Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.C(N(CC)CC)C.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>O1CCOCC1>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:22][CH2:21]1
Reactant: CN1CCNCC1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 25 °C
Yield: 76 %

Procedure:
A solution of 5-fluoro-2-nitrobenzenamine (3.0 g, 18.1 mmol), triethylamine (5.0 mL, 36.3 mmol), and 1-methylpiperazine (2.0 mL, 18.1 mmol) in dioxane (25 mL) was heated at reflux for 18 hr. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue dissolved in DCM (100 mL). This solution was washed with saturated aqueous sodium bicarbonate followed by brine, then dried over magnesium sulfate and concentrated under reduced pressure to give 5-(4-methylpiperazin-1-yl)-2-nitrobenzenamine (3.25 g) as a dark brown solid. A solution of 5-(4-methylpiperazin-1-yl)-2-nitrobenzenamine (3.25 g; 13.7 mmol) in absolute ethanol (40 mL) was hydrogenated at atmospheric pressure with 10% palladium on carbon (0.30 g; 2.7 mmol) at room temperature for 17 hr. The mixture was filtered through diatomaceous earth and concentrated under reduced pressure to give 4-(4-methylpiperazin-1-yl)benzene-1,2-diamine (2.36 g).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=2[O:5][C:4]([CH2:17][CH3:18])([CH2:15][CH3:16])[N:3]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1B(O)O>>[CH2:15]([C:4]1([CH2:17][CH3:18])[N:3]=[C:2]([C:23]2[CH:22]=[CH:21][C:20]([F:19])=[CH:25][C:24]=2[F:26])[C:7]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=2[O:5]1)[CH3:16]
Reactant: CCC1(CC)N=C(Cl)c2ccc([N+](=O)[O-])cc2O1
Reactant: OB(O)c1ccc(F)cc1F
Product: CCC1(CC)N=C(c2ccc(F)cc2F)c2ccc([N+](=O)[O-])cc2O1

Procedure:
The compound obtained in (3) described above (1.0 g) and 2,4-difluorophenylboronic acid (1.2 g) were treated in the same manner as Reference Example 39(2) to give the titled compound (0.6 g) as a yellow oil.
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([NH2:6])=[O:5])#[N:2].[NH:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)[NH2:18]>>[NH2:2][C:1]1[N:17]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=2)[N:18]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CSC(=C(C#N)C(N)=O)c1ccc(C)cc1
Product: Cc1ccc(-c2nn(-c3ccc(C(=O)O)cc3)c(N)c2C(N)=O)cc1
Yield: 73.9 %

Procedure:
The title compound was prepared from 2-cyano-3-methylthio-3-(4-tolyl)-acrylamide (464 mg, 2.0 mmol) and 4-hydrazinobenzoic acid (334 mg, 2.2 mmol) following the procedure used for the compound of Example 12. The crude product was purified by column chromatography (SiO2, 5-10% methanol +2% acetic acid in CH2Cl2) and by trituration with methanol to give the title compound as a light yellow solid (497 mg) m.p. >310° dec. δH (d6DMSO) 8.06 (2H, d, J 8.7 Hz), 7.75 (2H, d, J 8.6 Hz), 7.48 (2H, d, J 8.1 Hz), 7.29 (2H, d, J 8.0 Hz), 6.63 (2H, br s) and 2.36 (3H, s), carboxyl proton and amino protons not observed.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2I)[CH:7]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]([C:25]([NH:27][CH:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[C:29]([F:32])([F:31])[F:30])=[O:26])[S:23][CH:24]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:20]2[CH:21]=[C:22]([C:25]([NH:27][CH:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[C:29]([F:32])([F:31])[F:30])=[O:26])[S:23][CH:24]=2)[CH:7]=1
Reactant: Brc1cnc2c(I)cnn2c1
Reactant: CC1(C)OB(c2csc(C(=O)NC(c3ccccn3)C(F)(F)F)c2)OC1(C)C
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
Product: O=C(NC(c1ccccn1)C(F)(F)F)c1cc(-c2cnn3cc(Br)cnc23)cs1

Procedure:
6-bromo-3-iodopyrazolo[1,5-a]pyrimidine (1 eq) was mixed with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(2,2,2-trifluoro-1-pyridin-2-ylethyl)thiophene-2-carboxamide (1 eq, step B). Dioxane (10 mL) and 1M Na2CO3 (2 eq) were added. The mixture was evacuated and flushed with nitrogen under stirring, then Pd(Ph3P)4 (0.05 eq) was added in a flow of nitrogen. The temperature was brought to 90° C. The reaction mixture was stirred at this temperature overnight and concentrated. The residue was poured into a 5-fold excess of water. The mixture was extracted with chloroform. The organic layer was washed with brine, dried with MgSO4, and concentrated. The residue was purified by column chromatography (dichloromethane-methanol, 100:1) to give 4-(6-bromopyrazolo[1,5-a]pyrimidin-3-yl)-N-(2,2,2-trifluoro-1-pyridin-2-ylethyl)thiophene-2-carboxamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([CH2:19][NH:20][O:21][CH3:22])=[CH:17][CH:16]=1>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:20]([O:21][CH3:22])[CH2:19][C:18]2[CH:23]=[CH:24][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CONCc1ccc(OC)cc1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: COc1ccc(CN(OC)C(=O)C=C2OC(C)(C)OC2=O)cc1
Yield: 97 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(4-methoxybenzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (97% yield): mp 113-114° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 3.66 (3H, s, OCH3), 3.79 (3H, s, OCH3), 4.77 (2H, s, NCH2), 6.38 (1H, s, CH), 6.85 (2H, m, aromatics), 7.29 (2H, m, aromatics). Anal. calcd. for C16H19NO6: C, 59.80; H, 5.96; N, 4.35. Found: C, 59.87; H, 5.76; N, 4.17.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][C:4](=[O:13])[CH2:5][C@@H:6]([CH2:10][CH:11]=[CH2:12])[C:7]([OH:9])=O.O.ON1C2C=CC=CC=2N=N1.Cl.[CH2:28]([O:30][C:31](=[O:36])[C@H:32]([CH2:34][OH:35])[NH2:33])[CH3:29].C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:14][C:2]([CH3:1])([CH3:15])[CH2:3][C:4](=[O:13])[CH2:5][C@@H:6]([CH2:10][CH:11]=[CH2:12])[C:7]([NH:33][C@@H:32]([CH2:34][OH:35])[C:31]([O:30][CH2:28][CH3:29])=[O:36])=[O:9]
Reactant: C=CC[C@H](CC(=O)CC(C)(C)C)C(=O)O
Reactant: CCOC(=O)[C@@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@H](CC(=O)CC(C)(C)C)C(=O)N[C@@H](CO)C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.8 %

Procedure:
A solution (2R)-2-(4,4-dimethyl-2-oxopentyl)-4-pentenoic acid (Preparation 112) (15.91 g, 74.3 mmol), 1-hydroxybenzotriazole hydrate (11.00 g, 81.4 mmol), L-serine ethylester hydrochloride (13.84 g, 81.6 mmol) and N,N-diisopropylethylamine (27 ml, 156.0 mmol) in dichloromethane (280 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (15.67 g, 81.7 mmol) and stirred at room temperature for 18 hours under a nitrogen atmosphere. The reaction mixture was diluted with dichloromethane and washed with water, aqueous citric acid (2M), saturated sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulphate and filtered. The solvent was removed under reduced pressure to afford the title-compound as a yellow oil (23.8 g).
Reaction SMILES: C([CH:3]([C:32]([OH:34])=[O:33])[N:4]([CH2:15][P:16]([S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[S:17])[C:5](OCC1C=CC=CC=1)=O)C.Br.[CH2:36](OCC)C>C(O)(=O)C>[CH2:5]([N:4]([CH2:15][P:16]([S:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([S:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[S:17])[CH2:3][C:32]([OH:34])=[O:33])[CH3:36]
Reactant: CCC(C(=O)O)N(CP(=S)(Sc1ccccc1)Sc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCOCC
Agent: Br
Solvent: CC(=O)O
Product: CCN(CC(=O)O)CP(=S)(Sc1ccccc1)Sc1ccccc1

Procedure:
Ethyl-N-[bis(phenylthio)phosphinothioylmethyl]-N-(benzyloxycarbonyl)glycine (2.3 g.) was dissolved in 10 ml. of 35% hydrobromic acid in acetic acid and stirred for approximately one hour. Diethyl ether was added to precipitate the hydrobromide salt of the desired compound. The hydrobromide salt was washed an additional three times with diethyl ether. The oily residue was then dissolved in benzene and treated with excess propylene oxide and the resulting solution concentrated in vacuo to yield ethyl-N-[bis(phenylthio)phosphinothioylmethyl]-glycine as an oil, ND25 =1.413.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][C:11]1[C:16]([N+:17]([O-])=O)=[CH:15][C:14]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:13][C:12]=1[C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH3:35])[N:30]=[CH:29]2.C1COCC1>[Ni].O>[NH2:17][C:16]1[CH:15]=[C:14]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:13]=[C:12]([C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[N:31]([CH3:35])[N:30]=[CH:29]3)[C:11]=1[O:10][CH:2]1[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1
Reactant: COC(=O)CCc1cc(-c2ccc3c(cnn3C)c2)c(OC2Cc3ccccc3C2)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCc1cc(N)c(OC2Cc3ccccc3C2)c(-c2ccc3c(cnn3C)c2)c1
Reaction time: 7 h
Yield: 84.6 %

Procedure:
To methyl 3-[4-(indan-2-yloxy)-3-(1-methyl-1H-indazol-5-yl)-5-nitrophenyl]propionate (13.0 g), THF (138 ml), stabilized nickel (4.42 g, NIKKI CHEMICAL) and water (4 ml) were added, the mixture was stirred, then the interior of the system was purged with hydrogen, and the reaction was allowed under a hydrogen atmosphere at 50° C. for 7 hours with stirring. After confirming the completion of the reaction, the reaction solution was purged with nitrogen and filtered to obtain a filtrate, and the residue on the filter was washed with THF (34 ml) to obtain a wash solution. The filtrate and the wash solution were combined, activated carbon (2.6 g, Japan Envirochemical) was added to the combined solution, and the mixture was stirred for 1 hour at room temperature. The suspension was filtered to obtain a filtrate, and the residue on the filter was washed with THF (34 ml) to obtain a wash solution. Then, the resulting filtrate and the wash solution were combined, water (207 ml) was added to the combined solution over 1 hour, and the mixture was stirred for another 1 hour under ice cooling. Then, this mixture was filtered, and the solid on the filter was washed with water (68 ml) to obtain wet solid. This wet solid was dried under reduced pressure at 50° C. to obtain crystals of methyl 3-[3-amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)phenyl]propionate (10.3 g).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:7])([CH2:5][OH:6])[CH3:4].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.C([O-])(O)=O.[Na+]>CC1C=CC(S(O)(=O)=O)=CC=1.O.C1COCC1.ClCCl>[CH3:4][C:3]([CH3:7])([CH2:5][O:6][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1)[CH2:2][OH:1]
Reactant: CC(C)(CO)CO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(CO)COC1CCCCO1
Reaction time: 8 h
Yield: 58.9 %

Procedure:
To a solution of neopentyl glycol (6.0 g, 57.6 mmol) and 3,4-dihydro-2H-pyran (2.64 mL, 28.94 mmol) in 2:1 THF/dichloromethane (135 mL) was added p-TsOH.H2O (100 mg, 0.53 mmol) and the reaction stirred overnight. Solid NaHCO3 was then added and after rapid stirring for 15 min the reaction was filtered and concentrated to give a pale liquid. Purification by flash column chromatography on silica gel using 50% ethyl acetate in hexanes provided 2,2-dimethyl-3-(tetrahydro-pyran-2-yloxy)-propan-1-ol (3.21 g, 59%) as a pale liquid.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S([O:26][C@@H:27]([CH2:29][C@H:30](O)[CH3:31])[CH3:28])(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C>[C:3]1([C:9]2[CH:10]=[CH:11][C:12]([O:15][C@H:30]([CH2:29][C@@H:27]([OH:26])[CH3:28])[CH3:31])=[CH:13][CH:14]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H](C)C[C@@H](C)O)cc1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](O)C[C@H](C)Oc1ccc(-c2ccccc2)cc1
Reaction time: 3 h

Procedure:
0.26 g of 55% sodium hydride was mixed with 5 ml of DMF and 0.85 g of 4-phenylphenol was added dropwise thereto. After the completion of the reaction, 1.42 g of optically active (R,R)-2,4-pentanediol monotosylate in 5 ml of DMF was added dropwise thereto. After reacting at 90° C. for three hours, the reaction mixture was treated in a conventional manner. Then it was purified by silica gel column chromatography with the use of a mixture of n-hexane with ethyl acetate (7/3) as a developing solvent. Thus 0.77 g of optically active (S,S)-2-(4'-phenylphenoxy)pentan-4-ol was obtained. Separately, 0.08 g of 55% sodium hydride was mixed with 3 ml of DMF and a solution of 0.49 g of 5-n-decylpyrimidine in 3 of DMF was added dropwise thereto. Then a solution of 0.71 g of the (S,S)-2-(4'-phenylphenoxy)pentane-4-ol tosylate obtained above in 3 ml of DMF was added dropwise thereto and the obtained mixture was stirred at 90° C. for five hours. After cooling, the reaction mixture was poured into 100 ml of ice/water, extracted with ethyl ether, dried and freed of the solvent. The residue was then purified by silica gel column chromatography with the use of a mixture of n-hexane with ethyl acetate (8/2) as a developing solvent. Thus 0.82 g of optically active (s,S)-2-(4'-phenylphenoxy)-4-[4'-(5"-dicylpyrimidin-2"-yl)phenoxy]pentane was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[N:12]=[N:13][C:14]3[C:19]([C:20]=2[OH:21])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].N1C=CC=CC=1>CN(C)C=O>[C:22]([NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[N:12]=[N:13][C:14]3[C:19]([C:20]=2[OH:21])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:24])[CH3:23]
Reactant: Nc1cccc(NC(=O)c2nnc3ccccc3c2O)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(NC(=O)c2nnc3ccccc3c2O)c1
Temperature: 0 °C

Procedure:
N-(3-Amino-phenyl)-4-hydroxy-cinnoline-3-carboxamide (1 g) is reacted with acetic anhydride (5 ml) in dimethylformamide (50 ml) in the presence of pyridine (5 ml) at 80° C. for 2 hours. After cooling the reaction mixture is diluted with ice water and the precipitate is filtered and washed with water: washing with hot ethanol gives 0.75 g of N-(3-acetylamino-phenyl)-4-hydroxy-cinnoline-3-carboxamide.
Reaction SMILES: C(OC(N1CCC(NC(C2SC=CC=2NC2C=CN=C3NC=CC=23)=O)C1)=O)(C)(C)C.[CH2:31]([NH:38][CH2:39][CH2:40][NH2:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[CH3:42][C:43]1[S:47][C:46]([C:48](O)=[O:49])=[C:45]([NH:51][C:52]2[CH:57]=[CH:56][N:55]=[C:54]3[NH:58][CH:59]=[CH:60][C:53]=23)[CH:44]=1>>[CH2:31]([NH:38][CH2:39][CH2:40][NH:41][C:48]([C:46]1[S:47][C:43]([CH3:42])=[CH:44][C:45]=1[NH:51][C:52]1[CH:57]=[CH:56][N:55]=[C:54]2[NH:58][CH:59]=[CH:60][C:53]=12)=[O:49])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1cc(Nc2ccnc3[nH]ccc23)c(C(=O)O)s1
Reactant: NCCNCc1ccccc1
Agent: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: Cc1cc(Nc2ccnc3[nH]ccc23)c(C(=O)NCCNCc2ccccc2)s1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using N-benzylethylenediamine instead of 1-BOC-3-aminopyrrolidine and 5-Methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid instead of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid. LCMS (ESI) 406 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (1H, br. s.) 10.39 (1H, s) 8.02 (1H, d, J=5.42 Hz) 7.87 (1H, t, J=5.54 Hz) 7.26-7.36 (7H, m) 7.18-7.26 (1H, m) 6.83 (1H, d, J=5.47 Hz) 6.42 (1H, dd, J=3.47, 1.85 Hz) 3.76 (2H, s) 3.36 (2H, q, J=6.30 Hz) 2.69 (2H, t, J=6.39 Hz)
Reaction SMILES: [C:1]([O:5][P:6]([O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19](C(OCC2C=CC=CC=2)=O)[CH2:18][CH2:17]1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[P:6]([O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]1)([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7]
Reactant: CC(C)(C)OP(=O)(OCCN1CCN(C(=O)OCc2ccccc2)CC1)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OP(=O)(OCCN1CCNCC1)OC(C)(C)C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
A 100 ml flask was charged with benzyl 4-(2-(di-tert-butoxyphosphoryloxy)ethyl)piperazine-1-carboxylate (INTERMEDIATE 58, 0.90 g, 1.97 mmol) in MeOH (19.7 ml) and 10% palladium on charcoal (0.042 g, 0.04 mmol). The reaction mixture was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered and the filtrate concentrated in vacuo to give the title compound (0.63 g, yield: 99%), which was used in the preparation of INTERMEDIATE 61 without further purification.
Reaction SMILES: C(C1C=CC(C#C)=CC=1)(C)(C)C.C[Si]([C:17]#[C:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:32])([CH3:31])[CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:21][CH:20]=1)(C)C>>[CH3:32][C:25]([C:22]1[CH:23]=[CH:24][C:19]([CH:18]=[CH2:17])=[CH:20][CH:21]=1)([CH3:31])[CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)CCC(C)(C)c1ccc(C#C[Si](C)(C)C)cc1
Agent: C#Cc1ccc(C(C)(C)C)cc1
Product: C=Cc1ccc(C(C)(C)CCC(C)C)cc1

Procedure:
Using the same general procedure as described for Compound 21, but using instead trimethylsilyl [4-(1,1,4-trimethylpentyl)] phenylethyne (Compound 36), the title compound was synthesized as a colorless oil. PMR (CDCl3): & 0.81 (6H, d, J~6.6 Hz), 0.85-0.96 (2H, m), 1.29 (6H, s), 1.32-1.48 (1H, m). 1.55-1.66 (2H, m), 3.04 (1H, s), 7.29 (2H, d, J~8.4 Hz), 7.44 (2H, d, J~8.4 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=3)[CH:14]=2)=[C:5]([C:25]([O:27]CC)=[O:26])[CH:4]=[N:3]1.O.[OH-].[Li+]>CO.O>[CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=3)[CH:14]=2)=[C:5]([C:25]([OH:27])=[O:26])[CH:4]=[N:3]1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(-c3ccccc3)nn2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(-c3ccccc3)nn2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.6 %

Procedure:
A mixture of ethyl 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylate (480 mg, 1.23 mmol) and lithium hydroxide hydrate (155 mg, 3.69 mmol) in methanol (10 ml) and water (3.0 ml) was stirred for 18 hours at 25° C. The solvent was evaporated, the residue was diluted with water and the solution was acidified with hydrochloric acid to pH=0, the precipitated solid was collected, washed with water and dried in vacuo affording 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (435 mg, 98%) as light brown solid. Mp.: 259° C. MS: m/z=361.2 (M−H+).
Reaction SMILES: [S:1]1[C:5]([CH2:6][O:7][C:8]([NH:10][C@H:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:12][NH:13][CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[C:47](Cl)(=[O:49])[CH3:48].C(OCC)(=O)C>ClCCCl>[C:47]([N:13]([CH2:14][C@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1)=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:12][C@@H:11]([NH:10][C:8]([O:7][CH2:6][C:5]1[S:1][CH:2]=[N:3][CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:49])[CH3:48]
Reactant: CC(=O)Cl
Reactant: O=C(N[C@H](CNC[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)Cc1ccccc1)OCc1cncs1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(=O)N(C[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reaction time: 2 h
Yield: 60 %

Procedure:
The product from Example 26D (50 mg, 0.088 mmol) in 1,2-dichloroethane (2 mL) was treated with triethylamine (14 μl, 0.097 mmol) and acetyl chloride (6.30, 0.088 mmol) at ambient temperature. After stirring for two hours, the mixture was treated with ethyl acetate (8 mL), wash with aqueous 10% NaHCO3 (2×10 mL), brine (10 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified on a silica gel cartridge eluting with (chloroform:methanol, 99:1) to provide the title compound (32.1 mg, 60%). 1H NMR (CDCl3) δ 8.78 (d, 2H), 7.83 (d, 2H), 7.32-7.01 (m, 10H), 5.42 (d, 1H), 5.21 (d, 4H), 4.71 (br s, 1H), 4.01 (br s, 1H), 3.85 (m, 2H), 3.35 (m, 1H), 3.22 (dd, 1H), 3.00-2.55 (m, 5H), 1.57 (s, 3H); MS (ESI+) m/z 608 (M+H)+.
Reaction SMILES: [Mg].II.C[Si](C)(C)[N:6]1[CH2:11][CH2:10][CH:9]([C:12]([O:14]CC)=O)[CH2:8][CH2:7]1.[F:19][C:20]([F:30])([F:29])[O:21][C:22]1[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1.FC(F)(F)OC1C=CC(Br)=CC=1>[F:19][C:20]([F:30])([F:29])[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:12]([C:25]2[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:29])[F:30])=[CH:27][CH:26]=2)([OH:14])[CH:9]2[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1CCN([Si](C)(C)C)CC1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: OC(c1ccc(OC(F)(F)F)cc1)(c1ccc(OC(F)(F)F)cc1)C1CCNCC1
Temperature: 0 °C
Yield: 109.9 %

Procedure:
A stirred mixture of 5.0 grams (0.021 mole) of 4-trifluoromethoxyphenyl bromide, 13.8 grams (0.570 gram-atom) of magnesium turnings, and a crystal of iodine in 25 mL of anhydrous tetrahydrofuran was warmed to 50°-60° C. Once the Grignard reaction commenced, 500 mL of anhydrous tetrahydrofuran was added, and the reaction mixture temperature was adjusted to 45° C. To this was added a solution of 53.0 grams (0.230 mole) of ethyl N-(trimethylsilyl)piperidin-4-ylcarboxylate and 128.8 grams (0.534 mole) of 4-trifluoromethoxyphenyl bromide in 475 mL of anhydrous tetrahydrofuran at a rate to maintain the reaction mixture temperature at 45°-55° C. Upon completion of the addition, the reaction mixture heated at reflux for about two hours, after which the reaction mixture was poured into a stirred mixture of 550 mL of an aqueous solution saturated with ammonium chloride and 200 grams of ice. The mixture was then extracted with 650 mL of ethyl acetate. The organic layer was shaken with one 250 mL portion of an aqueous solution saturated with sodium bicarbonate, one 250 mL portion of aqueous 10% sodium hydroxide solution, and with two 200 mL portions of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 110 grams of residual oil. The oil was triturated with 500 mL of petroleum ether, and 67.0 grams of solid 4-[bis(trifluoromethoxyphenyl)hydroxymethyl]piperidine was collected by filtration. The filtrate was cooled, and an additional 15.5 grams of solid 4-[bis(trifluoromethoxyphenyl)hydroxymethyl]piperidine was collected by filtration. The total yield was 82%. The NMR spectrum was consistent with the proposed structure.