (279 mg, 2.06 mmol), EDC (395 mg, 2.06 mmol) and Intermediate 2 (278 mg, 1.65 mmol). The reaction mixture was stirred at rt for 2 h and concentrated under reduced pressure. The residue was redissolved in DCM, washed with sat NaHCO3, dried over MgSO4, filtered and concentrated under reduced pressure to give 632 mg of crude as an orange oil. The crude material was purified on preparative HPLC UV using the long high pH shallow gradient method (Mobile phase: 20-40% B; A: H2O with 10 mM NH4CO3 and 0.375% NH4OH v/v, B: CH3CN, 30 min run) on XBridge Prep C18 OBD, 50×250 mm, 10μ, Waters reverse phase column, providing 151 mg title compound (30.9%) as a solid (enantiomeric mixture). 1H NMR (400 MHz, CD3OD) δ ppm 1.01 (s, 2H) 1.08 (s, 4H) 1.34-1.43 (m, 1H) 1.55-1.70 (m, 4H) 1.96-2.12 (m, 5H) 2.25-2.37 (m, 1H) 2.40-2.48 (m, 1H) 2.61 (br. s., 2H) 3.45 (br. s., 2H) 3.75 (br. s., 1H) 7.26 (dd, J=8.20, 5.08 Hz, 2H) 7.80 (dd, J=8.40, 2.93 Hz, 2H); HRMS m/z calcd for C21H30N3O2 356.23325 [M+H]+, found 356.23286.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH:3]=[O:4].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1>CCOCC>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:3]([OH:4])[C:2]([CH3:6])([CH3:5])[CH3:1])=[CH:10][CH:9]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CC(C)(C)C=O
Solvent: CCOCC
Product: CC(C)(C)C(O)c1ccc(Cl)cc1

Procedure:
Grignard reaction of trimethylacetaldehyde (240.0 mg; 2.8 mmol) with 4-chlorophenylmagnesium bromide in anhydrous ether afforded 0.58 grams of 1-(4-chlorophenyl)-2,2-dimethylpropanol.