Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]=[C:22]=[CH:23][CH3:24])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[C@H:3]([C:7](O)=[O:8])[CH:4]([CH3:6])[CH3:5].[OH:25][N:26]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.NO>CN(C)C=O>[OH:25][NH:26][C:7](=[O:8])[CH:3]([N:2]([CH3:1])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]=[C:22]=[CH:23][CH3:24])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH:4]([CH3:6])[CH3:5]
Reactant: CC=C=CCOc1ccc(S(=O)(=O)N(C)[C@H](C(=O)O)C(C)C)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC=C=CCOc1ccc(S(=O)(=O)N(C)C(C(=O)NO)C(C)C)cc1
Yield: 62.6 %

Procedure:
The procedure of Example 13 was followed using the product from Example 21 (185 mg, 0.52 mmol), 1-hydroxybenzotriazol (84 mg, 0.62 mmol), 1-[3-(dimethylamino)-propyl]-3-ethylcarbodimide hydrochloride (140 mg, 0.73 mmol), N-methylmorpholine (0.86 mmol, 0.78 mmol), and hydroxylamine (0.159 ml, 2.6 mmol) in dimethylformamide (5 ml) to give 120 mg (63%) of the product.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:12]=1)[CH2:2][CH2:3][CH3:4].CCN(CC)CC.[H][H]>CCO.O=[Pt]=O>[CH2:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)CCC#Cc1cccc(NCc2ccc(OC)cc2)n1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCOC(=O)CCCCc1cccc(NCc2ccc(OC)cc2)n1
Yield: 94.5 %

Procedure:
A mixture of 14-5 (6.54 g, 17.8 mmol), Et3N (1.85 mL, 13.3 mmol), and PtO2 (0.405 g, 1.78) in EtOH (150 mL) was stirred under a balloon of hydrogen for 6 h. Filtration through celite and evaporative removal of the solvent afforded 6.23 g of 14-6 as a colorless oil. The crude product was used directly in the next step without purification.
Reaction SMILES: [C:1]([C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=1[C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:12][N:11]=1)([OH:3])=[O:2].N1C=CC=[CH:23][CH:22]=1.S(Cl)(Cl)=O>C(O)C>[C:1]([C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=1[C:10]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:12][N:11]=1)([O:3][CH2:22][CH3:23])=[O:2]
Reactant: O=C(O)C1=C(c2cc(-c3ccccc3)[nH]n2)CCCC1
Reactant: c1ccncc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1=C(c2cc(-c3ccccc3)[nH]n2)CCCC1
Reaction time: 2 h

Procedure:
A mixture of 3-(2-carboxy-1-cyclohexen-1-yl)-5-phenylpyrazole (15.0 g) and pyridine (125 ml) is treated at 25° C with thionyl chloride (13.5 g); after stirring for 2 hours, ethanol (40.0 g) is added, and the mixture is stirred for 3 hours. The reaction mixture is partitioned between water and methylene chloride; the organic layer is washed with water and evaporated to give 3-(2-carboethoxy-1-cyclohexen-1yl)-5-phenylpyrazole.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][C:12]1=[O:19])[CH2:8]2.I[CH3:21]>>[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH:16]3[CH2:17][CH2:18]3)[N:13]([CH3:21])[C:12]1=[O:19])[CH2:10]2
Reactant: O=c1[nH]c(C2CC2)cn1C1C2CC3CC(C2)CC1C3
Reactant: CI
Product: Cn1c(C2CC2)cn(C2C3CC4CC(C3)CC2C4)c1=O

Procedure:
This material was obtained in analogy to the procedure outlined in example 23 from 1-adamantan-2-yl-4-cyclopropyl-1,3-dihydro-imidazol-2-one (obtained in example 15, 100 mg) by alkylation with iodomethane (82 mg). 1-Adamantan-2-yl-4-cyclopropyl-3-methyl-1,3-dihydro-imidazol-2-one was obtained as a light yellow oil (52 mg). MS (EI): 272.3 (M+).
Reaction SMILES: CO[C:3](=[O:9])[CH:4]=[C:5]([NH2:8])OC.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:14][NH:15][NH2:16]>O1CCOCC1>[NH2:8][C:5]1[NH:16][N:15]([CH2:14][C:13]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:11]([Cl:10])[CH:12]=2)[C:3](=[O:9])[CH:4]=1
Reactant: COC(=O)C=C(N)OC
Reactant: NNCc1ccc(Cl)c(Cl)c1
Solvent: C1COCCO1
Product: Nc1cc(=O)n(Cc2ccc(Cl)c(Cl)c2)[nH]1
Reaction time: 2 h

Procedure:
144 g (10% excess) of β-amino-β-methoxyacrylic acid methyl ester are introduced into 500 ml of dioxane. 191 g of 3,4-dichlorobenzylhydrazine are introduced into the reaction mixture while flushing with nitrogen. The mixture is stirred for 2 hours at 60°, the solvent is driven off on a rotary evaporator, the residue is worked with 600 ml of 2 N NaOH and extracted with ether, and the aqueous phase is stirred with animal charcoal for one-half hour. After filtration, the mixture is adjusted to pH 5 with dilute acetic acid. The product which initially is obtained as an oil becomes crystalline on rubbing and is finally purified by recrystallising it again from alcohol. 139 g, corresponding to about 54% of theory, of the compound identified above, as felted colorless needles of melting point 159° are obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([Cl:30])[N:18]=[C:17](Cl)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.O.Cl>CS(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([Cl:30])[N:18]=[C:17]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[N:16]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: C1COCCN1
Reactant: COc1ccccc1Oc1c(Cl)nc(Cl)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1Oc1c(Cl)nc(N2CCOCC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Yield: 45 %

Procedure:
4-t-Butyl-N-[2,6-dichloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide (5) (482 mg; 1.0 mmol) was dissolved in dimethyl sulfoxide (5 ml). Morpholine (175 mg; 2.0 mmol) was added to the solution, and the resultant mixture was stirred overnight at 100° C. After being cooled, the reaction mixture was poured into water, made acidic with hydrochloric acid, and extracted with ethyl acetate, being washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2), to thereby obtain 240 mg (yield: 45%) of the title compound as a white powder.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]([F:22])([F:21])[O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:18][C:17]1[CH:19]=[CH:20][C:14]([O:13][C:12]([F:11])([F:21])[F:22])=[CH:15][CH:16]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: FC(F)(F)Oc1ccc(Nc2nc3ccccc3[nH]2)cc1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 4-(trifluoromethoxy)aniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (white solid, mp 250-251° C.). MS(ES+) m/z 294 ([M+1]+, 100).
Reaction SMILES: C(O)C.[OH-].[Na+].C([N:8]([C:21]1[CH:26]=[C:25]([Cl:27])[C:24]([Cl:28])=[CH:23][C:22]=1[Cl:29])[CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:10]([OH:12])=[O:11])C>O>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:9]([C:10]([OH:12])=[O:11])[NH:8][C:21]1[CH:26]=[C:25]([Cl:27])[C:24]([Cl:28])=[CH:23][C:22]=1[Cl:29]
Reactant: CCN(c1cc(Cl)c(Cl)cc1Cl)C(C(=O)O)c1ccccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccccc1C(Nc1cc(Cl)c(Cl)cc1Cl)C(=O)O
Reaction time: 4 h

Procedure:
To a stirred and refluxed solution of 40 parts of ethanol, 25 parts of water and 2 parts of sodium hydroxide are added 5 parts of ethyl 2-(o-methoxyphenyl)-N-(2,4,5-trichlorophenyl)glycine and stirring at reflux temperature is continued for 4 hours. The reaction mixture is evaporated. The residue is dissolved in 250 parts of water. The solution is shaken with 80 parts of ether and the aqueous phase is acidified with concentrated hydrochloric acid solution. The product is extracted twice with 80 parts of ether. The combined extracts are dried and evaporated. The solid residue is crystallized from 50 parts of glacial acetic acid at room temperature, yielding 3.2 parts of 2-(o-methoxyphenyl)-N-(2,4,5-trichlorophenyl)glycine; mp. 188.3° C.
Reaction SMILES: C(O[C:5]1([CH3:14])[CH:9]=[CH:8][C:7](=[O:10])[CH:6]1[CH2:11][C:12]#[CH:13])(=O)C.S(=O)(=O)(O)[OH:16]>>[OH:16][CH:9]1[CH2:8][C:7](=[O:10])[C:6]([CH2:11][C:12]#[CH:13])=[C:5]1[CH3:14]
Reactant: C#CCC1C(=O)C=CC1(C)OC(C)=O
Reactant: O=S(=O)(O)O
Product: C#CCC1=C(C)C(O)CC1=O
Reaction time: 1 h

Procedure:
In the same flask as in Example 1, 20% sulfuric acid (10 ml) was charged, and dl-3-acetoxy-2-propargyl-3-methyl-4-cyclopentenone (1.92 g) was dropwise added thereto in 1 hour while keeping the inner temperature at 0° C. After completion of the dropwise addition, the resultant mixture was stirred at the same temperature as above for 3 hours. The reaction mixture was subjected to post-treatment and purification as in Example 1 to give 1.38 g of 4-hydroxy-2-propargyl-3-methyl-2-cyclopentenone. Yield, 91%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][C:13](=O)[CH3:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:16]([NH2:18])=[O:17]>C(O)=O>[CH:16]([NH:18][CH:13]([CH3:14])[CH2:12][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:11][CH2:10][CH2:9]1)=[O:17]
Reactant: CC(=O)CC1(c2ccc(Cl)cc2)CCC1
Reactant: NC=O
Solvent: O=CO
Product: CC(CC1(c2ccc(Cl)cc2)CCC1)NC=O
Temperature: 175 °C

Procedure:
1-[1-(4-chlorophenyl)cyclobutyl]propan-2-one prepared as described in Example 3 (25 g) and 98% formic acid (10 ml) were added to formamide (22 ml) at 160° C. The temperature was raised to 175° C. and maintained at this temperature for sixteen hours. The mixture was cooled, extracted with dichloromethane. The extract was washed with water and evaporated to give a gum which was crystallised from petroleum ether (b.p. 40°-60° C.) to give N-formyl-2-[1-(4-chlorophenyl)cyclobutyl]-1-methylethylamine (m.p. 71°-73° C.).
Reaction SMILES: [CH:1]([S:4]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)=[O:5])([CH3:3])[CH3:2].[CH2:11]([N:14]([CH2:18][CH2:19][CH3:20])[C:15](Cl)=[O:16])[CH2:12][CH3:13].O1CCCC1>C(N(CC)CC)C>[CH2:11]([N:14]([CH2:18][CH2:19][CH3:20])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:4]([CH:1]([CH3:3])[CH3:2])=[O:5])=[N:7]1)=[O:16])[CH2:12][CH3:13]
Reactant: CCCN(CCC)C(=O)Cl
Reactant: CC(C)S(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)n1cnc(S(=O)C(C)C)n1

Procedure:
A mixture of 6.4 g. 3-isopropylsulphinyl-1,2,4-triazole, 8.0 ml. dipropylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 10 ml. dry triethylamine was refluxed under anhydrous conditions for 2 hours. The cooled reaction mixture was filtered and the filtrate distilled under reduced pressure to give 1-dipropylcarbamoyl-3-isopropylsulphinyl-1,2,4-triazole as an oily residue which subsequently solidified, m.p. 15° - 20° C. Elemental analysis satisfactory.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH3:20]>>[CH2:19]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:23][CH2:22]1)[CH3:20]
Reactant: Clc1ccccc1OCCOc1nccnc1Cl
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2nccnc2OCCOc2ccccc2Cl)CC1

Procedure:
The title compound was prepared in an analogous manner to Example 4, Step 2, starting from 2-chloro-3-[2-(2-chlorophenoxy)ethoxy]pyrazine*(150 mg, 0.53 mmol) and N-ethylpiperazine (221 mg, 1.93 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 100 mg (52%) of the title product. Anal. (C18H24Cl4O2) C, H, N.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]2[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=2)[CH2:32][CH2:31]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([C:7]([NH:9][CH2:10][C:11]3[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])=[O:8])[CH:20]=[C:2]([C:40]3[CH:39]=[CH:38][C:37]([CH2:36][N:33]4[CH2:34][CH2:35][O:30][CH2:31][CH2:32]4)=[CH:42][CH:41]=3)[CH:3]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Reactant: OB(O)c1ccc(CN2CCOCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 29 %

Procedure:
To a stirred solution of 5-bromo-3-(cyclohexyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.) and (4-(morpholinomethyl)phenyl)boronic acid (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and the solution was purged with argon for 15 min. Then Pd (PPh3)4 (0.1 equiv.) was added and solution was purged again for 10 min. Reaction mixture was heated at 100° C. for 4 h. On completion, the mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the title compound (0.070 g, 29% yield). LCMS: 557.40 (M+1)+; HPLC % 98.83 (@254 nm) (Rt; 4.303; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.15 (t, 1H, J=4 Hz), 7.56 (d, 2H, J=7.6 Hz), 7.36 (d, 2H, J=8 Hz), 7.28 (s, 1H), 7.13 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.4 Hz), 3.57 (m, 4H), 3.48 (s, 2H), 2.74 (t, 1H), 2.64 (s, 3H), 2.36 (m, 4H), 2.20 (s, 6H), 2.10 (s, 3H), 1.69-1.71 (m, 3H), 1.53-1.56 (m, 2H), 1.41-1.44 (m, 2H), 1.10-1.23 (m, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]([N+:12]([O-])=O)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.[ClH:15]>O>[ClH:15].[NH2:12][C:11]1[C:3]([S:2][CH3:1])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12
Reactant: CSc1nn2ccccc2c1[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: CSc1nn2ccccc2c1N
Reaction time: 1 h

Procedure:
4 g. 2-Methylthio-3-nitropyrazolo[1,5-a]pyridine (see Heterocycles, 6, 379/1977; Chem. Pharm. Bull., 25 1528/1977) are dissolved in 200 ml. concentrated hydrochloric acid and mixed with 20 g. stannous chloride dihydrate. After 1 hour, there are again added 15 g. stannous chloride dihydrate, 15 ml. concentrated hydrochloric acid and 200 ml. water. After a further reaction period of 1 hour, the reaction mixture is poured on to ice, the yellow solution is rendered alkaline and extracted with ethyl acetate. The organic phase is dried and evaporated, the residue is dissolved in a little ethanol and mixed with ethereal hydrochloric acid in order to form the hydrochloride. There are obtained 3.9 g. (95% of theory) of the title compound; m.p. 226° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C@H:23]3[CH2:28][CH2:27][C@H:26]([CH2:29][C:30](O)=[O:31])[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[O:15])=[N:11][N:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:66]1[CH2:75][CH2:74][CH:69]([C:70]([O:72][CH3:73])=[O:71])[CH2:68][CH2:67]1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C@H:23]3[CH2:28][CH2:27][C@H:26]([CH2:29][C:30]([N:66]4[CH2:75][CH2:74][CH:69]([C:70]([O:72][CH3:73])=[O:71])[CH2:68][CH2:67]4)=[O:31])[CH2:25][CH2:24]3)=[CH:21][CH:22]=2)=[O:15])=[N:11][N:10]=1
Reactant: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4ccccc4F)o3)cc2)CC1
Reactant: COC(=O)C1CCNCC1
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: COC(=O)C1CCN(C(=O)C[C@H]2CC[C@H](c3ccc(NC(=O)c4nnc(Nc5ccccc5F)o4)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (trans-4-{4-[({5-[(2-fluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]phenyl}cyclohexyl)acetic acid (Example 112, 300 mg, 0.68 mmol) in DMF (3 mL) was added HATU (286 mg, 0.75 mmol), diisopropylethylamine (0.14 mL, 0.75 mmol) followed by methyl isonipecotate (0.15 mL, 0.75 mmol). The reaction mixture was allowed to stir at ambient temperature overnight. The DMF was evaporated and the residue re-dissolved in DMSO/MeCN/H2O (7:2:1); a suspension formed which was filtered, washed with ether (2×10 mL) and dried to leave the title compound (137 mg). The filtrate was purified on an acidic reverse phase HPLC system eluting 5-95% MeCN 0.2% TFA, isolated 112 mg of the title compound (249 mg, 65%) as a solid; 1H NMR δ 1.07-1.16 (m, 2H), 1.36-1.53 (m, 4H), 1.75-1.88 (m, 7H), 2.24 (d, 2H), 2.41-2.47 (m, 1H), 2.59-2.65 (m, 2H), 3.11 (t, 1H), 3.62 (s, 3H), 3.85 (d, 1H), 4.26 (d, 1H), 7.14-7.34 (m, 5H), 7.68 (d, 2H), 8.04 (t, 1H), 10.75 (s, 1H), 10.93 (s, 1H); MS m/e MH+ 564.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[N:41][CH:40]=[CH:39][N:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[N:41][CH:40]=[CH:39][N:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Brc1cnccn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cnccn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromopyrazine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.249, m/z=374; 1H NMR (CDCl3) 1.12 (s, 3H), 1.28 (s, 3H), 1.58 (m, 3H), 2.19-2.20 (m, 4H), 2.39 (m, 1H), 2.89 (m, 1H), 5.74 (m, 1H), 7.09 (m, 2H), 7.28-7.40 (m, 5H), 7.78 (m, 2H), 8.48 (m, 1H), 8.59 (m, 1H), 8.94 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.Br[C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:9]=2)[CH:7]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: COc1ccc(Cl)cc1-c1n[nH]cc1NC(=O)c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)n1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC)n1
Temperature: 50 °C
Reaction time: 5 h
Yield: 86.7 %

Procedure:
A suspension of N-(3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (1.0 g, 2.7 mmol, 1 equiv), ethyl 2-bromoisobutyrate (0.597 mL, 4.07 mmol, 1.50 equiv), and cesium carbonate (1.77 g, 5.42 mmol, 2.00 equiv) in N,N-dimethylformamide (15 mL) was heated at 50° C. After 5 h, the reaction mixture was concentrated in vacuo, and the resulting residue was partitioned between saturate aqueous sodium chloride solution (30 mL) and ethyl acetate (20 mL). The aqueous was extracted with ethyl acetate (2×20 mL). The combined organic was dried over anhydrous sodium sulfate, filtered, and concentrated to provide crude product (1.13 g, 84% yield). LCMS (ESI): M+H=483.2.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[N:12][NH:13][N:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].O[CH2:16][C:17]([CH3:23])([CH3:22])[C:18]([O:20][CH3:21])=[O:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[N:12][N:13]([CH2:16][C:17]([CH3:23])([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[N:14]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)C(C)(C)CO
Reactant: CC(C)c1ccc(-c2nn[nH]n2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Cn1nnc(-c2ccc(C(C)C)cc2)n1
Reaction time: 2 h
Yield: 30 %

Procedure:
To a solution of crude 5-(4-isopropylphenyl)-2H-tetrazole (1.0 g, ˜5.3 mmol), methyl 3-hydroxy-2,2-dimethylpropanoate (830 mg, 8.0 mmol), and PPh3 (2.1 g, 8.0 mmol) in THF (5 mL) was added DEAD (1.35 mL, 8.0 mmol) dropwise. The reaction mixture was stirred for 2 h. LC/MS indicated the reaction was complete. The reaction mixture was filtered and purified on RP-HPLC using a mixture of acetonitrile and H2O to give methyl 3-(5-(4-isopropylphenyl)-2H-tetrazol-2-yl)-2,2-dimethylpropanoate (480 mg, 32% for two steps). LRMS (M+H+) m/z 303.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][C:8]=1[CH3:14])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:23]=[O:24]>O1CCCC1>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([CH:23]=[O:24])=[CH:9][C:8]=1[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Br)ccc1C(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1C(=O)OC(C)(C)C
Temperature: -95 °C
Reaction time: 1.25 h

Procedure:
A solution of 4-bromo-2-methyl-benzoic acid tert-butyl ester (Example 4.1) (75 g) in dry tetrahydrofuran (750 ml) was cooled to −100° C. A solution of butyl lithium (1.6M in hexane) (163 ml) was added dropwise at −100° C. Dimethylformamide (“DMF”) (1.14 ml) was added at −100° C. The reaction mixture was stirred at −95° C. for 75 minutes. The reaction was quenched by addition of aqueous ammonium chloride (saturated) (8 ml) at −90° C. The mixture was stirred for 10 minutes at −90° C., warmed to 0° C. and poured onto a mixture of ice and water. The mixture was allowed to warm to ambient temperature and then extracted twice with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate, and concentrated to give 4-formyl-2-methyl-benzoic acid tert-butyl ester (60.3 g) as yellow oil. 1H-NMR (CDCl3, 400 MHz): 10.03 (s, 1H), 7.93 (d, 1H), 7.75 (m, 2H), 2.65 (s, 3H), 1.65 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.CCN(C(C)C)C(C)C.Br[CH:27]([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(O)C>[CH2:31]([O:30][C:28](=[O:29])[CH:27]([N:12]1[CH2:11][CH2:10][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][N:7]=2)[CH2:14][CH2:13]1)[CH3:33])[CH3:32]
Reactant: CCOC(=O)C(C)Br
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)C(C)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
To a solution of 1-[5-(trifluoromethyl)pyrid-2-yl]piperazine (2.00 g, 8.65 mmol) in ethanol (25 mL) and DIPEA (3.3 mL, 19.0 mmol) was added ethyl 2-bromopropionate (1.20 mL, 9.51 mmol). The reaction mixture was heated to 70° C. After 14 hours, the reaction mixture was cooled to room temperature, concentrated and purified by flash chromatography on silica gel with elution using 50% ethyl acetate/hexanes to give 2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]propionic acid ethyl ester.