Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[C:5]([CH3:12])=[CH:4][N+:3]=1[O-:13].C([Cl:17])(=O)C>>[Cl:17][C:6]1[C:5]([CH3:12])=[CH:4][N+:3]([O-:13])=[C:2]([CH3:1])[C:7]=1[CH3:8]
Reactant: Cc1c[n+]([O-])c(C)c(C)c1[N+](=O)[O-]
Reactant: CC(=O)Cl
Product: Cc1c[n+]([O-])c(C)c(C)c1Cl
Reaction time: 0.33 h

Procedure:
The 2,3,5-trimethyl-4-nitropyridine 1-oxide (13.4 g, 73.6 mmol) obtained in the step (11c) was added to acetyl chloride (80 ml, 1.125 mmol) at −30° C. in a nitrogen atmosphere. The mixture was stirred at −30° C. to room temperature for 4 hours and 20 minutes. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography (NH silica gel: 300 g, elution solvent: heptane, heptane/ethyl acetate=50/50, ethyl acetate, ethyl acetate/methanol=10/1) to obtain fractions containing a pure product of the title compound and fractions containing a crude product of the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([NH:10][C:11](=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([OH:22])[CH:19](C)[CH3:20])[CH:13]=1)([CH3:9])([CH3:8])[CH3:7]>ClCCl>[CH3:1][S:2]([O:22][CH:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:11](=[O:23])[NH:10][C:6]([CH3:9])([CH3:8])[CH3:7])[CH:13]=1)[CH2:19][CH3:20])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)C(O)c1cccc(C(=O)NC(C)(C)C)c1
Solvent: ClCCl
Product: CCC(OS(C)(=O)=O)c1cccc(C(=O)NC(C)(C)C)c1
Reaction time: 1.5 h

Procedure:
A solution of methanesulfonyl chloride (165 mg, 1.44 mmol) in dichloromethane (2.0 mL) was added to a stirred solution of N-tert-butyl-3-(1-hydroxy-2-methylpropyl)benzamide (300 mg, 1.20 mmol) in dichloromethane (8.0 mL). After 1.5 hours stirring, the mixture was partitioned between dichloromethane and aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum to afford the intermediate 1-(3-(tert-butylcarbamoyl)phenyl)propyl methanesulfonate.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(C(OO)=[O:23])=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[C:1]1([CH:7]=[CH:8][CH2:9][C:10]23[O:23][CH:15]2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1ccccc1
Reactant: C(=Cc1ccccc1)Cc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: C1=CC2OC2(CC=Cc2ccccc2)C=C1
Reaction time: 96 h
Yield: 71 %

Procedure:
7.8 g of o-phenylallylbenzene was added to 120 ml of chloroform solution containing perbenzoic acid prepared from 25 g of benzoyl peroxide and the mixture was allowed to stand at about 5° C for 4 days. The resulting mixture was washed with sodium hydroxide solution, Mohr's salt solution, then water, and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was distilled under reduced pressure to obtain a fraction having a boiling point of 145° to 155° C/3 mmHg, which was chromatographed on a silica gel, eluted with chloroform, and there was obtained 6.0 g (yield 71%) of o-penylallylbenzene oxide as an oily substance.
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:7][CH2:6]1)=O.[NH2:8][C:9]([NH2:11])=[S:10]>CO>[CH:5]1([C:3]2[N:8]=[C:9]([NH2:11])[S:10][CH:2]=2)[CH2:7][CH2:6]1
Reactant: NC(N)=S
Reactant: O=C(CBr)C1CC1
Solvent: CO
Product: Nc1nc(C2CC2)cs1

Procedure:
A solution of 2-Bromo-1-cyclopropyl-ethanone (CAS [69267-75-0], Indian J. Chem. Sect. B, 22(9), 841(1983) (1 g, 6.1 mmol) and thiourea (0.481 g, 6.1 mmol) in 15 ml of methanol was refluxed overnight. The solvent was evaporated off and the title compound was obtained as an off-white solid (1.38 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1I.C[O:11][C:12]([C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=1B(O)O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:14]=1[C:12](=[O:11])[NH:8]2
Reactant: COC(=O)c1cc(O)ccc1B(O)O
Reactant: Nc1nccc(Cl)c1I
Product: O=c1[nH]c2nccc(Cl)c2c2ccc(O)cc12
Yield: 17.2 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 1 using 4-chloro-3-iodopyridin-2-amine (500 mg, 1.96 mmol) and 2-methoxycarbonyl-4-hydroxy-phenylboronic acid (765 mg, 2.75 mmol) to provide 217 (83 mg, 17% yield) as a white solid. LC-MS (M+H=247, obsd.=247).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12](=[O:14])[CH3:13])=[C:7]([CH3:15])[CH:6]=1)([CH3:3])[CH3:2].[Br-:16].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:16][CH2:13][C:12]([C:8]1[C:9]([CH3:11])=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][C:7]=1[CH3:15])=[O:14]
Reactant: CC(=O)c1c(C)cc(OC(C)C)cc1C
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: Cc1cc(OC(C)C)cc(C)c1C(=O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of 1-(4-isopropoxy-2,6-dimethylphenyl)ethanone (4.3 g, 20.9 mmol) in acetonitrile (41.7 mL) was added tetrabutylammoniumtribromide (TBABr3, 11.1 g, 22.9 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(4-isopropoxy-2,6-dimethylphenyl)ethanone (5.9 g), which was used directly for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10][CH3:11])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:32](=[O:39])(=[O:38])[NH:33]C(C)(C)C)=[CH:22][C:21]=2[F:40])[C:15]([CH2:41][CH2:42][CH2:43][CH3:44])=[N:14]1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10][CH3:11])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:32](=[O:39])(=[O:38])[NH2:33])=[CH:22][C:21]=2[F:40])[C:15]([CH2:41][CH2:42][CH2:43][CH3:44])=[N:14]1
Reactant: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Br)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Br)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Yield: 88 %

Procedure:
The title compound was prepared from 2-[2-bromo-5-(propionylamino)-phenyl]-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step E) by reaction with trifluoroacetic acid in the presence of anisole according to the procedure of Example 28, Step G, giving an 88% yield of the title compound as an off-white foam; homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 630,632 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:18][C:19]1[C:27]([C:28]2[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[O:30][N:29]=2)=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:23](=[O:24])[C:22]3[CH:26]=[C:27]([C:28]4[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[O:30][N:29]=4)[C:19]([CH3:18])=[N:20][CH:21]=3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1ncc(C(=O)O)cc1-c1noc(C(F)(F)F)n1
Reactant: CC(C)(CN)c1nc(-c2ccc(Cl)cc2)cs1
Product: Cc1ncc(C(=O)NCC(C)(C)c2nc(-c3ccc(Cl)cc3)cs2)cc1-c1noc(C(F)(F)F)n1
Yield: 59 %

Procedure:
This compound was synthesized from 2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropan-1-amine and 6-methyl-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (28 mg, yield 59%). 1H NMR (400 MHz, CDCl3) δ 9.11 (br s, 1H), 8.80 (br s, 1H), 8.07 (br s, 1H), 7.79-7.77 (d, J=8.8 Hz, 2H), 7.43 (s, 1H), 7.35-7.33 (d, J=8.8 Hz, 2H), 3.86-3.84 (d, J=5.5 Hz, 2H), 3.02 (s, 3H), 1.57 (s, 6H). MS (ESI) m/z: Calculated for C23H19ClF3N5O2S: 521.09. found: 522.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16]>C(N(CC)CC)C.[Cu]I.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>[Cl:1][C:2]1[C:3]([C:19]#[C:18][Si:15]([CH3:17])([CH3:16])[CH3:14])=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1cc(Cl)c(I)cc1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)cc1O
Temperature: 65 °C
Yield: 104.5 %

Procedure:
A solution of methyl 5-chloro-2-hydroxy-4-iodobenzoate (690 g, 2.2 mol), copper (I) iodide (4.2 g, 22 mmol) in triethylamine (5.6 L) was degassed with nitrogen for 5-10 minutes, treated with bis(triphenylphosphine)palladium(II) chloride (16 g, 22 mmol) and (trimethylsilyl)acetylene (470 mL, 3.3 mol), degassed with nitrogen for 2 minutes, and heated at 65° C. The heat was removed and the reaction temperature increased from 65 to 85° C. by itself. The temperature was dropped to 75° C. after 30 minutes with stirring. The reaction was cooled to room temperature, filtered over a pad of celite and rinsed with ethyl acetate (3 L). The filtrate was concentrated and dried on a high vacuum pump for 72 hours to give the desired product (650 g, quantitative) as a yellow solid. HPLC 91.3% pure @ 220 nm. LCMS for C13H16ClO3Si (M+H)+: m/z=283.1; Found: 282.8; 1H NMR (400 MHz, DMSO-d6): δ 10.5 (br s, 1 H), 7.76 (s, 1 H), 7.13 (s, 1 H), 3.85 (s, 3 H), 0.24 (s, 9 H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([N+:22]([O-])=O)=[C:6]([C:10]3[CH:19]=[C:18]4[C:13]([CH:14]=[CH:15][C:16]([O:20][CH3:21])=[CH:17]4)=[CH:12][CH:11]=3)[CH:7]=2)[O:2]1>C(OCC)(=O)C.[Pd]>[NH2:22][C:5]1[CH:4]=[C:3]2[O:2][CH2:1][O:9][C:8]2=[CH:7][C:6]=1[C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][C:16]([O:20][CH3:21])=[CH:17]2)=[CH:12][CH:11]=1
Reactant: COc1ccc2ccc(-c3cc4c(cc3[N+](=O)[O-])OCO4)cc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc2ccc(-c3cc4c(cc3N)OCO4)cc2c1
Yield: 82.5 %

Procedure:
7-(4,5-Methylenedioxy-2-nitrophenyl)-2-methoxynaphthalene 48 (100 mg, 0.31 mmol) was hydrogenated overnight in ethyl acetate (35 mL) at 40˜45 lb./sq. in. using 10% palladium on carbon (30 mg) as catalyst. The reaction solution was passed through a Celite bed and the catalyst was washed with ethyl acetate (10 mL×3). The ethyl acetate solution was concentrated in vacuo gave the crude product. The residue was chromatographed using a 75:25 mixture of hexanes:ethyl acetate to give 49 (75 mg) in 83% yield; IR (KBr) 3426, 3366, 2364, 2339, 1629, 1503, 1487, 1467, 1233, 1215, 1187 cm−1; 1H NMR (CDCl3) δ3.64 (2H, s), 3.94 (3H, s), 5.92 (2H, s), 6.40 (1H, s), 6.76 (1H, s), 7.15-7.20 (2H, m), 7.40 (1H, dd, J1=8.3, J2=1.7), 7.75-7.85 (3H, m); 13C NMR δ55.83, 98.35, 101.27, 106.25, 110.65, 119.35, 120.29, 125.82, 127.35, 128.31, 128.72, 129.67, 135.34, 137.99, 138.99, 141.17, 148.16, 158.49; HRMS (EI) calcd for C18H15NO3 m/z: 293.1052; found: 293.1052.
Reaction SMILES: CC(C)([O-:4])C.[K+].[Br:7][C:8]1[CH:9]=[C:10]([C@@H:14]2[NH:19][C:18](=[O:20])[CH2:17][CH2:16][C@H:15]2[N+]([O-])=O)[CH:11]=[CH:12][CH:13]=1>ClCCl.CO>[Br:7][C:8]1[CH:9]=[C:10]([CH:14]2[NH:19][C:18](=[O:20])[CH2:17][CH2:16][C:15]2=[O:4])[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CC[C@@H]([N+](=O)[O-])[C@H](c2cccc(Br)c2)N1
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: O=C1CCC(=O)C(c2cccc(Br)c2)N1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
Potassium t-butoxide (38.7 g) was added to a stirred solution of the trans-6-(3-bromo-phenyl)-5nitro-piperidin-2-one (96.3 g) in dichloromethane (500 ml) and methanol (500 ml). The mixture was cooled to -70° and ozone was vigorously bubbled through the stirred solution for 7 h. The mixture was purged with nitrogen and pH6.5 phosphate buffer (500 ml) added. Sodium thiosulphate (120 g) and water (500 ml) were added and the mixture stirred as it warmed to room temperature overnight. The mixture was tested for peroxides then extracted with dichloromethane (600 ml×3). The combined organic extracts were washed with water (500 ml) then saturated brine (500 ml), dried (MgSO4) and evaporated in vacuo. Trituration with ether and hexane gave the title compound as a white solid (70.0 g).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]I)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1-4 (6.45 g, 19.0 mmol), 4-bromophenol (3.29 g, 19 mmol), and Cs2CO3 (3.10 g, 9.5 mmol) in 50 mL of DMF was stirred at room temperature for 18 hr. The solution was then diluted with 200 mL ethyl acetate and washed with H2O (4×100 mL), then dried over Na2SO4, filtered and concentrated. Flash chromatography (silica, 30% EtOAc/hexanes) gave 36-1 as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([CH3:23])[CH:15]=2)[CH:10]=[CH:9][N:8]=1)=[O:5].[H][H]>CO.CC(O)=O.[Pt]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:12]=2)=[CH:15][C:16]=1[CH3:23]
Reactant: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c(C)c2)ccn1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Solvent: CC(=O)O
Product: COCC(=O)Nc1cc(Oc2ccc(N)c(C)c2)ccn1

Procedure:
A solution of 2-methoxy-N-(4-(3-methyl-4-nitrophenoxy)pyridin-2-yl)acetamide (208 mg, 0.656 mmol) in a mixture of MeOH (10.0 mL) and AcOH (0.5 mL) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, 40° C., 55 mm 10% Pt/C Cat-Cart, full hydrogen mode) and was then evaporated in vacuo to afford the title compound, Intermediate H3, (192 mg, 97%); Rt 1.19 min (Method 2); m/z 288 (M+H)+ (ES+); which was used directly in the next step (below).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:16][CH3:17])=[O:15])=[CH:12][CH:11]=1.Cl[C:21]1[CH:30]=[CH:29][N:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][C:25]([CH2:31][CH2:32][CH3:33])=[N:26]2.C(O)C>>[CH3:17][NH:16][C:14](=[O:15])[C:13]1[CH:18]=[CH:19][C:10]([S:9][C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[NH:1][C:21]2[C:22]3[C:27](=[N:26][C:25]([CH2:31][CH2:32][CH3:33])=[CH:24][CH:23]=3)[N:28]=[CH:29][CH:30]=2)=[CH:11][CH:12]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: CNC(=O)c1ccc(Sc2ccc(C)cc2N)cc1
Solvent: CCO
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(C(=O)NC)cc3)ccnc2n1

Procedure:
The product from Example 85b (0.155 g, 0.57 mmol) was reacted with the product from Example 2g as a 3.15M solution in ethanol (0.18 mL, 0.57 mmol) for 24 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.180 g, 56%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3 H) 1.72-1.91 (m, 2 H) 2.41 (s, 3 H) 2.75 (d, J=4.41 Hz, 3 H) 2.97 (t, J=7.35 Hz, 2 H) 6.36 (d, J=6.99 Hz, 1 H) 7.20 (d, J=8.46 Hz, 2 H) 7.33-7.47 (m, 2 H) 7.50 (d, 1 H) 7.63 (d, J=8.46 Hz, 2 H) 7.77 (d, J=8.82 Hz, 1 H) 8.30-8.44 (m, J=6.62, 6.62 Hz, 2 H) 8.91 (d, J=8.82 Hz, 1 H) 10.86-11.09 (s, 1 H); MS (ESI+) m/z 443.2 (M+H)+; (ESI−) m/z 441.2 (M−H)−.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[C:11]([NH2:12])=[C:10]2[CH2:13][CH2:14][CH2:15][C:9]2=[N:8]1.N1C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C(Cl)Cl>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][C:25]=1[C:26]([NH:12][C:11]1[N:7]([CH2:6][C@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[N:8]=[C:9]2[CH2:15][CH2:14][CH2:13][C:10]=12)=[O:27]
Reactant: Nc1c2c(nn1C[C@@H]1CCCO1)CCC2
Reactant: COc1ccc(C(F)(F)F)cc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(F)(F)F)cc1C(=O)Nc1c2c(nn1C[C@H]1CCCO1)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a solution of the product of Example 32A (340 mg, 1.64 mmol) and pyridine (535 μL, 6.56 mmol) in CH2Cl2 (20 mL) was added 2-methoxy-5-(trifluoromethyl)benzoyl chloride (470 mg, 1.97 mmol) dropwise. The mixture was stirred at ambient temperature for 1 h. The mixture was concentrated under reduced pressure and was purified by column chromatography (SiO2, 40% hexanes/EtOAc) to provide the title compound 550 mg (82%). MS (DCI/NH3) m/z 410 (M+H)+.
Reaction SMILES: Cl.[OH:2][CH:3]([C:11]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15](=[O:22])[NH:16]2)[CH:4]([NH:7][CH:8]([CH3:10])[CH3:9])[CH2:5][CH3:6].[CH:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>FC(F)(F)C(O)=O>[CH:23]1([C:29]([O:2][CH:3]([C:11]2[CH:20]=[CH:19][C:18]([O:21][C:3]([CH:11]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:12]3)=[O:2])=[C:17]3[C:12]=2[CH:13]=[CH:14][C:15](=[O:22])[NH:16]3)[CH:4]([NH:7][CH:8]([CH3:10])[CH3:9])[CH2:5][CH3:6])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCC(NC(C)C)C(O)c1ccc(O)c2[nH]c(=O)ccc12
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CCC(NC(C)C)C(OC(=O)C1CCCCC1)c1ccc(OC(=O)C2CCCCC2)c2[nH]c(=O)ccc12
Temperature: 85 °C
Yield: 136.8 %

Procedure:
3.36 g of 5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxycarbostyril hydrochloride was dissolved in 20 ml of trifluoroacetic acid, and 8.8 g of cyclohexanecarboxylic acid chloride was added to the solution. The mixture was then heated at a temperature of 85° C. while refluxing. The reaction mixture was concentrated and diethyl ether was added to the residue to crystallize the product. The crystals thus obtained were separated by filtration and washed with diethyl ether. The resulting crystals were extracted successively with a saturated aqueous solution of sodium bicarbonate and chloroform, and the organic layer was washed with water, dried and concentrated to dryness. The resulting residue was crystallized from a mixture of diethyl ether and petroleum benzene to obtain 3.59 g of 5-(1-cyclohexylcarbonyloxy-2-isopropylaminobutyl)-8-cyclohexylcarbonyloxycarbostyril having a melting point of 162° to 163° C. (after recrystallization from chloroform-n-hexane).
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].CN.C[CH2:35][N:36]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:36][CH3:35])=[O:25])[CH2:19]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:30][CH:31]=1)([CH3:3])[CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC[C@@H](C(=O)O)C3)n3nccc3n2)cc1
Agent: CN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H]1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Yield: 54.4 %

Procedure:
A solution of (R)-1-(5-(4-(2-hydroxypropan-2-yl)benzamido)pyrazolo[1,5-a]pyrimidin-7-yl)piperidine-3-carboxylic acid (Compound 84, 100 mg, 0.236 mmol), methylamine (15 mg, 0.472 mmol), EDCI (90 mg, 0.472 mmol), and HOBT (16 mg, 0.118 mmol) in DMF (4.22 mL) were stirred for 12 hours at room temperature. The reaction was complete as determined by LCMS analysis. The reaction mixture was then partitioned between ethyl acetate and water and the separated organic layer was dried over Mg2SO4, filtered, and concentrated under reduced pressure. Purification by preparatory HPLC, 20-40% (MeCN/H2O gradient+0.01% TFA) provided the titled compound as a yellow solid (56 mg, 53%). 1H NMR (DMSO-d6) δ: 10.90 (s, 1H), 8.10 (d, J=2.3 Hz, 1H), 8.00 (d, J=8.6 Hz, 2H), 7.55-7.65 (m, J=8.6 Hz, 2H), 7.40 (s, 1H), 6.36 (d, J=2.3 Hz, 1H), 4.35 (br. s., 3H), 3.25 (dd, J=12.3, 10.7 Hz, 1H), 3.05 (br. s., 1H), 2.55-2.64 (m, 3H), 1.93 (br. s., 1H), 1.79-1.88 (m, 1H), 1.73 (d, J=10.9 Hz, 2H), 1.45 (s, 6H). ESI-MS: m/z 437.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][C:12]([O:14]CC)=O.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][C:23]#[N:24])=[CH:20][CH:19]=1>>[C:23]([CH2:22][C:21]1[CH:25]=[CH:26][C:18]([NH:17][C:12](=[O:14])[CH2:11][C:3]2[N:2]([CH3:1])[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[N:4]=2)=[CH:19][CH:20]=1)#[N:24]
Reactant: N#CCc1ccc(N)cc1
Reactant: CCOC(=O)Cc1nc2ccccc2n1C
Product: Cn1c(CC(=O)Nc2ccc(CC#N)cc2)nc2ccccc21
Yield: 74.9 %

Procedure:
1.14 g of ethyl 2-(1-methylbenzimidazol-2-yl)acetate and 970 mg of 4-aminobenzylcyanide were subjected to a condensation reaction to obtain 1.19 g of 4′-cyanomethyl-2-(1-methylbenzimidazol-2-yl)acetanilide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25](=O)[CH3:26])=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:25]([CH3:26])[CH2:24][CH2:23][C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CCC(C)=O)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: COc1ccc(CCC(C)Nc2c(C)noc2-c2ccc(Br)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-(4-methoxy-phenyl)-butan-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([F:8])[CH:3]=1.[Li+].CC([N-]C(C)C)C.[Cl:17][CH2:18][CH2:19][CH2:20]I>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([F:8])[C:3]=1[CH2:20][CH2:19][CH2:18][Cl:17]
Reactant: ClCCCI
Reactant: Fc1cc(Cl)ccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1nccc(Cl)c1CCCCl
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 76.9 %

Procedure:
To a cooled (−78° C.) solution of 4-chloro-2-fluoro-pyridine (2.0 g, 15 mmol) in THF (15 mL) is added LDA solution (9.1 mL, 18 mmol, 2.0 M in THF). After the mixture is allowed to stir at −78° C. for 90 min, 1-chloro-3-iodo-propane (4.9 mL, 46 mmol) is added and the mixture is allowed to slowly warm to room temperature for 16 hrs. Then reaction is quenched with saturated NH4Cl and the mixture is extracted with DCM (3×). The combined organic layers are washed with brine, dried over Na2SO4 and concentrated to give the crude product. Purification by flash column chromatography affords 2.4 g of 4-chloro-3-(3-chloro-propyl)-2-fluoro-pyridine.