Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:15])/[C:3](/[C:13]#[N:14])=[N:4]/[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Br:12].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:20]C1C=CC=CC=1>Cl>[ClH:20].[NH2:14][C:13]1[C:11]2[C:6](=[C:7]([Br:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:2]([NH2:1])=[O:15]
Reactant: N#C/C(=N\Nc1ccccc1Br)C(N)=O
Reactant: Clc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: NC(=O)c1nnc2c(Br)cccc2c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
(E)-2-Amino-N′-(2-bromophenyl)-2-oxoacetohydrazonoyl cyanide (50.1 g, 187.5 mmol), AlCl3 (100 g, 750 mmol), and chlorobenzene (419 mL, 412 mol) were stirred at 115° C. overnight under N2. The reaction mixture was subsequently cooled to RT and 2M HCl (820 mL) was slowly added. The reaction mixture was stirred at 100° C. for 1 hour and then cooled. The product was collected by vacuum filtration, rinsed with EtOH (200 mL) and Et2O (100 mL), and dried under high vacuum to give an HCl salt of the title compound as a yellow solid (31.25 g, 62.5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.91 (1H, s), 9.43 (1H, s), 8.61-8.59 (1H, d, J=8.4 Hz), 8.43 (1H, s), 8.32-8.30 (1H, d, J=7.6 Hz), 7.94 (1H, s), 7.69-7.65 (1H, m); LC-MS (5-95% ACN in H2O gradient with 0.02% NH4OAc, tR 2.659 minutes) ESI+APCI m/z [M+H]+ 267.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([NH:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([CH2:11][NH:10][C:8]3[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[NH:6][N:7]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1cc(NCc2c(-c3ccc(F)cc3)noc2C)n[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)O)[nH]n1
Reaction time: 12 h
Yield: 81.7 %

Procedure:
5-{[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2H-pyrazole-3-carboxylic acid methyl ester (900 mg, 2.72 mmol) was then dissolved in THF (20 mL) and lithium hydroxide monohydrate (686 mg, 16.34 mmol) in water (15 mL) added and the resulting mixture stirred for 12 h. After evaporation the mixture was diluted with water (10 mL) and citric acid (10%) and extracted with ethyl acetate (2×80 mL). The combined extracts were then dried with sodium sulfate, filtered and evaporated to afford 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2H-pyrazole-3-carboxylic acid (703 mg, 91%) as an off white solid. MS: m/e=317.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][N:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:16][C:12]=3[C:11](=[O:23])[N:10]([CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[C:9]2=[O:37])[CH:3]=1.[ClH:38]>C(Cl)Cl.O1CCOCC1>[ClH:38].[CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][N:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[S:16][C:12]=3[C:11](=[O:23])[N:10]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:9]2=[O:37])[CH:3]=1
Reactant: Cc1cc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)no1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)no1

Procedure:
A solution of tert-butyl 4-{1-[(5-methylisoxazol-3-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (841 mg; compound B6) in DCM (15 ml) is reacted with a solution of hydrogen chloride in 1,4-dioxane (1.5 ml, 4.0 M) according to the procedure described in example B28 to afford the title compound as a solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=1.Cl.[NH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:11]([C:4]1[CH:3]=[C:2]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=1)[CH3:12]
Reactant: CCc1cc(Cl)n2nccc2n1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNc1cc(CC)nc2ccnn12

Procedure:
1.8 g (9.9 mmol) 7-Chloro-5-ethylpyrazolo[1,5-a]pyrimidine (Example 1, Step B) and 1.4 g (10.0 mmol) ethyl 2-aminoacetate hydrochloride were dissolved in 50 ml dry ethanol. 500 mg (4.7 mmol) sodium carbonate were added, and the mixture was heated with reflux for 2 h. The inorganic material was filtered off, the residue treated with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and evaporated in vacuo to give the crude title compound as an oil, which was pure enough according to its 1H-NMR spectrum and was used for the reaction of the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[CH:16]=2)[C:11]([OH:13])=O)=[N:6][CH:7]=1.[CH3:23][C:24]1[N:29]=[CH:28][C:27]([C@H:30]([NH2:32])[CH3:31])=[CH:26][N:25]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[CH:16]=2)[C:11]([NH:32][C@@H:30]([C:27]2[CH:26]=[N:25][C:24]([CH3:23])=[N:29][CH:28]=2)[CH3:31])=[O:13])=[N:6][CH:7]=1
Reactant: Cc1ncc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)O)c2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)N[C@H](C)c3cnc(C)nc3)c2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(5-methylpyridin-2-yl)-5-(thiazol-2-yloxy)benzoic acid (40 mg, 0.13 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(2-methylpyrimidin-5-yl)ethanamine (40 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol), and N,N-diisopropylethylamine (120 μL, 0.69 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the product as a light color solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]([O:18][N:19]=[C:20]([C:22]3[CH:39]=[CH:38][C:25]([CH2:26][N:27]4[CH2:30][CH:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]4)=[CH:24][CH:23]=3)[NH2:21])=O)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O1CCCC1>C(#N)C>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:18][N:19]=[C:20]([C:22]4[CH:39]=[CH:38][C:25]([CH2:26][N:27]5[CH2:28][CH:29]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:30]5)=[CH:24][CH:23]=4)[N:21]=3)[S:10][C:11]=2[C:12]([F:13])([F:15])[F:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(C(N)=NOC(=O)c3cc(-c4ccccc4)c(C(F)(F)F)s3)cc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)cc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.3 %

Procedure:
To a solution of tert-butyl 1-(4-(N′-(4-phenyl-5-(trifluoromethyl)thiophene-2-carbonyloxy)carbamimidoyl)benzyl)azetidine-3-carboxylate (744 mg, 1.33 mmol) in acetonitrile (30 mL) was added a 1M solution of TBAF in tetrahydrofuran (3.99 mL, 3.99 mmol), and the reaction mixture was allowed to stir at room temperature for 3 days. The volatiles were removed under reduced pressure, and the residue was chromatographed on a 5×12 cm silica gel column, eluting with a 0-50% EtOAc/Hex gradient. The essentially pure fractions containing product were concentrated to afford tert-butyl 1-(4-(5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (521 mg, 0.962 mmol, 72.4% yield) as a colorless solid. HPLC ret. time=3.63 min. (YMC Combi S-5 4.6×50 mm ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=542.22. 1H NMR (500 MHz, CDCL3) δ ppm 1.46 (s, 9H), 3.25-3.31 (m, 3H), 3.52-3.58 (m, 2H), 3.69 (s, 2H), 7.43 (d, J=8.25 Hz, 2H), 7.47 (m, 5H), 7.91 (s, d, J=1.65 Hz, 1H), and 8.09 (d, J=8.25 Hz, 2H).
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=1.[CH3:15][N:16]([CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=[O:25])[CH3:17]>O1CCCC1.[Fe].[Cl-]>[CH3:17][N:16]([CH2:18][CH:19]1[C:20]([OH:25])([C:7]2[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH2:21][CH2:22][CH2:23][CH2:24]1)[CH3:15]
Reactant: CN(C)CC1CCCCC1=O
Reactant: COc1cccc(Br)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1cccc(C2(O)CCCCC2CN(C)C)c1
Reaction time: 0.17 h
Yield: 89.2 %

Procedure:
To 120 mL of anhydrous tetrahydrofuran (THF) cooled to −50° C. was added 400 mL of sec-butyl lithium (0.52 mol, 1.3 M solution in cyclohexane). The resulting yellow suspension was stirred for 10 min and then 63.56 g of neat 3-bromoanisole (0.34 mol) was added dropwise with stirring. The yellow suspension turned red, and then a white precipitate formed. The resulting white suspension was stirred for 30 min. In a separate vessel 52.75 g of (±) 2-((dimethylamino)methyl) cyclohexanone was dissolved in 107 mL of anhydrous THF at 0° C. To the resulting solution of (±) 2-((dimethylamino)methyl) cyclohexanone was added, dropwise with stirring, a solution of 1.03 g of iron (mH) chloride (6.3 mmol, 1 mol percent) in anhydrous THF. The resulting violet solution was transferred dropwise to the stirred white suspension at −50° C. using a metering pump. The resulting reaction mixture was quenched with 100 mL of water, the organic phase separated, the aqueous phase was extracted twice with 100 mL diethyl ether, and the diethyl ether extracts combined. The combined diethyl ether extracts were dried over sodium sulfate, filtered, and the diethyl ether solvent was removed under reduced pressure to provide 89.82 g (0.303 mol, 89% yield) of the above-titled mixture in a ratio of 93.9:6.1 as determined using HPLC.
Reaction SMILES: C(O[C:4]1[CH:5]=C(C=C[C:11]=1C)C=O)C.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=[O:18].C(Br)C=C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:5]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=[O:18])[CH:4]=[CH2:11]
Reactant: CCOc1cc(C=O)ccc1C
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: CN(C)C=O
Product: C=CCOc1cc(C=O)ccc1OC

Procedure:
The title compound was prepared analogously to 3-ethoxy-4-methyl-benzaldehyde (intermediate B10) by reaction of 3-hydroxy-4-methoxy-benzaldehyde with allylbromide in DMF using K2CO3 as base (see also A. W. White, R. Almassy, A. H. Calvert, N. J. Curtin, R. J. Griffin, Z. Hostomsky, K. Maegley, D. R. Newell, S. Srinivasan and B. T. Golding J. Med. Chem. 2000, 43, 4084-4097).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:7][C:6]([Cl:8])=[N:5][CH:4]=1.Cl.[CH3:10][O:11][C:12](=N)[NH:13][N+:14]([O-:16])=[O:15]>[OH-].[Na+].O>[CH3:10][O:11][C:12](=[N:13][N+:14]([O-:16])=[O:15])[NH:1][CH2:2][C:3]1[S:7][C:6]([Cl:8])=[N:5][CH:4]=1
Reactant: COC(=N)N[N+](=O)[O-]
Reactant: NCc1cnc(Cl)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
5-(Aminomethyl)-2-chlorothiazole (1.49 g, 10.0 mmol) was dissolved in diluted hydrochloric acid (15 ml, 10.0 mmol), and O-methyl-N-nitroisourea (1.31 g, 11.0 mmol) was added. The pH was 2.1 at this time. This reaction mixture was adjusted to pH 6.2 with aqueous sodium hydroxide solution (0.1 N, 4 ml, 0.40 mmol) using pH meter. Water (1 ml) was added to increase the whole volume to 20 ml. After 16 hours of stirring at room temperature (pH was 7.1 at this time), the resulting white crystals were collected by filtration under reduced pressure, and washed with water. The washed crystals were dried under reduced pressure (80° C., 2 hours) to provide 1.62 g (64.6% yield) of O-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[N+:9]([C:12]1[CH:13]=[C:14]([C:22](Cl)=[O:23])[C:15]2[O:20][CH2:19][CH2:18][O:17][C:16]=2[CH:21]=1)([O-:11])=[O:10].O>C(C(C)=O)C>[CH3:8][N:5]1[CH2:6][CH2:7][N:2]([NH:1][C:22]([C:14]2[C:15]3[O:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=2)=[O:23])[CH2:3][CH2:4]1
Reactant: CN1CCN(N)CC1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc2c1OCCO2
Solvent: CCC(C)=O
Solvent: O
Product: CN1CCN(NC(=O)c2cc([N+](=O)[O-])cc3c2OCCO3)CC1
Temperature: 10 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
33 g of 1-amino-4-methylpiperazine was dissolved in 630 ml of methyl ethyl ketone. The mixture was cooled to 10° C. and 61 g of 7-nitro-1,4-benzodioxane-5-carbonyl chloride were introduced by portions. The mixture was stirred for two hours and then the solid was filtered off and washed with 150 ml of methyl ethyl ketone. The obtained product was purified by transformation into the base (M.P.: 212° C.) and recrystallized by treatment with hydrochloric ethanol. 45 g of N-(4-methyl-1-piperazinyl)-7-nitro-1,4-benzodioxane-5-carboxamide were obtained (M.P.: 210° C. with one mole of water). The structure was confirmed by nuclear magnetic resonance and infrared analyses.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[C:9]([CH:13]1[CH2:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[C:16]2=[C:24]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:25]3[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:30]=3[N:15]2[CH2:14]1)([O:11][CH3:12])=[O:10].IC>C1COCC1>[CH:35]1([C:24]2[C:25]3[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:30]=3[N:15]3[CH2:14][C:13]([C:9]([O:11][CH3:12])=[O:10])([CH3:2])[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16]=23)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)OC)Cc1ccccc1-3
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C)(C(=O)OC)Cc1ccccc1-3
Temperature: -50 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
A solution of LDA in THF (1.2 mL of 0.5 N, 0.60 mmol) was added to a solution of methyl (±)-6-carbomethoxy-13-cyclohexyl-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (160 mg, 0.37 mmol) in THF (5 mL) at −78° C. Stirring was continued at −78° C. for 15 min when the mixture was slowly warmed to −50° C. Iodomethane (35 μL, 0.56 mmol) was added and the mixture was slowly warmed to −10° C. Stirring was continued for 30 min. The solution was quenched with MeOH. The solution was extracted with ethyl acetate and the extract washed with dilute HCl (2×), brine (3×), and then dried (Na2SO4). The extract was concentrated and the crude product purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a white solid (140 mg, 85%). ESI-MS m/z 446 (MH+) 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.19-1.33 (m, 3 H) 1.31-1.52 (m, 3 H) 1.63-1.84 (m, 3 H) 1.87-2.15 (m, 4 H) 2.34 (d, J=13.73 Hz, 0.4 H) 2.70 (d, J=13.73 Hz, 0.6 H) 2.88-3.12 (m, 2 H) 3.21 (d, J=13.73 Hz, 0.4 H) 3.33 (d, J=14.65 Hz, 0.6 H) 3.75 (d, J=10.68 Hz, 3 H) 3.95 (s, 3 H) 4.34 (d, J=14.65 Hz, 0.4 H) 4.87 (d, J=14.65 Hz, 0.6 H) 7.30-7.48 (m, 4 H) 7.69-7.79 (m, 1 H) 7.82-7.92 (m, 1 H) 8.11 (s, 0.4 H) 8.22 (s, 0.6 H).
Reaction SMILES: [C:1]([N:9]=[C:10]=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[CH:23]=1>C(Cl)Cl>[C:1]([NH:9][C:10]([NH:28][C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH3:12])[CH:27]=[CH:26][N:25]=1)=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: COc1ccccc1CCc1ccnc(N)c1
Solvent: ClCCl
Product: COc1ccccc1CCc1ccnc(NC(=O)NC(=O)c2ccccc2)c1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
Benzoyl isocynate (132 mg, 0.896 mmol) is added to a solution of 4-[2-(2-methoxy-phenyl)-ethyl]-pyridin-2-ylamine (93.0 mg, 0.407 mmol) in CH2Cl2 (4 mL), and the mixture is stirred at 60° C. After 20 hours, the mixture is concentrated to give the crude product, which is used in the next step without purification.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:22])[CH2:20][NH2:21])=[CH:15][CH:14]=2)=[CH:9]1.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>>[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH2:22][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:20][NH2:21])=[CH:15][CH:14]=2)=[CH:9]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: NCC(CC(=O)OCc1ccccc1)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propyl amine trifluoroacetate (prepared in example 1) and benzyl chloroformate in a manner analogous to the procedure described in Example 1.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13]C)=O)(C(C)(C)C)(C)C.CC(C)C(=O)[CH2:20][C:21]#[N:22]>>[OH:8][CH2:9][C:10]([CH3:15])([CH3:16])[C:11](=[O:13])[CH2:20][C:21]#[N:22]
Reactant: COC(=O)C(C)(C)CO[Si](C)(C)C(C)(C)C
Reactant: CC(C)C(=O)CC#N
Product: CC(C)(CO)C(=O)CC#N
Yield: 29 %

Procedure:
Prepared from methyl 3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropanoate (6 g, 24.39 mmol) according to the method described for 4-methyl-3-oxopentanenitrile Example XA Step 1. Purification via silica gel chromatography eluting with 33% ethyl acetate in petroleum ether afforded 5-hydroxy-4,4-dimethyl-3-oxopentanenitrile as a yellow oil (1 g, 29%). 1H NMR (300 MHz, CDCl3) δ 3.76 (s, 2H), 3.61 (s, 2H), 1.19 (s, 6H).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH2:33][CH2:34][CH2:35][OH:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:21]=3[C:22]([F:23])([F:24])[F:25])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:32][CH2:33][CH2:34][CH2:35][OH:36])=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCCCO)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 0.33 h
Yield: 34.4 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-VII, 40 mg, 0.093 mmol), 3-aminopropan-1-ol (10.47 mg, 0.139 mmol), HATU (45.9 mg, 0.121 mmol), and 4-methylmorpholine (37.6 mg, 0.372 mmol) were dissolved in DMF (1 mL). It was stirred for 20 min and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.1 min) to provide (R/S)-2-hydroxy-N-(3-hydroxypropyl)-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (20 mg, 0.032 mmol, 34.4% yield): LCMS=488.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.42-8.50 (1 H, m), 8.12 (2 H, dd, J=8.57, 3.30 Hz), 7.51-7.73 (7 H, m), 5.11 (1 H, s), 3.58 (2 H, t, J=6.15 Hz), 3.35 (2 H, t, J=6.81 Hz), 1.74 (2 H, quin, J=6.59 Hz); HPLC peak RT=6.8 min (Method A).
Reaction SMILES: C([O:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:12]1[CH2:14][CH2:13]1)(=O)C.[OH-].[Na+]>CO>[CH:12]1([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[OH:4])[CH2:14][CH2:13]1
Reactant: CC(=O)Oc1c(C)cccc1C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(C2CC2)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A magnetic stirrer bar was attached to a 1 L round bottom flask. 2-Cyclopropyl-6-methylphenyl acetate (32.5 g), methanol (90 ml) and an aqueous 4M NaOH solution (90 ml) were added thereto, and the mixture was stirred at room temperature for 2 hours. After most of methanol was removed by concentration, the obtained mixture was cooled in ice-water and water (500 ml) and 4M hydrochloric acid (120 ml) were added thereto, followed by stirring of the mixture. This was extracted with a 10% ethyl acetate-90% hexane (V/V) solvent mixture (3×200 ml). The organic layer was combined and successively washed with water (3×200 ml) and a saturated aqueous NaCl solution (200 ml), followed by drying with anhydrous sodium sulfate. After the solid was removed by filtration, the filtrate was concentrated to obtain 27.09 g (purity: 54.6%) of a crude product of 2-cyclopropyl-6-methylphenol.
Reaction SMILES: S(O[C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:21]2[CH:26]=[CH:25][C:24](OS(C)(=O)=O)=[C:23]([N+:32]([O-:34])=[O:33])[CH:22]=2)([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])=[CH:8][C:7]=1[N+:35]([O-:37])=[O:36])(C)(=O)=O.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(#N)C>[NH:38]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:21]2[CH:26]=[CH:25][C:24]([NH:32][C:23]3[CH:24]=[CH:25][CH:26]=[CH:21][CH:22]=3)=[C:23]([N+:32]([O-:34])=[O:33])[CH:22]=2)([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])=[CH:8][C:7]=1[N+:35]([O-:37])=[O:36])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CS(=O)(=O)Oc1ccc(C(c2ccc(OS(C)(=O)=O)c([N+](=O)[O-])c2)(C(F)(F)F)C(F)(F)F)cc1[N+](=O)[O-]
Reactant: Nc1ccccc1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(C(c2ccc(Nc3ccccc3)c([N+](=O)[O-])c2)(C(F)(F)F)C(F)(F)F)ccc1Nc1ccccc1
Yield: 159.3 %

Procedure:
A solution of 60 g (0.103 mol) of 2,2-bis-(4-mesyloxy-3-nitrophenyl)-hexafluoropropane and 122.8 g (1.32 mol) of aniline in 400 ml of acetonitrile is heated under reflux for 24 hours. In the course of this the methanesulfonic acid salt of aniline is precipitated, and is removed by filtration with suction. The filtrate is freed from the solvent and from excess aniline by distillation under reduced pressure. Recrystallizing the residue from ethanol gives 47.3 g of 2,2-bis-(4-anilino-3-nitrophenyl)-hexafluoropropane (80% yield). M.p. 165-166° C.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].F[C:11]1[C:16]([CH3:17])=[C:15]([I:18])[CH:14]=[CH:13][N:12]=1>O1CCCC1>[CH:1]1([O:7][C:11]2[C:16]([CH3:17])=[C:15]([I:18])[CH:14]=[CH:13][N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(I)ccnc1F
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(I)ccnc1OC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cyclohexanol (0.501 g) in tetrahydrofuran (3.5 mL) was treated with NaH (0.1 g) until gas evolution ceased. 2-Fluoro-4-iodo-3-methylpyridine (0.237 g) in tetrahydrofuran (1.5 mL) was added. The reaction mixture was stirred at room temperature for 0.5 hours and was quenched with ice-water. The resulting mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC, and was eluted with petroleum ether to provide the title compound.