Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.[CH2:14]=[C:15]([CH3:17])[CH3:16].CS(O)(=O)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:15]([N:3]1[N:2]=[N:1][C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH:10]=[O:11])=[CH:12][CH:13]=2)=[N:4]1)([CH3:17])([CH3:16])[CH3:14]
Reactant: O=Cc1ccc(-c2nnn[nH]2)cc1
Reactant: C=C(C)C
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)n1nnc(-c2ccc(C=O)cc2)n1

Procedure:
In an autoclave, 5.0 9 (28.7 mmol) of 4-(tetrazol-5-yl)-benzaldehyde (Step 35.1) in 33 ml of toluene are heated at 110° C. for 2 hours with -2.4 g of isobutene and 377 μl of methanesulfonic acid. When cold the reaction mixture is diluted with 50 ml of ethyl acetate, washed twice with sat. NaHCO3 solution, once with water and brine, dried (Na2SO4) and concentrated by evaporation. Crystallization from ethanol yields 4-(2-tert-butyl-tetrazol-5-yl)-benzaldehyde; 1H-NMR (DMSO-d6) 10.11 (s, HCO), 8.31 (d, J=8, 2H), 8.11 (d, J=8, 2H), 1.78 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5](=[NH:8])[NH:6][OH:7].[C:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=O)=[CH:20][CH:19]=1)#[N:17].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:8]=[C:22]([C:21]3[CH:25]=[CH:26][C:18]([C:16]#[N:17])=[CH:19][CH:20]=3)[O:7][N:6]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)Oc1ccc(C(=N)NO)cc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(C#N)cc3)n2)cc1Cl
Temperature: 110 °C
Yield: 84.7 %

Procedure:
3-Chloro-N-hydroxy-4-isopropoxybenzimidamide (10 g, 43.7 mmol) was dissolved in DMF (219 ml) under nitrogen. The mixture was heated at about 110° C. for about 10 min. A solution of 4-cyanobenzoyl chloride (7.24 g, 43.7 mmol) dissolved in DMF (30 mL) was added dropwise over about 20 min and the reaction heated at about 110° C. for about 4 h. until LCMS shows reaction complete. The reaction was cooled in an ice bath and poured into rapidly stirred water (1000 mL). The resulting white precipitate was collected by vacuum filtration and washed with water. The precipitate was dissolved in methylene chloride and washed with 1 N HCl and then brine. The methylene chloride was dried over sodium sulfate, filtered, and evaporated. Heptane and DCM were added to the residue and the mixture heated until the DCM had boiled off after which the mixture was allowed to cool. Solids did not dissolve in hot heptane. The resulting solid was collected by vacuum filtration and washed with heptane to provide 4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzonitrile (12.568 g, 37.0 mmol, 85% yield) as a tan solid: LCMS (Table 1, Method a) Rt=4.58 min.; MS m/z: 340.20 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]2[C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][CH:25]=[CH:24]3)=[CH:6][CH:5]=1.[CH3:30]I>C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]2[C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([CH3:30])[CH:25]=[CH:24]3)=[CH:6][CH:5]=1
Reactant: O=c1c2ccccc2nc(-c2ccc3[nH]ccc3c2)n1-c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccc2cc(-c3nc4ccccc4c(=O)n3-c3ccc(Cl)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
NaH (60% in oil) (0.006 g, 0.14 mmol) was added to a 0° C. solution of 3-(4-chlorophenyl)-2-(1H-indol-5-yl)quinazolin-4(3H)-one (0.14 mmol) in THF (5 mL). After stirring for 15 min, MeI (0.01 mL, 0.16 mmol) was added, and the reaction was warmed to room temperature for 1 hour. After quenching with H2O, diluting with EtOAc, washing with brine, drying with Na2SO4, and filtering, the mixture was concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 10% to 70% EtOAc in heptane, afforded the title compound as a white solid (65%). 1H-NMR (300 MHz, DMSO-d6): δ8.18 (d, J=6.8 Hz, 1H), 7.87-7.90 (m, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.66 (s, 1H), 7.57-7.59 (m, 1H), 7.21-7.47 (m, 6H), 7.12 (d, J=7.0 Hz, 1H), 6.4 (d, J=2.9 Hz, 1H), 3.74 (s, 3H). MS (APCI) m/z: 386 (M+H)+.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[OH:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:11]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25]>CO.C1(C)C=CC=CC=1>[OH:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([O:18][CH3:1])=[O:17])[CH:13]=[CH:12][C:11]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1CO
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(-c2ccccc2C)c(CO)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.7 %

Procedure:
(Trimethylsilyl)diazomethane (21 mL, 12.4 mmol) was added dropwise into a solution of 2-(hydroxymethyl)-2′-methylbiphenyl-4-carboxylic acid (2.0 g, 8.3 mmol) in MeOH (20 mL) and toluene (20 mL) at 0° C. After 10 minutes at 0° C., the resulting mixture was stirred at RT for 2 hours. The reaction mixture was concentrated under vacuum to give the title compound (2.1 g, quantitative), used without further purification in the next step. HPLC (Method A) Rt 3.95 min (purity 95.5%). 1H NMR (CDCl3, 300 MHz) δ 8.23 (d, J=1.3 Hz, 1H), 7.98 (dd, J=7.8, 1.9 Hz, 1H), 7.28-7.18 (m, 4H), 7.08 (d, J=7.3 Hz, 1H), 4.42 (d, J=5.7 Hz, 2H), 3.92 (s, 3H), 2.01 (s, 3H), 1.61 (t, J=5.7 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[N:15]=[C:14]([C:23](O)=[O:24])[CH:13]=2)[CH:5]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:7]=1.[S:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[N:15]=[C:14]([C:23]([N:28]3[CH2:29][CH2:30][S:26][CH2:27]3)=[O:24])[CH:13]=2)[CH:5]=[C:6]([O:8][CH:9]([F:10])[F:11])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(Cl)cc(OC(F)F)c2)n(-c2cccnc2)n1
Reactant: C1CSCN1
Product: O=C(c1cc(-c2cc(Cl)cc(OC(F)F)c2)n(-c2cccnc2)n1)N1CCSC1

Procedure:
95 mg (0.26 mmol) of the compound of Example 54A is reacted analogously to the synthesis of the compound of Example 3 with 25 mg (0.28 mmol) of thiazolidine for 30 minutes at room temperature. 65 mg (57% of theory) of the title compound is obtained.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].Cl.O.C(Cl)(Cl)Cl.[CH3:15][CH2:16][C@@H:17]([C:19](O)=[O:20])[CH3:18]>[Cl-].[Zn+2].[Cl-]>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:19](=[O:20])[CH:17]([CH3:18])[CH2:16][CH3:15]
Reactant: CC[C@H](C)C(=O)O
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC(C)C(=O)c1ccc(O)cc1O
Temperature: 110 °C
Yield: 31.7 %

Procedure:
16.3 g of anhydrous zinc chloride was dissolved in 10.3 g of S-(+)-2-methylbutanoic acid by heating to 110° C. 13.2 g of resorcinol was added to the mixture and then the temperature of the admixture was raised to 150° C. over a period of 30 minutes under stirring. The reaction mixture was then cooled to the room temperature, and a mixture composed of 25 ml of hydrochloric acid and 25 ml of water was added thereto. The reaction mixture was then subjected to extraction for three times, each by using 50 ml of ethyl ether. The extracts were joined together and rinsed with an aquesous solution of NaHCO3 for three times, and then rinsed with water for three times. Anhydrous Na2SO4 was added to the rinsed extract to dry the ethyl ether extract. Ethyl ether was removed to obtain a liquid reaction product which was refined through silica gel column chromatography while using chloroform as the eluent. As a result, 6.2 g of 3-hydroxy-4 -(1-oxo-2-methylbutyl)phenol was obtained.
Reaction SMILES: C(N[C@H](C(O)=O)CC(C)C)(=O)C.[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([C@H:24]([NH2:30])[CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH3:14].C([NH:34][C:35]1[CH:45]=[CH:44][CH:43]=[C:37]2[C:38]([O:40][C:41](=O)[C:36]=12)=[O:39])(=O)C>C(O)(=O)C>[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:24]([N:30]2[C:41](=[O:40])[C:36]3[C:37](=[CH:43][CH:44]=[CH:45][C:35]=3[NH2:34])[C:38]2=[O:39])[CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH3:14]
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Reactant: CCOc1cc([C@H](N)CS(C)(=O)=O)ccc1OC
Agent: CC(=O)N[C@@H](CC(C)C)C(=O)O
Solvent: CC(=O)O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Yield: 82.8 %

Procedure:
A 500 mL 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser. The reaction vessel was charged with (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-yl amine N-acetyl-L-leucine salt (25 g, 56 mmol, 98% ee), 3-acetamidophthalic anhydride (12.1 g 58.8 mmol), and glacial acetic acid (250 mL). The mixture was refluxed over night and then cooled to <50° C. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The resulting solution was washed with water (250 mL×2), saturated aqeous NaHCO3 (250 mL×2), brine (250 mL×2), and dried over sodium sulphate. The solvent was evaporated in vacuo, and the residue recrystallized from a binary solvent containing ethanol (150 mL) and acetone (75 mL). The solid was isolated by vacuum filtration and washed with ethanol (100 mL×2). The product was dried in vacuo at 60° C. to a constant weight, affording 19.4 g (75% yield) of S-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-aminoisoindoline-1,3-dione with 98% ee. Chiral HPLC (15/85 EtOH/20 mM KH2PO4@pH 3.5, Ultron Chiral ES-OVS from Agilent Technology, 150 mm×4.6 mm, 0.4 mL/min., @240 nm): 25.4 min (S-isomer, 98.7%), 29.5 min (R-isomer, 1.2%). 1H-NMR (CDCl3) δ:1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68-3.75 (dd, 1H), 3.85 (s, 3H), 4.07-4.15 (q, 2H), 4.51-4.61 (dd, 1H), 5.84-5.90 (dd, 1H), 6.82-8.77 (m, 6H), 9.46 (s, 1H). 13C-NMR (DMSO-d6) δ: 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74, 167.46, 169.14, 169.48.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[OH-].[K+].[CH:13]1([CH2:16]Br)[CH2:15][CH2:14]1>C(O)C>[CH:13]1([CH2:16][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([NH2:10])=[O:9])[CH2:15][CH2:14]1
Reactant: NC(=O)c1ccccc1O
Reactant: BrCC1CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1ccccc1OCC1CC1

Procedure:
Salicylamide (15.22 g), potassium hydroxide (85%, 7.73 g) and cyclopropylmethyl bromide (16.024 g) were heated together under reflux in absolute ethanol (100 ml) for 91/2 hours. The cooled mixture was filtered to remove inorganic products and the filtrate was evaporated to an oil. The oil was dissolved in 1:1 toluene:ethyl acetate (200 ml) and the solution was washed with 10% potassium hydroxide solution (2×30 ml), water (50 ml) and saturated brine (50 ), dried (Na2SO4), and concentrated under reduced pressure, leaving 2-(cyclopropylmethoxy)benzamide as an oil which crystallised (17.606 g, 83%), mp 95°-100° C.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([OH:15])=[O:14])=[O:8])(=[O:3])[CH3:2].[CH2:27](O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([S:4][CH2:5][CH:6]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([O:15][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:14])=[O:8])(=[O:3])[CH3:2]
Reactant: OCc1ccccc1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cc(C(=O)O)ccc1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cc(C(=O)OCc2ccccc2)ccc1C
Yield: 64.4 %

Procedure:
3-[(2-Acetylthiomethyl-3-phenylpropionyl)amino]-4-methylbenzoic acid (compound of Example 21) (0.5 g), 4-dimethylaminopyridine (0.05 g), benzyl alcohol (0.17 g) and dichloromethane (20 ml) are mixed, and to the mixture is added EDC.HCl (0.27 g) with stirring under ice cooling, and the mixture is stirred at room temperature overnight. Dichloromethane is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate, and the mixture is washed with 5% aqueous sodium hydrogen carbonate solution, 10% hydrochloric acid and saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate, and then ethyl acetate is distilled off under reduced pressure. The residue is dissolved in acetonitrile and purified by a medium pressure column chromatography with CHP-20P (eluent, water-acetonitrile). The fractions containing the desired compound are collected and the water and acetonitrile are distilled off under reduced pressure to give the title compound (0.40 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:8]=1.[B:22](OC)([O:25]C)[O:23]C.Cl>C1COCC1>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([B:22]([OH:25])[OH:23])=[CH:8][CH:9]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: COB(OC)OC
Reactant: CCCCCCCCOc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(B(O)O)cc1
Temperature: 25 °C

Procedure:
n-Butyllithium (23 ml, 2.5M in hexane, 0.058 mol) was added dropwise to a stirred, cooled (-78° C.) solution of compound 26 (15.00 g, 0.053 mol) in dry THF (168 ml) under dry nitrogen. The reaction mixture was maintained under these conditions for 2.5 h and then a solution of trimethyl borate (10.98 g, 0.106 mol) in dry THF (50 ml) was added dropwise at -78° C. The reaction mixture was allowed to warm to room temperature overnight and then stirred for 1 h with 10% hydrochloric acid (120 ml). The product was extracted into ether (twice), and the combined ethereal extracts were washed with water and dried (MgSO4). The solvent was removed in vacuo to yield an off white solid.
Reaction SMILES: I[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:3]=1.[CH2:13]([OH:16])[C:14]#[CH:15]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:3]=[C:2]([C:15]#[C:14][CH2:13][OH:16])[O:6][N:5]=1
Reactant: C#CCO
Reactant: Ic1cc(-c2ccccn2)no1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: OCC#Cc1cc(-c2ccccn2)no1
Temperature: 65 °C
Yield: 22 %

Procedure:
A solution of 2-(5-iodo-3-isoxazolyl)pyridine (prepared as described in WO0232919, 1.38 g, 5 mmol) and dichlorobis(triphenylphosphine)palladium(II) (35 mg, 0.05 mmol) in 8 mL triethylamine was degassed with nitrogen. Propargyl alcohol (560 mg, 10 mmol) was added and the mixture was heated at 65° C. for 16 h. The reaction mixture was cooled to room temperature, concentrated to remove the solvent. The residue was diluted with ethyl acetate (100 mL), washed with saturated NaHCO3, water and brine. The organic layer was dried and concentrated. Purification by chromatography (SiO2, 1:1 hexane/ethyl acetate) yielded 220 mg (22%) of the title compound. MS 201 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:14])[CH2:12][CH2:11][C:10]2=[O:15])=[C:4]([CH3:16])[CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:16])[C:5]([C:9]2[C:13](=[O:14])[CH2:12][CH2:11][C:10]=2[O:15][CH3:17])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)cc(C)c1C1C(=O)CCC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC1=C(c2c(C)cc(Br)cc2C)C(=O)CC1
Temperature: 27.5 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(4-bromo-2,6-dimethylphenyl)cyclopentane-1,3-dione (40 g, 0.143 mol) in acetone (2000 ml) is added anhydrous potassium carbonate (98.5 g, 0.714 mol) and iodomethane (45 ml, 0.72 mol). The resulting mixture is stirred at 25-30°C. for 16 hours, then volatile solvents are removed in vacuo, and the residue is diluted with distilled water (200 ml) and extracted with ethyl acetate (3×500 ml). Organic fractions are combined, washed with distilled water, brine, then dried over sodium sulphate, filtered and the filtrate concentrated in vacuo. The crude product is purified by flash column chromatography to afford 2-(4-bromo-2,6-dimethylphenyl)-3-methoxycyclopent-2-enone.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16](=O)[CH2:17][CH2:18][C:19]2[S:20][C:21]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:22]=3[C:23]=2[CH2:24][CH2:25][CH3:26])=[CH:4][C:5]([CH3:15])=[C:6]([CH:14]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl.[NH2:37][OH:38].C([O-])(=O)C.[Na+]>CCO.O>[OH:1][C:2]1[C:3]([C:16](=[N:37][OH:38])[CH2:17][CH2:18][C:19]2[S:20][C:21]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:22]=3[C:23]=2[CH2:24][CH2:25][CH3:26])=[CH:4][C:5]([CH3:15])=[C:6]([CH:14]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: NO
Reactant: CCCc1c(CCC(=O)c2cc(C)c(OCC(=O)OCC)cc2O)sc2cc(C(F)(F)F)ccc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCc1c(CCC(=NO)c2cc(C)c(OCC(=O)OCC)cc2O)sc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Yield: 37.6 %

Procedure:
To a solution of Ethyl 5-hydroxy-2-methyl-4-[3-[3-propyl-6-(trifluoromethyl)benzothiophen-2-yl]propionyl]-phenoxyacetate (obtained in Example 22-(4), 19 mg, 0.0381 mmol) in EtOH (0.4 mL) was added hydroxylamine hydrochloride (2.9 mg, 0.0419 mmol) and sodium acetate (3.8 mg, 0.0457 mmol) in water (0.3 mL). The mixture was heated for 10 hours under reflux and cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was recrystallized from chloroform-hexane, to give the titled compound as a white crystal (7.5 mg, yield 38%).
Reaction SMILES: N1C=C[CH:3]=N1.[N:6]1([CH:11](C)[CH2:12][NH:13][C:14]([C:16]2[C:20]([Br:21])=[C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[NH:18][N:17]=2)=[O:15])[CH2:10][CH2:9]C[CH2:7]1>>[CH2:10]([N:6]([CH3:7])[CH2:11][C@H:12]([NH:13][C:14]([C:16]1[C:20]([Br:21])=[C:19]([NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[NH:18][N:17]=1)=[O:15])[CH3:3])[CH3:9]
Reactant: CC(CNC(=O)c1n[nH]c(NC(=O)c2ccccc2Cl)c1Br)N1CCCC1
Reactant: c1cn[nH]c1
Product: CCN(C)C[C@@H](C)NC(=O)c1n[nH]c(NC(=O)c2ccccc2Cl)c1Br

Procedure:
The pyrazole acid, prepared as described in Procedure 8, was coupled with (R)—N-ethyl-N-methyl-1,2-propanediamine (prepared as shown in Procedure 2) using the method of Procedure 3.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][C:24]([OH:27])([CH3:26])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[OH:27][C:24]1([CH3:26])[CH2:25][N:22]([C:3]2[C:2]([C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: OB(O)c1cccnc1
Product: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cccnc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 128 using 5-bromo-6-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 128.1) and pyridin-3-ylboronic acid. HPLC (Condition 4) tR=4.45 min, UPLC-MS (Condition 3) tR=0.95 min, m/z=445.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 3H) 3.46-3.61 (m, 4H) 5.43 (s, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.44-7.54 (m, 1H) 7.74-7.90 (m, 3H) 8.02 (d, J=1.95 Hz, 1H) 8.58 (dd, J=4.69, 1.56 Hz, 1H) 8.64 (d, J=2.35 Hz, 1H) 8.75 (d, J=2.35 Hz, 1H) 10.19 (s, 1H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].Cl[C:18]1[N:23]=[C:22]([C:24]2[C:32]3[C:27](=[CH:28][N:29]=[C:30]([C:33]4[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=4)[CH:31]=3)[N:26]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][O:40]3)[N:25]=2)[CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH3:38][N:36]1[CH:37]=[C:33]([C:30]2[CH:31]=[C:32]3[C:24]([C:22]4[N:23]=[C:18]([O:1][C@@H:2]5[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]5)[CH:19]=[CH:20][CH:21]=4)=[N:25][N:26]([CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][O:40]4)[C:27]3=[CH:28][N:29]=2)[CH:34]=[N:35]1
Reactant: Cn1cc(-c2cc3c(-c4cccc(Cl)n4)nn(C4CCCCO4)c3cn2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc3c(-c4cccc(O[C@@H]5CCCN(C(=O)OC(C)(C)C)C5)n4)nn(C4CCCCO4)c3cn2)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 28.2 %

Procedure:
To (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (61.2 mg, 0.30 mmol) in anhydrous DMF (3 mL) was added sodium hydride (40.5 mg, 1.01 mmol, 60% in mineral oil), and the reaction mixture was stirred at 60° C. under N2 for 1 h. A solution of 3-(6-chloropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (40.0 mg, 0.10 mmol) in anhydrous DMF (˜1.0 mL) was then added, and the reaction mixture was stirred at 90° C. under N2 for 16 h. The reaction mixture was quenched with aqueous saturated NH4Cl solution and was extracted with ethyl acetate (3×). The combined organic layers were dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified using flash chromatography (Si-PPC gradient elution, solvent: 0-60% MeOH/EA) to give (3R)-tert-butyl 3-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yloxy)piperidine-1-carboxylate as a foam (15.8 mg, 27.9%). LC/MS: m/z 560.4 [M+1].
Reaction SMILES: N1C2C(=CC=CC=2)C(=O)C1=O.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2=[O:23].BrCCC1CC1.Br[CH2:31][C:32]1[O:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=1>>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:31][C:32]1[O:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=1)[C:17](=[O:22])[C:16]2=[O:23]
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: O=C1Nc2ccc(F)cc2C1=O
Agent: BrCCC1CC1
Agent: O=C1Nc2ccccc2C1=O
Product: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccc(F)cc21

Procedure:
Following the procedure as described in PREPARATION 2A, and making non-critical variations to replace isatin with 5-fluoroisatin, and (2-bromoethyl)cyclopropane with 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (59%) as a red solid: 1H NMR (300 MHz, DMSO-d6) δ 7.54-7.50 (m, 1H), 7.47-7.44 (m, 1H), 7.20 (dd, 1H), 7.14-7.13 (m, 1H), 6.75 (d, 1H), 4.99 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ 182.4 (d), 160.7, 158.5 (d), 157.5, 153.0 (d), 146.5 (d), 139.9 (q), 124.3, 119.3 (d), 114.5 (d), 112.7 (d), 112.0 (d), 110.5, 36.8.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH:14]=[CH:15][CH:16]([OH:21])[CH2:17][C:18](=[O:20])[CH3:19].N1C=CC=CC=1>CCOCC>[Br:1][CH2:2][C:3]([O:21][CH:16]([CH:15]=[CH:14][C:8]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=1[Cl:6])[CH2:17][C:18](=[O:20])[CH3:19])=[O:4]
Reactant: O=C(Br)CBr
Reactant: CC(=O)CC(O)C=Cc1ccc(Cl)cc1Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)CC(C=Cc1ccc(Cl)cc1Cl)OC(=O)CBr
Temperature: 20 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
2-Bromoacetyl bromide (1.1 ml, 13.2 mmole) was added dropwise to a stirred solution of 6-(2,4-dichlorophenyl)-4-hydroxy-5-hexene-2-one (3.4 g, 13.1 mmole) and pyridine (1.07 ml, 13.2 mmole) in ether (100 ml) at 0° C. The ice bath was removed and the reaction mixture was stirred at 20° C. for 2 hours and then diluted with H2O (100 ml). The organic layer was separated and washed with 1 N HCl (100 ml), H2O (2×100 ml) and brine, dried over MgSO4, filtered and evaporated. The residual oil was chromatographed on a 60 mm column with 15 cm of silica gel (230-400 mesh) Elution with methylene chloride-acetone (99:1; v:v; 1.9 L) provided the title compound (2.8 g, 56%); pmr (CDCl3) δ2.2 (3H, s), 2.92 (2H, t), 3.85 (2H, s), 5.9 (H, m), 6.15 (H, m) 6.95-7.5 (4H, m).