Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN([CH:4]=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13]([N:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])C.[H-].[Na+]>CN(C=O)C>[CH3:17][N:16]([CH3:18])[S:13]([C:12]1[C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:5][CH:4]=1)(=[O:15])=[O:14]
Reactant: CN(C)C=Nc1ccccc1CS(=O)(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1c[nH]c2ccccc12
Temperature: 40 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
The crude product from Step 3 was dissolved in DMF (7 ml) and to this solution was added sodium hydride (60% in oil, 0.353 g, 8.82 mmole) in portions under a nitrogen atmosphere. After the initial bubbling subsided, the temperature was raised to 40° C. and left at that temperature overnight. Tlc analysis of the reaction mixture showed the presence of starting material and thus the temperature was raised to 60° C. and heated another 24 h. After cooling the reaction mixture was partitioned between 1.5 M HCl and ethyl acetate. The organic layer was separated and washed with bicarbonate solution, and then with brine. After drying over magnesium sulfate and filtration, the solvent was removed under reduced pressure to afford 0.547 g of the crude product. Purification by column chromatography (silica gel, 5:95 ethyl acetate:methylene chloride) afforded 0.437 g of the pure 1H-Indole-3-sulfonic acid dimethylamide (66% yield).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:37][CH2:38][C@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1C(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.ClCCl>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([NH:37][CH2:38][C@@H:39]3[CH2:43][CH2:42][CH2:41][NH:40]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CN
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1cc(NC[C@@H]2CCCN2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 138 °C
Yield: 24.5 %

Procedure:
A suspension of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide [WO 2005/002577] (1.5 g, 2.81 mmol) 1,1-dimethylethyl (2R)-2-(aminomethyl)-1-pyrrolidinecarboxylate (N-Boc prolinamine) (1.41 g, 7.025 mmol) and potassium carbonate (777 mg, 5.62 mmol) in 6 mL of DMSO was heated for 18 h at 150° C. (temperature detected 138° C.). A HPLC/MS check showed a 50% conversion with partial loss of the Boc protecting group. The reaction was heated under microwave irradiation to 160° C. for 1 h and to 180° C. for two cycles of 1 h and 1.5 h, respectively. The suspension was diluted with dichloromethane and extracted with sat. NaHCO3 and the organics were dried (Na2SO4) and the solution was loaded on a SCX cartridge, washed with dichloromethane (100 mL) and methanol (200 mL, this wash allowed the recovery of the unreacted chloropyridine) and eluted with 2M NH3 in MeOH. The crude thus obtained, which contained both the Boc-protected and unprotected compounds, was purified by flash chromatography (silica, cyclohexane:EtOAc 80:20 to EtOAc). Isolated 350 mg of Boc-protected amine and 410 mg of the title compound. This last compound was purified further by a boc-protection, flash chromatography, TFA deprotection and SCX isolation procedure. Final yield: 165 mg.
Reaction SMILES: OC1C(O)=C2C(C(=O)C(C3C=CC(OC)=CC=3)=CO2)=CC=1.C(OC(=O)C)(=O)C.[C:29]([O:32][C:33]1[CH:57]=[CH:56][C:36]([C:37]2[C:46](=[O:47])[C:45]3[C:40](=[C:41]([O:52][C:53](=[O:55])[CH3:54])[C:42]([O:48][C:49](=[O:51])[CH3:50])=[CH:43][CH:44]=3)[O:39][CH:38]=2)=[CH:35][CH:34]=1)(=O)C>N1C=CC=CC=1>[C:49]([O:48][C:42]1[C:41]([O:52][C:53](=[O:55])[CH3:54])=[C:40]2[C:45]([C:46](=[O:47])[C:37]([C:36]3[CH:35]=[CH:34][C:33]([O:32][CH3:29])=[CH:57][CH:56]=3)=[CH:38][O:39]2)=[CH:44][CH:43]=1)(=[O:51])[CH3:50]
Reactant: CC(=O)Oc1ccc(-c2coc3c(OC(C)=O)c(OC(C)=O)ccc3c2=O)cc1
Agent: COc1ccc(-c2coc3c(O)c(O)ccc3c2=O)cc1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(-c2coc3c(OC(C)=O)c(OC(C)=O)ccc3c2=O)cc1

Procedure:
7,8-Diacetoxy-4′-methoxyisoflavone was prepared from 7,8-dihydroxy-4′-methoxyisoflavone (0.82 g, 2.9 mmol), acetic anhydride (4.9 ml) and pyridine (0.9 ml) as described for 4′,7,8-triacetoxyisoflavone. Yield: (0.9 g, 85%) m.p. 165° C. 1H NMR (CDCl3): δ 2.36, 2.42 (each s, 3H, OCOCH3), 3.84 (s, 3H, OCH3), 6.98 (d, 2H, J 9.0 Hz, ArH), 7.25 (d, 1H, J 8.7 Hz, H6), 7.48 (d, 2H, J 9.0 Hz H8), 7.95 (s, 1H, H2), 8.20 (d, 1H, J 9.1 Hz, H5). Mass spectrum: m/z 368 (M, 20%); 326 (15); 312 (18); 284 (80):
Reaction SMILES: O.O[N:3]1[C:7]2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.[O:33]=[C:34]([NH:43][C@H:44]([C:49]([NH:51][CH:52]([CH2:61][CH:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]1)[CH:53]([P:55](CC)([O:57][CH3:58])=[O:56])[OH:54])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C)C=O>[CH:62]1([CH2:61][C@H:52]([NH:51][C:49](=[O:50])[C@H:44]([CH2:45][CH:46]([CH3:47])[CH3:48])[NH:43][C:34](=[O:33])[CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:53]([P:55]([NH:3][CH3:7])(=[O:56])[O:57][CH3:58])[OH:54])[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]1
Reactant: On1nnc2ccccc21
Reactant: CCP(=O)(OC)C(O)C(CC1CCCCC1)NC(=O)[C@H](CC(C)C)NC(=O)CCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CNP(=O)(OC)C(O)[C@H](CC1CCCCC1)NC(=O)[C@H](CC(C)C)NC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.8 %

Procedure:
1-Hydroxybenzotriazole hydrate (225 mg, 1.47 mmol), N,N-diisopropylethylamine (237.8 μl, 1.365 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (281.8 mg, 1.47 mmol) were sequentially added to a solution of the title B compound obtained from the previous reaction and the title B compound from Example 17 (276 mg, 1.26 mmol) in 5 ml dimethylformamide of 0°. The reaction mixture was warmed and stirred at room temperature for 24 hours after which it was concentrated, then treated with 30 ml pH=4.01 buffer and extracted with ethyl acetate (3×25 ml). The combined organic extracts were washed sequentially with saturated NaHCO3 (2×20 ml). Saturated NaCl (1×15 ml), dried and concentrated to give 398 mg crude product. Chromatographic purification (40 g silica gel, 1:1 hexane/ethyl acetate followed by 30:1 CHCl3 /MeOH) yielded 320 mg (60%) pure title compound. It was crystallized from ethyl acetate, m.p.=175°-177° C., [α[D =-74° (c=0.64, CH3OH) and characterized by MS, IR, 1H NMR, 13C NMR and 31P NMR [30.8 and 30.65 ppm (1.5:1.0) w.r.t. H3PO4 as external reference, CDCl3, 36.5 MHz].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:5]=[CH:4][N:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:25]=[C:24](I)[N:23]=[C:22]2[CH:27]([CH3:29])[CH3:28])=[CH:17][N:16]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:24]2[N:23]=[C:22]([CH:27]([CH3:29])[CH3:28])[N:21]([C:18]3[CH:17]=[N:16][C:15]([Cl:14])=[CH:20][CH:19]=3)[CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C[Si](C)(C)C#Cc1ccnc(Cl)c1
Reactant: CC(C)c1nc(I)cn1-c1ccc(Cl)nc1
Product: CC(C)c1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccc(Cl)nc1

Procedure:
The title compound, MS: m/e=358.1 (M+H+), was prepared in accordance with the general method of example B, step 2, from 2-Chloro-4-trimethylsilanylethynyl-pyridine and 2-Chloro-5-(4-iodo-2-isopropyl-imidazol-1-yl)-pyridine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)=[O:5])[CH3:2].Br[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:18][CH:17]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)=[CH:20][CH:21]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Product: CCOC(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cc2)cc1
Yield: 5.6 %

Procedure:
The title compound (2.4 mg, 6%) was prepared from {4-[(ethyloxy)carbonyl]phenyl}boronic acid (19.4 mg, 0.1 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (Example 9, Step 2, 36 mg, 0.10 mmol) in a manner similar to Example 9, Step 3. LRMS (ESI), m/z 448 (M+Na).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CN(C)C=O>[N:12]1([C:2]2[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: Nc1cc(Cl)ncc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: Nc1cc(N2CCOCC2)ncc1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 8 h

Procedure:
Into a 50-mL sealed tube, were placed a solution of 2-chloro-5-nitropyridin-4-amine (500 mg, 2.88 mmol) in N,N-dimethylformamide (20 mL) and morpholine (503 μL, 5.77 mmol). The reaction mixture was stirred overnight at 55° C. The reaction was then quenched by the addition of 100 mL of water. The reaction mixture was extracted with 3×150 mL of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. This resulted in 733 mg (crude) of the title compound as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:19]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:19][C:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C(=O)OC)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.3 %

Procedure:
To a stirred solution of dimethyl 2-(4-nitrophenyl)malonate (10 g, 39.52 mmol, 1.0 eq) and K2CO3 (10.9 g 79.05 mmol 2.0 eq) in DMF (40 mL), was added methyl iodide (4.94 mL, 79.05 mmol 2.0 eq) at 0° C. and the mixture stirred at RT for 18 h. K2CO3 was filtered out and the filtrate concentrated under vacuum. The residue was diluted with water (80 mL) and extracted with EtOAc (2×80 mL). The organic layer was separated washed with brine solution, dried over anhydrous Na2SO4 and the solvent evaporated to get dimethyl 2-methyl-2-(4-nitrophenyl)malonate (7 g, 66%; TLC system: EtOAc/PE (3:7), Rf: 0.5.)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([CH3:23])(=[O:22])=[O:21])[C:3]=1[CH3:24].[CH3:25][O:26][C:27]1[N:32]=[CH:31][C:30]([C:33]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:36][C:34]=2[NH2:35])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:35][C:34]1[CH:36]=[C:37]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH:38]=[CH:39][C:33]=1[C:30]1[CH:31]=[N:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=1)=[C:3]([CH3:24])[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([CH3:23])(=[O:22])=[O:21])=[N:5]2
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Cl
Reactant: COc1ccc(-c2ccc(N3CCOCC3)cc2N)cn1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(N3CCOCC3)cc2Nc2c(C)c(-c3ccccc3S(C)(=O)=O)nc3cc(F)cc(F)c23)cn1

Procedure:
Essentially prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline (50.0 mg, 0.140 mmol) and 2-(6-methoxypyridin-3-yl)-5-morpholinoaniline in toluene to give 5,7-difluoro-N-(2-(6-methoxypyridin-3-yl)-5-morpholinophenyl)-3-methyl-2-(2-(methylsulfonyl)-phenyl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 8.34 (1H, d, J=2.0 Hz), 8.20 (1H, d, J=7.8 Hz), 7.73-7.83 (2H, m), 7.63-7.73 (1H, m), 7.40-7.47 (1H, m), 7.38 (1H, d, J=7.2 Hz), 7.14 (1H, d, J=8.4 Hz), 6.94 (1H, ddd, J=13.7, 8.6, 2.5 Hz), 6.86 (1H, d, J=13.7 Hz), 6.82 (1H, dd, J=8.5, 0.7 Hz), 6.55 (1H, d, J=7.4 Hz), 6.32 (1H, br. s.), 3.99 (3H, s), 3.78 (4H, t, J=4.2 Hz), 3.00-3.32 (7H, m), 1.96 (3H, s). Mass Spectrum (ESI) m/e=617.2 (M+1).
Reaction SMILES: [OH:1][C:2]1(/[CH:8]=[CH:9]/[CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[H-].[Na+].[CH3:20]I>C1COCC1>[CH3:20][O:1][C:2]1(/[CH:8]=[CH:9]/[CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:3][CH2:4][O:5][CH2:6][CH2:7]1
Reactant: CI
Reactant: OC1(/C=C/COC2CCCCO2)CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(/C=C/COC2CCCCO2)CCOCC1

Procedure:
The desired compound was prepared by addition of a solution in THF of 4-hydroxy-4-[3-(tetrahydropyran- 2-yloxy)-trans-prop-1-enyl]tetrahydro-pyran, prepared as in step 2, to a suspension of NaH in THF, followed by alkylation of the resulting anion with methyl iodide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])=[CH:5][CH:4]=1.CS(O[C@@H:22]1[CH2:26][CH2:25][NH:24][C:23]1=[O:27])(=O)=O.CCN(C(C)C)C(C)C>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C@H:22]3[CH2:26][CH2:25][NH:24][C:23]3=[O:27])[CH2:13][CH2:12]2)=[O:10])=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)O[C@@H]1CCNC1=O
Reactant: COc1ccc(C(=O)C2CCNCC2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)C2CCN([C@H]3CCNC3=O)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.1 %

Procedure:
To a suspension of (4-methoxyphenyl)(piperidin-4-yl)methanone (34 g, 155 mmol) and (R)-2-oxopyrrolidin-3-yl methanesulfonate (34.7 g, 194 mmol) in acetonitrile (388 mL) at room temperature was added DIPEA (108 mL, 620 mmol) and the reaction was heated to 60 C for 29 h then allowed to cool to room temperature and stirred for an additional 24 h. The reaction mixture was concentrated in vacuo to afford a waxy solid which was taken up in ethyl acetate (300 mL) and sonicated. The mixture was filtered and the resulting white solid was washed with ethyl acetate (200 mL) to yield 21.05 g. The combined filtrates were concentrated and purified via silica gel chromatography (330 g isco 0.01% NH4OH 5-10% MeOH/ethyl acetate). Pure fractions were combined, concentrated in vacuo and then taken up in ethyl acetate (80-100 mL) and stirred. A white precipitate formed that was collected by filtration. The filtrate was concentrated to a gold oil, taken up in ethyl acetate to afford a white precipitate that was collected by filtration. A total of 27.7 g of the title material was obtained as a white solid. Calculated MS=302.4. found MS (ESI) m/e 303.4 (M+H+)
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=[O:15].[CH3:16][N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=O>>[CH3:16][N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:7]1=[O:15]
Reactant: CN1CCCC1=O
Reactant: O=C1Cc2ccccc2N1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCCC1=C1C(=O)Nc2ccccc21
Reaction time: 0.25 h

Procedure:
Under nitrogen, N-methyl-2-pyrrolidone (3 ml) was cooled in an ice-water bath. Phosphorus oxychloride (0.91 ml, 0.01 mole) was added dropwise. After stirring 15 minutes, the bath was removed and 2(1H,3H)indolone (oxindole, 1.3 g, 0.01 mole) in 3 ml. additional N-methyl-2-pyrrolidone (3 ml) was added dropwise. The temperature rose to 40° C. The reaction mixture was then heated at 80° for 16 hours, cooled and partitioned between ethyl acetate and water. The aqueous layer was washed with fresh ethyl acetate, basified to pH 9 with 6N NaOH and clarified by filtration. The filtrate was extracted with ethyl acetate. The extract was evaporated to dryness and the resulting title product triturated with ethyl acetate, 0.24 g, m.p. 268°-271° C. (dec). See Ind. J. Chem. 12:940-942 (1974).
Reaction SMILES: [NH2:1]/[C:2](=[N:16]\[OH:17])/[C@H:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4].[C:18](N1C=CN=C1)(=O)[CH3:19]>O1CCOCC1>[CH3:18][C:19]1[O:17][N:16]=[C:2]([C@H:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:4])[N:1]=1
Reactant: CC(=O)n1ccnc1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)/C(N)=N/O
Solvent: C1COCCO1
Product: Cc1nc([C@@H](C)NC(=O)OCc2ccccc2)no1
Temperature: 90 °C
Reaction time: 16 h
Yield: 44.4 %

Procedure:
To a solution of benzyl [(1R,2Z)-2-amino-2-(hydroxyimino)-1-methylethyl]carbamate (2.25 g, 9.48 mmol) in dioxane (80 ml) was added 1-acetyl-1H-imidazole (3.13 g, 28.5 mmol) and the mixture heated to 90° C. After 16 h, the solution was concentrated and the residue was dissolved in 200 mL of dichloromethane. The mixture was washed with 100 mL of aqueous saturated sodium bicarbonate (2×) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) to give the title compound (1.1 g). MS 262.1 (M+1).
Reaction SMILES: C(O[C:4](=O)[CH:5]([F:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C1COCC1.[H-].[Na+].C(OC(=O)/C=C/[C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]2)=[C:28]([O:38][CH3:39])[CH:27]=1)C>O.C(OCC)(=O)C>[CH2:9]([O:8][C:6](=[O:7])/[C:5](/[F:11])=[CH:4]\[C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]2)=[C:28]([O:38][CH3:39])[CH:27]=1)[CH3:10]
Reactant: CCOC(=O)C(F)C(=O)OCC
Reactant: CCOC(=O)/C=C/c1ccc(-n2cnc(C)c2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)/C(F)=C\c1ccc(-n2cnc(C)c2)c(OC)c1
Temperature: 25 °C
Yield: 56 %

Procedure:
2-fluoro malonic acid diethyl ester (670 μL) was added to a THF (8 mL) suspension of sodium hydride (170 mg) under ice-cooling, and the reaction solution was agitated under ice-cooling for 20 minutes and further agitated at room temperature for 1 hour. After dropping the THF (2 mL) solution of (E)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid ethyl ester (1 g) obtained above to the reaction solution over 10 minutes and the reaction solution was agitated at room temperature for 30 minutes, and heated to reflux for 8 hours. After the reaction solution was allowed to be cooled to room temperature, ethyl acetate and water was added and the organic layer was washed with a saturated ammonium chloride solution. After drying the organic layer over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: from hexane to hexane:ethyl acetate=1:1), and 593 mg (56%) of (E)-2-fluoro-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid ethyl ester was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[C:8]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C(Cl)(Cl)Cl.[CH3:22][O:23][C:24](Cl)=[O:25]>C(N(CC)CC)C>[CH3:22][O:23][C:24]([NH:1][C:2]1[N:6]2[CH:7]=[C:8]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[O:25]
Reactant: COC(=O)Cl
Reactant: Nc1cnc2ccc(Sc3ccccc3)cn12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1cnc2ccc(Sc3ccccc3)cn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.0 g. of 3-amino-6-(phenylthio) imidazo [1,2-a] pyridine in 25 ml. of chloroform containing 0.401 g. of triethyl amine is treated dropwise with 0.378 g. of methylchloroformate. The reaction mixture is stirred for 3 hours at room temperature. The chloroform is removed in vacuo and the residue is triturated with water. The solids are collected by filtration, washed well with water and dried. Recrystallization from dimethylformamideethane yields pure 3-(methoxycarbonylamino) 6-(phenylthio) imidazo [1,2-a] pyridine m.p. 211°-215° C.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH2:16][OH:17])=[CH:15][C:10]=3[N:9]=[CH:8]2)[CH:2]=1.[H-].[Na+].I[CH3:27]>CN(C=O)C.O>[C:1]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH2:16][O:17][CH3:27])=[CH:15][C:10]=3[N:9]=[CH:8]2)[CH:2]=1
Reactant: OCc1ccc2c(c1)ncn2-c1cccc(-c2ccccc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1ccc2c(c1)ncn2-c1cccc(-c2ccccc2)c1
Reaction time: 8 h

Procedure:
To a solution of 1--(3-biphenylyl)-5-hydroxymethylbenzimidazole (61a) (0.16 g, 0.5 mmol) in dry DMF (1.5 ml) under nitrogen, was added a 80% sodium hydride suspension (20 mg, 0.7 mmol) and then iodomethane (33.5 μl, 0.5 mmol). The reaction mixture was stirred overnight and then poured in water. Neutralization with 4M aqueous HCl was followed by extraction with ethyl acetate. The extract was evaporated to dryness and purified by chromatography. The product was dissolved in dry ether and precipitated as the hydrochloride. Yield: 130 mg, 0.4 mmol, 80%. mp 70°-72° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C@@H:26]([CH2:27][C:28]([O:30]CC)=[O:29])[C@H:25]([CH3:33])[C:24]([C:34]([F:37])([F:36])[F:35])=[N:23]3)=[CH:18][CH:17]=2)[CH2:11][CH2:10]1.C(Cl)(=O)C.Cl.FC1C=CC(OC)=CC=1N1CCC(OC2C=CC(N3[C@@H](CC(O)=O)[C@H](C)C(C(F)(F)F)=N3)=CC=2)CC1.B(Br)(Br)Br>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]3[C@@H:26]([CH2:27][C:28]([OH:30])=[O:29])[C@H:25]([CH3:33])[C:24]([C:34]([F:35])([F:36])[F:37])=[N:23]3)=[CH:20][CH:21]=2)[CH2:11][CH2:10]1
Reactant: CCOC(=O)C[C@H]1[C@H](C)C(C(F)(F)F)=NN1c1ccc(OC2CCN(c3cc(O)ccc3F)CC2)cc1
Agent: BrB(Br)Br
Agent: COc1ccc(F)c(N2CCC(Oc3ccc(N4N=C(C(F)(F)F)[C@@H](C)[C@@H]4CC(=O)O)cc3)CC2)c1
Agent: Cl
Solvent: CC(=O)Cl
Solvent: CCO
Product: C[C@@H]1C(C(F)(F)F)=NN(c2ccc(OC3CCN(c4cc(O)ccc4F)CC3)cc2)[C@H]1CC(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ethyl 2-((4S,5S)-1-(4-((1-(2-fluoro-5-hydroxyphenyl)piperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate: To a solution of EtOH (0.86 mL) was added acetyl chloride (0.18 mL, 2.6 mmol) to generate anhydrous HCl. After addition, the mixture was warmed to room temp, and 2-((4S,5S)-1-(4-((1-(2-fluoro-5-methoxyphenyl)piperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid (Example 1, 0.044 g, 0.086 mmol) was added. The mixture was stirred at rt for 1.5 h. The reaction mixture was evaporated to dryness. The residue was dissolved in CH2Cl2 (0.6 mL) and was cooled to −78° C., and BBr3 (0.8 mL, 8.46 mmol) was added. The reaction mixture was stirred for 2 h, and was warmed to −40° C. overnight. The reaction solution was poured over ice and, after 30 min agitation, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated to give 85 mg of a yellow oil that was purified via silica chromatography to give 25 mg of desired product as a clear oil. Anal. Calc'd for C26H29F4N3O4: 523.21, LCMS obs. [M+H]=524.1.