Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([C:24]#[N:25])=[C:12]([S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:11]=1.[ClH:33]>C(#N)C.[Cu](Cl)Cl>[Cl:33][C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([C:24]#[N:25])=[C:12]([S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:11]=1
Reactant: Cl
Reactant: N#Cc1c(N)nc(Sc2ccccc2)c(C#N)c1-c1ccccc1
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: N#Cc1c(Cl)nc(Sc2ccccc2)c(C#N)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under argon, 24.5 g (182 mmol) of anhydrous copper(II) chloride are suspended in 180 ml of acetonitrile, and 21.4 g (182 mmol) of isopentyl nitrite are then added dropwise. After 20 minutes of stirring at room temperature, 10 g (30.5 mmol) of 2-amino-4-phenyl-6-(phenylsulfanyl)-3,5-pyridinedicarbonitrile [Kambe et al., Synthesis, 531-533 (1981)] are added. The mixture is stirred at room temperature over the weekend. For work-up, 150 ml of 1 N hydrochloric acid are added to the mixture, the mixture is extracted 4× with dichloromethane and the organic phase is washed once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue is triturated with a little ethyl acetate and allowed to stand in a fridge for one hour. The crystals are filtered off with suction and washed with a little cold ethyl acetate and diethyl ether.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]2[NH:22][C:11]3=[CH:12][C:13]4[C:14]([CH3:21])([CH3:20])[C:15](=[O:19])[NH:16][C:17]=4[CH:18]=[C:10]3[N:9]=2)=[N:4][NH:5][C:6]=1[CH3:7].[C:23](Cl)(=[O:25])[CH3:24]>>[CH3:21][C:14]1([CH3:20])[C:13]2[CH:12]=[C:11]3[NH:22][C:8]([C:3]4[C:2]([NH:1][C:23](=[O:25])[CH3:24])=[C:6]([CH3:7])[NH:5][N:4]=4)=[N:9][C:10]3=[CH:18][C:17]=2[NH:16][C:15]1=[O:19]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]nc(-c2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)N4)c1N
Product: CC(=O)Nc1c(-c2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)N4)n[nH]c1C

Procedure:
N-[3-(7,7-Dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-5-methyl-1H-pyrazol-4-yl]-acetamide was prepared using 2-(4-amino-5-methyl-1H-pyrazol-3-yl)-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (60 mg, 0.21 mmol) and acetyl chloride. The title compound was obtained as white powder (3.7 mg).
Reaction SMILES: Cl.N1C=CC=CC=1N1CCN([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[C:27](=[O:28])[C:26]3[CH:29]=[CH:30][CH:31]=[C:24]4[C:25]=3[C:20](=[CH:21][CH:22]=[CH:23]4)[C:19]2=[O:32])CC1.[Br:33][CH2:34]CCCCBr.BrCCCCBr>>[Br:33][CH2:34][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:27](=[O:28])[C:26]2[CH:29]=[CH:30][CH:31]=[C:24]3[C:25]=2[C:20](=[CH:21][CH:22]=[CH:23]3)[C:19]1=[O:32]
Reactant: BrCCCCCBr
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCN(c2ccccn2)CC1
Agent: Cl
Solvent: BrCCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCBr

Procedure:
Following the procedure of part (a) of example 46 but substituting 1,5-dibromopentane for the 1,4-dibromobutane, one obtains 2-(5-bromopentyl)-1H-benz[de]isoquinoline-1,3(2H)-dione; m.p. 113°-115°.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:13][CH2:14][Mg+].[Br-].ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl.CCOC(C)=O>C1COCC1>[CH2:13]([C:5]1[C:6]2[NH:10][CH:9]=[N:8][C:7]=2[CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:14]
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Reactant: CC[Mg+]
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1c([N+](=O)[O-])ccc2nc[nH]c12
Temperature: -15 °C
Reaction time: 2 h
Yield: 52.4 %

Procedure:
To a solution of 5-nitro-benzimidazole (2.8 g, 17 mmol) in THF was added 16 ml of EtMgBr solution (48 mmol) and reaction mixture was stirred for 2 h at −15° C. A solution of tetrachloro-1,4-benzoquinone (8.8 g, 36 mmol) in THF was added dropwise into reaction mixture, which was allowed to warm up to 25° C. over 1 h. Silica gel(20 g) was added into reaction mixture and solvent was removed in vacuo to provide a brown silica gel powder which was subjected to column chromatography (EtOAc, neat) to provide 1.7 g (8.9 mmol, 52%) of 4-ethyl-5-nitrobenzimidazole, which was subsequently subjected to hydrogenation (H2, Pd/C) to yield 1.32 g (8.2 mmol) of 4-ethyl-5-aminobenzimidazole.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][C:22]([F:25])([F:24])[F:23])[CH2:11][N:10]2C(OC(C)(C)C)=O)=[O:8])[CH2:5][CH2:4]1)#[N:2]>C(O)=O>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][C:22]([F:25])([F:23])[F:24])[CH2:11][NH:10]2)=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](Sc2ccccc2OC(F)(F)F)C[C@H]1C(=O)NC1(C#N)CC1
Solvent: O=CO
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](Sc3ccccc3OC(F)(F)F)CN2)CC1

Procedure:
The reaction of the amide 11D with formic acid yielded (2S,4R)-N-(1-cyanocyclopropyl)-4-(2-(trifluoromethoxy)phenylthio)pyrrolidine-2-carboxamide as a colorless viscous oil (quant.). MS ISP (m/e): 372.1 (94) [(M+H)]+, 262.1 (100).
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([NH2:12])=[CH:6][C:5]=1[O:13][CH3:14])([CH3:3])=[CH2:2]>C(O)C.[Pd]>[CH:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([NH2:12])=[CH:6][C:5]=1[O:13][CH3:14])([CH3:3])[CH3:2]
Reactant: C=C(C)c1c(OC)cc(N)cc1OC
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)cc(OC)c1C(C)C
Reaction time: 8 h
Yield: 69 %

Procedure:
A solution of 4-Isopropenyl-3,5-dimethoxy-phenylamine (take directly from step 5) in ethanol (200 mL) was hydrogenated overnight at room temperature and 1 psig of H2 gas using 10% palladium on charcoal catalyst (200 mg). The reaction was filtered through Celite and the pad was washed with additional ethanol. Concentration of the filtrate and purification by silica gel column chromatography eluting with 70/30 hexane/ethyl acetate yielded 4-Isopropyl-3,5-dimethoxy-phenylamine (1.4 g, 69%) as a pale pink solid, MS (M+H)=196.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH2:23](Br)[CH:24]=[CH2:25].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:25][CH:24]=[CH2:23])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
A solution of 3-(4-hydroxyphenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (500 mg, 1.67 mmol) in methyl ethyl ketone (6 mL) was treated with allyl bromide (232 mg, 1.92 mmol, 0.17 mL) and potassium carbonate (311 mg, 2.25 mmol) and then heated to reflux. After 18 h, the mixture was cooled to ambient temperature and then partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and then the organic phases were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (100 mL SiO2, hexanes to 10% ethyl acetate/hexanes) to provide the desired product (478 mg, 84%) as a clear, colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.22 (t, J=8.0 Hz, 2H), 7.16 (d, J=8.8 Hz, 2H), 6.97 (dt, J=7.6, 1.2 Hz, 1H), 6.83 (d, J=7.8 Hz, 2H), 6.84 (t, J=8.4 Hz, 2H), 6.05 (ddd, J=17.2, 10.6, 5.2 Hz, 1H), 5.41 (dd, J=17.2, 1.6 Hz, 1H), 5.28 (dd, J=10.8, 1.4 Hz, 1H), 4.22 (d, J=5.2 Hz, 2H), 4.19 (q, J=6.8 Hz, 2H), 3.27 (A of AB, J=14 Hz, 1H), 3.11 (B of AB, J=14 Hz, 1H), 1.40 (s, 3H), 1.21 (t, J=6.8 Hz, 3H).
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])[C:2]([NH2:4])=[S:3].BrBr>C(Cl)(Cl)Cl>[NH2:4][C:2]1[S:3][C:6]2[C:7]([C:8]([OH:10])=[O:9])=[CH:11][CH:12]=[CH:13][C:5]=2[N:1]=1
Reactant: NC(=S)Nc1cccc(C(=O)O)c1
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: Nc1nc2cccc(C(=O)O)c2s1
Temperature: 25 °C
Reaction time: 60 h
Yield: 98 %

Procedure:
To a suspension of 3-thioureidobenzoic acid (1.06 g, 5.41 mmol) in chloroform (25 mL) was added a solution of bromine (0.4 mL, 8.0 mmol) dropwise at room temperature. The resulting mixture was heated under reflux for 3 hrs and allowed to stir at room temperature for 60 hrs. The solvent was evaporated, water was added and the resulting solids were isolated by filtration. The crude product was washed with water and dried to yield 1.03 g (98%) of the title compound as a gray solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-:3])=[O:2].[N+:11]([O-])([OH:13])=[O:12].S(=O)(=O)(O)O>C(Cl)Cl>[N+:11]([C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH3:10])[CH:6]=[CH:7][CH:8]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Reaction time: 2 h
Yield: 99 %

Procedure:
68.6 g (0.5 mol) of 2-nitrotoluene were dissolved in 80 ml of methylene chloride and 38.6 g (0.6 mol) of 98% by weight nitric acid, followed by the addition under reflux with stirring over a period of 1 hour at boiling temperature of 40 g of 100% by weight sulphuric acid. After stirring for 2 hours under reflux, the methylene chloride phase was separated off without cooling and washed three times while still hot with 3 × 200 ml of water. After the washing water had been carefully separated off, the methylene chloride was distilled off, leaving 89.9 g (98% of the theoretical yield) of dinitrotoluene containing 99% of 2,4- and 2,6-dinitrotoluene.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][N:13]([C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[C:12](=[O:23])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:24](Br)[CH:25]=[CH2:26].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1>[CH2:26]([C@H:11]1[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH2:14][N:13]([C@@H:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16])[C:12]1=[O:23])[CH:25]=[CH2:24]
Reactant: C=CCBr
Reactant: C[C@H](c1ccccc1)N1C[C@@H](CO[Si](C)(C)C(C)(C)C)CC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H]1C(=O)N([C@H](C)c2ccccc2)C[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: -5 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
(4S)-4-(tert-Butyldimethylsilyloxy)methyl-2-oxo-1-[(1R)-1-phenylethyl]pyrrolidine (333.5 g, 1.00 mol) and allyl bromide (90.9 mL, 1.05 mol) were dissolved in tetrahydrofuran (1.10 L). Lithium hexamethyldisilazide (1.0 M solution in tetrahydrofuran) (1.10 L, 1.10 mol) was added dropwise at −15° C., and the mixture was stirred at −5° C. for one hour. The reaction solution was extracted with a saturated ammonium chloride solution and ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. Thereafter, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=4:1→2:1) to give 327 g of the title compound as a colorless syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][CH:6]([C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10](OC)=[O:11])[CH3:7].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][CH:6]([C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[CH2:10][OH:11])[CH3:7]
Reactant: COC(=O)c1ccccc1C(C)Oc1cccc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(Oc1cccc(Cl)c1)c1ccccc1CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A solution of the crude methyl 2-[1-(3-chlorophenoxy)ethyl]benzoate described above (14.8 g) in THF (50 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (1.93 g) in THF (70 ml) cooled to 0°-5° C. Following the addition, the reaction mixture was stirred at about 0° C. for 30 minutes, then at room temperature for 2 hours. It was poured carefully into water and was extracted with ether. The extracts were washed successively with water (×2) and brine, then dried and concentrated to give 2-[1-(3-chlorophenoxy)ethyl]benzyl alcohol (11.72 g, 85% pure by GC) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:15]1([C:21]2[C:29]3[S:28][C:27]4[C:30](B(O)O)=[CH:31][CH:32]=[CH:33][C:26]=4[C:25]=3[CH:24]=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)C.C1(C)C=CC=CC=1>[C:15]1([C:21]2[C:29]3[S:28][C:27]4[C:30]([C:2]5[CH:3]=[CH:4][C:5]6[NH:6][C:7]7[C:12]([C:13]=6[CH:14]=5)=[CH:11][CH:10]=[CH:9][CH:8]=7)=[CH:31][CH:32]=[CH:33][C:26]=4[C:25]=3[CH:24]=[CH:23][CH:22]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OB(O)c1cccc2c1sc1c(-c3ccccc3)cccc12
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(-c2cccc3c2sc2c(-c4ccc5[nH]c6ccccc6c5c4)cccc23)cc1
Yield: 59 %

Procedure:
In a 50-mL three-neck flask were put 1.0 g (4.1 mmol) of 3-bromocarbazole, 1.2 g (4.1 mmol) of 6-phenyl-4-dibenzothienylboronic acid, and 62 mg (0.20 mmol) of tris(2-methylphenyl)phosphine. To this mixture were added 15 mL of toluene, 5 mL of ethanol, and 5 mL of a 2.0M aqueous sodium carbonate solution. This mixture was degassed by being stirred while the pressure was reduced. To this mixture was added 9 mg (0.041 mmol) of palladium(II) acetate, and the mixture was stirred at 80° C. for 3 hours under a nitrogen stream. After the stirring, the aqueous layer of this mixture was subjected to extraction with toluene, and the solution of the extract and the organic layer were combined and washed with saturated brine. The organic layer was dried over magnesium sulfate. This mixture was separated by gravity filtration, and the filtrate was concentrated to give a solid. This solid was purified by silica gel column chromatography (a developing solvent in which the toluene/hexane ratio was 1:2 and then a developing solvent in which the toluene/hexane ratio was 3:2). Addition of ethyl acetate/hexane to the obtained solid was followed by irradiation with ultrasonic waves, and the solid was collected by suction filtration, so that 1.0 g of a white solid which was the object of the synthesis in 59% yield. The synthesis scheme of Step 1 is illustrated in (a-13).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:28][C:29]1[CH:38]=[C:37]2[C:32]([C:33]([N:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)=[N:34][C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[OH:45])=[N:36]2)=[CH:31][CH:30]=1.[OH:52][C@@H:53]([CH2:57][CH:58]([CH3:60])[CH3:59])[C:54](O)=[O:55].C(N(CC)CC)C>CN(C=O)C>[OH:52][C@@H:53]([CH2:57][CH:58]([CH3:60])[CH3:59])[C:54]([N:49]1[CH2:50][CH2:51][N:46]([C:33]2[C:32]3[C:37](=[CH:38][C:29]([CH3:28])=[CH:30][CH:31]=3)[N:36]=[C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[OH:45])[N:34]=2)[CH2:47][CH2:48]1)=[O:55]
Reactant: CC(C)C[C@H](O)C(=O)O
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCN(C(=O)[C@@H](O)CC(C)C)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an N2 atmosphere, BOP (137 mg, 0.31 mmol) was added in a single portion to a stirring solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (100 mg, 0.31 mmol), (S)-2-hydroxy-4-methylpentanoic acid (41 mg, 0.31 mmol), and triethylamine (43 μL, 0.31 mmol) in DMF (0.5 ml). After stirring the mixture for 1 h at room temperature, it was partitioned between H2O and ether. The organic phase was washed with H2O (3×20 mL), dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 1:1 ethyl acetate/hexane gave (S)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one as a white solid. LC/MS: m/z 435.3 (M+H)+ at 2.62 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) d 8.44 (dd, J=8.2, 1.7 Hz, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.67 (s, 1H), 7.40-7.36 (m, 2H), 6.96-6.93 (m, 2H), 4.92 (d, J=7.2 Hz, 1H) 4.41-4.36 (m, 1H), 4.06-3.67 (m, 8H), 2.51 (s, 3H), 1.85-1.73 (m, 1H), 1.49-1.35 (m, 2H), 0.93-0.91 (m, 6H) ppm.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:30])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][C:21]([O:25][CH:26]([CH3:28])[CH3:27])=[C:22]([Cl:24])[CH:23]=3)[O:15][N:14]=2)=[CH:8][C:7]=1[CH3:29].[C:31](O)(=[O:34])[CH2:32][OH:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl.CC(=O)OCC>[Cl:24][C:22]1[CH:23]=[C:18]([C:16]2[O:15][N:14]=[C:13]([C:9]3[CH:10]=[C:11]([CH3:12])[C:6]([O:5][CH2:4][CH:3]([OH:30])[CH2:2][NH:1][C:32](=[O:33])[CH2:31][OH:34])=[C:7]([CH3:29])[CH:8]=3)[N:17]=2)[CH:19]=[N:20][C:21]=1[O:25][CH:26]([CH3:27])[CH3:28]
Reactant: Cc1cc(-c2noc(-c3cnc(OC(C)C)c(Cl)c3)n2)cc(C)c1OCC(O)CN
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(-c2noc(-c3cnc(OC(C)C)c(Cl)c3)n2)cc(C)c1OCC(O)CNC(=O)CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.3 %

Procedure:
To a solution of (RS)-1-amino-3-{4-[5-(5-chloro-6-isopropoxy-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propan-2-ol (313 mg, 0.6 mmol) in DCM (10 mL), glycolic acid (95 mg, 1.25 mmol) and Hünig's base (233 mg, 1.8 mmol) are added. The mixture is cooled to 0° C. and TBTU (236 mg, 0.74 mmol) is added. The mixture is stirred at 0° C. for 1 h, then at rt for 16 h before it is diluted with EA (250 mL), washed with 1N aq. NaOH solution (3×25 mL), 1N aq. KHSO4 (25 mL) and brine (25 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified by prep. HPLC to give N—((RS)-3-{4-[5-(5-chloro-6-isopropoxy-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide (42 mg) as a white powder; LC-MS: tR=1.06 min; [M+1]+=491.48; 1H NMR (CD3OD) δ 1.45 (d, J=6.3 Hz, 6H), 2.38 (s, 6H), 3.47 (dd, J=13.6, 7.3 Hz, 1H), 3.66 (dd, J=13.6, 4.5 Hz, 1H), 3.87 (m, 2H), 4.04 (s, 2H), 4.14 (m, 1H), 5.52 (m, 1H), 7.78 (s, 2H), 8.43 (s, 1H), 8.85 (s, 1H)
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].Br[CH2:14][CH2:15][OH:16]>C(Cl)Cl>[OH:16][CH2:15][CH2:14][NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[O:3][C:2]([F:11])([F:12])[F:1]
Reactant: Nc1ccccc1OC(F)(F)F
Reactant: OCCBr
Solvent: ClCCl
Product: OCCNc1ccccc1OC(F)(F)F
Temperature: 115 °C
Yield: 46.5 %

Procedure:
A stirred mixture of 5.64 g of 97% 2-trifluoromethoxyaniline and 3.4 mL of 97% 2-bromoethanol was heated at 115° C. for 8 h. After cooling to r.t., 50 ml, of CH2Cl2 was added and the solution was washed with 20% aq. sodium carbonate and H2O (3×20 mL), dried (anhydrous Na2SO4) and evaporated to dryness in vacuo. The residue was purified by flash chromatography (CHCl3-2 N methanolic NH3 100:0.5) affording 3.18 g (46.5%) of the title compound as a yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].[N:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>>[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][N:13]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)CCCCCCN
Reactant: O=Cc1ccc(-c2cnccn2)cc1
Agent: Cl
Product: COC(=O)CCCCCCNCc1ccc(-c2cnccn2)cc1

Procedure:
The title compound of Step A was prepared from 7-amino-heptanoic acid methyl ester hydrochloride, of Preparation 1, and 4-pyrazin-2-yl-benzaldehyde, of Preparation 27, using the method described in Example 1, Step A. 1H NMR (400 MHz, CDCl3) δ 9.01 (d, 1H), 8.61 (m, 1H), 8.48 (d, 1H), 7.97 (d, 2H), 7.46 (d, 2H), 3.85 (s, 2H), 3.65 (s, 3H), 2.63 (t, 2H), 2.29 (t, 2H), 1.62 (m, 2H), 1.54 (m, 2H), 1.33 (m, 4H); MS 328 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:14][CH2:13][CH2:12][O:11]1.[OH:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=1)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[O:11]1[CH2:12][CH2:13][O:14][CH:10]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:15][C:16]1[CH:17]=[C:18]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[CH:27]=[CH:28][CH:29]=1
Reactant: BrCCCCCCCCC1OCCO1
Reactant: O=C(c1ccccc1)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccccc1)c1cccc(OCCCCCCCCC2OCCO2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 84.2 %

Procedure:
2-(8-Bromooctyl)-1,3-dioxolane (3.89 g, 14.69 mmol) was added to a mixture of 3-hydroxybenzophenone (3 g, 15.13 mmol) and potassium carbonate (4.17 g, 30.21 mmol) in dimethyl formamide (50 mL). The reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution, saturated aqueous ammonium chloride solution and dried (sodium sulfate), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in iso-hexane to afford the title compound (4.73 g, 84%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24](O)=[O:25])[CH2:19]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([N:12]2[CH2:11][CH2:10][N:9]([C:4]3[C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:14][CH2:13]2)=[O:25])[CH2:19]1
Reactant: CC1CCCC(C(=O)O)C1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC1CCCC(C(=O)N2CCN(c3ncccc3C(F)(F)F)CC2)C1
Yield: 45 %

Procedure:
Coupling of 1-(3-(trifluoromethyl)pyridin-2-yl)piperazine (271 mg, 1.17 mmol) with 3-methylcyclohexanecarboxylic acid (100 mg, 0.70 mmol) was carried out according to a similar procedure described for example 19A using N,N-dimethylformamide (1 mL) as solvent and benzotriazole-1 yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (700 mg, 1.56 mmol) as coupling agent. 1-[(3-methylcyclohexyl)carbonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine was obtained in 45% yield (112 mg) as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH2:6][CH2:5]2.Br[CH2:23][CH:24]1[CH2:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:21])[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:23][CH:24]3[CH2:26][CH2:25]3)=[CH:18][CH:19]=1)[CH2:6][CH2:5]2
Reactant: BrCC1CC1
Reactant: O=C(N[C@H]1CCc2cc(Br)ccc2C1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(N[C@H]1CCc2cc(Br)ccc2C1)c1ccc(OCC2CC2)cc1
Temperature: 75 °C

Procedure:
A mixture of N—((S)-6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-4-hydroxybenzamide (5.00 g), bromomethylcyclopropane (2.20 g), cesium carbonate (5.5 g) and DMF (50 ml) was heated to 75° C. for 12 hours. The cooled reaction mixture was admixed with water and extracted with ethyl acetate. The organic phase was washed three times with water, dried over magnesium sulfate and concentrated. The product was thus obtained with the molecular weight of 400.32 (C21H22BrNO2); MS (ESI): 400 (M+H+).