Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[Cl:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([N+:38]([O-:40])=[O:39])[CH:36]=2)[N:31]=[CH:30][CH:29]=1>CO.Cl>[ClH:27].[NH2:24][C:19]1[N:18]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:25]=[CH:26][C:3]([NH:2][C:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([N+:38]([O-:40])=[O:39])[CH:36]=5)[N:31]=[CH:30][CH:29]=4)=[CH:4][CH:5]=3)=[CH:15][CH:14]=2)[CH:22]=[C:21]([CH3:23])[N:20]=1
Reactant: O=[N+]([O-])c1ccc2nccc(Cl)c2c1
Reactant: Cc1cc(Nc2ccc(NC(=O)c3ccc(N)cc3)cc2)nc(N)n1
Agent: Cl
Solvent: CO
Product: Cc1cc(Nc2ccc(NC(=O)c3ccc(Nc4ccnc5ccc([N+](=O)[O-])cc45)cc3)cc2)nc(N)n1

Procedure:
To a solution of amine E5 (304 mg, 0.82 mmol) in dry MeOH (30 mL) were sequentially added 4-chloro-6-nitroquinoline (F1) (171 mg, 0.82 mmol) and c.HCl (1-2 drops), and the resulting mixture was refluxed for ˜12 h. MS and TLC analysis after this time showed some F1 was still present in the reaction mixture, so further aliquots of E5 (171 mg, 0.82 mmol) and c.HCl (1-2 drops) were added at 12 h and 24 h. Solvent was then removed from the reaction mixture, and the resulting residue dissolved in MeOH, and then re-concentrated under reduced pressure. The residue was subjected to a further MeOH azeotrope cycle, and the resulting residue was then reprecipitated from MeOH:Et2O to afford Cpd. H as an amorphous yellow solid (383 mg, 86%). 1H NMR (400 MHz, DMSO): 2.28 [s, 3H, ArCH3], 6.18 [brs, 1H, ArH], 7.11 [d, J=6.59 Hz, 1H, ArH], 7.65 Hz [d, J=8.52 Hz, 2H, ArH], 7.81 [m, 5H, ArH &ArNH2], 8.17 [d, J=8.52 Hz, 2H, ArH], 8.25 [d, J=9.30 Hz, 1H, ArH], 8.69 [m, 2H, ArH], 9.77 [s, 1H, ArH], 10.42 [s, 1H, ArH], 10.62 [br s, 1H, ArNHAr], 11.20 [v br s, 1H, ArNHAr], 12.63 [v br s, 1H, ArC(O)NH]. LCMS (APCl+): 508 (100%). HPLC: 98.5%.
Reaction SMILES: [C:1]([NH:8][C:9]1([C:12](O)=[O:13])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].CN1CCNCC1[Al+]C1CNCCN1C.[H-].[Na+].[Cl-]>O1CCCC1.CCOCC>[C:1]([NH:8][C:9]1([CH:12]=[O:13])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: CN1CCNCC1[Al+]C1CNCCN1C
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC1(C=O)CC1
Temperature: 0 °C

Procedure:
N-Boc-1-amino-1-cyclopropanecarboxylic acid is dissolved in tetrahydrofuran and stirred at 0° C. under argon. Bis(N-methylpiperazinyl)aluminum hydride is added and the reaction mixture is heated to reflux overnight. Ether is then added, and the excess hydride is quenced with saturated NaCl. The aqueous phase is separated and extracted with ether. The combined organic phases are washed with 2M NaOH, 2M HCl and saturated NaCl. The solution is dried over Na2SO4 and evaporated to yield N-Boc-1-amino-1-cyclopropanecarboxaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][C:6](=O)/[C:5]/2=[CH:14]\[O:15][CH3:16].S(=O)(=O)(O)[OH:18]>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH:6]=[C:5]2[C:14]([O:15][CH3:16])=[O:18]
Reactant: CO/C=C1\C(=O)OC(=O)c2ccc(F)cc21
Reactant: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1coc(=O)c2ccc(F)cc12
Temperature: 45 °C

Procedure:
To a suspension of (4Z)-6-fluoro-4-(methoxymethylene)-1H-isochromene-1,3(4H)-dione (1.30 g) in methanol (20 ml) was slowly added sulfuric acid (1.5 ml). The mixture was heated at 40-50° C. for 3 h. As the reaction proceeded the sub-title compound crystallized out. The reaction was cooled to room temperature and a white solid was collected by filtration and washed with cold methanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:6]([CH3:7])=[CH:5][CH2:4][C@@H:3]1[CH:8]([OH:10])[CH3:9].Br[CH2:13]Br>C(Br)(=O)C.C(OCC)C.[Zn]>[CH3:7][C:6]12[CH2:13][CH:5]1[CH2:4][C@H:3]([CH:8]([OH:10])[CH3:9])[C:2]2([CH3:1])[CH3:11]
Reactant: BrCBr
Reactant: CC1=CC[C@H](C(C)O)C1(C)C
Agent: CC(=O)Br
Agent: [Zn]
Solvent: CCOCC
Product: CC(O)[C@H]1CC2CC2(C)C1(C)C
Reaction time: 0.17 h
Yield: 4.2 %

Procedure:
A drop of acetyl bromide (1 drop) was added to a mixture of activated (with 1N HCl) zinc (19.6 g, 0.3 mol), cuprous bromide (1.5 g, 0.01 mol) and 1-((1S)-2,2,3-trimethylcyclopent-3-enyl)ethanol (ca. 20% ee, 15.4 g, 0.3 mol) in diethyl ether (50 ml). After 10 minutes stirring, dibromomethane (52.0 g, 0.3 mol) was added and stirring at reflux continued for 6 h. The solid was filtered off and washed with MTBE. The combined organic phases were washed with water and diluted citric acid solution, dried (MgSO4), concentrated in vacuo and distilled using a 5 cm Widmer-column to give 1-((3S)-1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)ethanol (2.1 g, 12.5% yield, colourless liquid; GC/MS: 3 main diastereomeric pairs of enantiomers 33+30.5+20%). Analytical samples of the three main pairs of enantiomers were obtained by flash chromatography (MTBE/hexane 1:3)
Reaction SMILES: [CH2:1]([N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[P:24]([OH:27])([OH:26])[OH:25].P(Cl)(Cl)Cl>O>[CH2:1]([N:11]([CH:12]([P:24]([OH:27])(=[O:25])[OH:26])[P:24]([OH:27])(=[O:26])[OH:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCN(C=O)CCCCCCCCCC
Reactant: OP(O)O
Solvent: O
Solvent: ClP(Cl)Cl
Product: CCCCCCCCCCN(CCCCCCCCCC)C(P(=O)(O)O)P(=O)(O)O
Temperature: 70 °C
Yield: 130 %

Procedure:
81.4 parts of didecylformamide and 20.5 parts of phosphorous acid were slowly reacted with 34.3 parts of phosphorus trichloride at 70°C, and the mixture was maintained at 70°C for a further 3 hours. The product was hydrolyzed by the addition of 500 parts of water, the diphosphonic acid thereby being precipitated. This was dissolved in ethanol, precipitated with acetone and dried in vacuo at 50°C. N,N-didecylaminomethane-diphosphonic acid was obtained in a yield of 130% based on PCl3 or 65% based on total phosphorus.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][C@@H:19]([CH3:23])[CH2:18]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:24](I)([CH3:26])[CH3:25]>CC#N.CCOC(C)=O>[CH:24]([N:20]1[CH2:21][CH2:22][N:17]([C:15]([O:14][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:16])[CH2:18][CH:19]1[CH3:23])([CH3:26])[CH3:25]
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)CCN1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)N1CCN(C(=O)OCc2ccccc2)CC1C
Temperature: 25 °C

Procedure:
Potassium carbonate (11.2 g) was added to a solution of (S)-1-benzyloxycarbonyl-3-methylpiperazine (D19)(10.18 g) in CH3CN (60 ml), followed by isopropyl iodide (11.3 ml) and the mixture was heated at reflux overnight. The reaction mixture was then allowed to cool to rt and the inorganics were filtered off. The filtrate was evaporated to give an oil which was taken up in EtOAc (100 ml) and washed with water (2×50 ml). The EtOAc layer was dried (MgSO4) and concentrated to give the title compound (D26) as an oil (8 g). LCMS electrospray (+ve) 277 (MH+).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:53])([F:52])[C:10]1[CH:11]=[C:12]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[CH2:13][N:14]([CH3:44])[C:15]([N:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)[CH2:19][C@@H:18]1[C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[CH3:43])=[O:16]>C(Cl)Cl>[F:53][C:9]([F:8])([F:52])[C:10]1[CH:11]=[C:12]([CH:45]=[C:46]([C:48]([F:49])([F:51])[F:50])[CH:47]=1)[CH2:13][N:14]([CH3:44])[C:15]([N:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]2)[CH2:19][C@@H:18]1[C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[CH3:43])=[O:16]
Reactant: Cc1cc(F)ccc1[C@H]1C[C@@H](N2CCN(C(=O)OC(C)(C)C)CC2)CCN1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(F)ccc1[C@H]1C[C@@H](N2CCNCC2)CCN1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.1 %

Procedure:
TFA (1 mL) was added to a solution of intermediate 15b (155 mg) in anhydrous DCM (5 mL). The solution was stirred at r.t. for 3 hours, then it was concentrated in vacuo. The residue was diluted in a saturated potassium carbonate solution (10 mL) and extracted with DCM (2×20 mL) and AcOEt (20 mL). The combined organic extracts were dried and concentrated in vacuo to give the title compound (104 mg) as an oil.
Reaction SMILES: [CH3:1][N:2]([CH:6]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[CH3:7])[C:3](=[O:5])[CH3:4].Cl[C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][N:2]([CH:6]([CH:8]1[CH2:9][CH2:10][N:11]([C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:12][CH2:13]1)[CH3:7])[C:3](=[O:5])[CH3:4]
Reactant: Clc1ncccn1
Reactant: CC(=O)N(C)C(C)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)N(C)C(C)C1CCN(c2ncccn2)CC1
Yield: 57.5 %

Procedure:
A mixture of N-methyl-N-[1-(4-piperidinyl]ethyl]acetamide (Example 6; 2.3 g, 10.4 mmole), 2-chloropyrimidine (1.37 g, 12 mmole), and sodium carbonate (3.18 g, 30 mmole) were reacted in a manner similar to that given for Example 7. The crude product was chromatographed on silica gel using 5% methanol/ethyl acetate as the eluent to give product as a viscous, orange oil (1.57 g, 56.9%).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([C:17]2[NH:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=2)[CH:14]=[CH:15][CH:16]=1.FC1C=C(C(=O)C)C=CC=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:58][CH2:59][C:60]([N:62]1[CH2:67][CH2:66][CH:65]([O:68][C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([C:75]([F:78])([F:77])[F:76])[CH:70]=2)[CH2:64][CH2:63]1)=[O:61]>CN(C=O)C.O>[O:61]=[C:60]([N:62]1[CH2:63][CH2:64][CH:65]([O:68][C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([C:75]([F:78])([F:76])[F:77])[CH:70]=2)[CH2:66][CH2:67]1)[CH2:59][NH:58][C:22]([C:19]1[CH:18]=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[CH:12]=2)[NH:21][N:20]=1)=[O:24]
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(O)c1cc(-c2cccc(F)c2)[nH]n1
Agent: CC(=O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cc(-c2cccc(F)c2)[nH]n1
Reaction time: 8 h
Yield: 57.86 %

Procedure:
DIPEA (165 mg, 1.3 mmol) was added to a stirred solution of 5-(3-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid (75 mg, 0.36 mmol) (prepared by the method used for the synthesis of Intermediate 29, starting from 3′-fluoroacetophenone) in DMF (2 mL) followed by HOBt (51 mg, 0.38 mmol) and EDCI.HCl (73 mg, 0.38 mmol). After 2 minutes 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (120 mg, 0.36 mmol) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford the residue. The residue was purified by dissolving in ethyl acetate and then reprecipitating with hexane to afford 103 mg (57.86% Yield) of 5-(3-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 491, 92.15%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 8.1 (m, 1H), 7.46 (m, 4H), 7.1 (m, 5H), 4.8 (m, 1H), 4.2 (d, 2H), 3.9 (m, 1H), 3.7 (m, 1H), 3.4 (m, 1H), 3.3 (m, 1H), 1.9 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[NH:8][C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=3)=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:11]=2)=[CH:4][C:3]=1[O:31]C.Cl.N1C=CC=CC=1.[NH4+].[OH-]>O>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[NH:8][C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=3)=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:11]=2)=[CH:4][C:3]=1[OH:31]
Reactant: COc1cc(Cc2nc(-c3ccc4ncccc4c3)c(-c3cccc(C)n3)[nH]2)ccc1F
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(O)c3)nc2-c2ccc3ncccc3c2)n1
Temperature: 190 °C
Reaction time: 1.33 h
Yield: 69 %

Procedure:
A mixture of 6-(2-(4-fluoro-3-methoxybenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoline (Example 80, prepared according to the method described in US 2008/0319012 A1) (948 mg, 2.23 mmol) and pyridine hydrochloride (95 g) was stirred at 190° C. for 80 min. Then the hot reaction mixture was poured into H2O (60 mL) and added NH4OH solution to pH 5. The aqueous solution was extracted with CH2Cl2 (30 mL, 7 times) and then the organic layer was dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by MPLC (MeOH:CH2Cl2=1:30 (v/v) to 1:15 (v/v)) to afford the solid, which was recrystallized from CH2Cl2/Et2O to give the title compound (635 mg, 69%). 1H NMR (300 MHz, CDCl3) δ 2.34 (3H, s), 3.95 (2H, s), 6.50 (1H, d), 6.56-6.57 (1H, m), 6.79 (1H, dd), 6.91 (1H, d), 7.25-7.33 (2H, m), 7.78 (1H, m), 7.91-7.97 (2H, m), 8.03 (1H, s), 8.81 (1H, d), 10.80 (1H, bs), 11.48 (1H, bs). MS (ESI) m/z 411 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=O.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]C#N)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:3][N:1]=[C:4]3[CH:5]=[CH:6][C:7]([C:10]4[N:14]([C:15]5[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=5)[N:13]=[CH:12][CH:11]=4)=[CH:8][C:9]=23)=[CH:25][CH:24]=1
Reactant: Cc1ccc(-n2nccc2-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: N#CCc1ccc(Cl)cc1
Product: Cc1ccc(-n2nccc2-c2ccc3noc(-c4ccc(Cl)cc4)c3c2)cc1

Procedure:
The title compound, light green solid (107 mg, 78%), MS (ISP) m/z=386.2 [(M+H)+], mp 204° C., was prepared in accordance with the general method of example 1 from 5-(4-nitro-phenyl)-1-p-tolyl-1H-pyrazole (intermediate E) (100 mg, 353 μmol) and commercially available 2-(4-chloro-phenyl)-acetonitrile.
Reaction SMILES: C(Cl)CCl.Cl.[CH3:6][N:7]1[C:14](=[O:15])[CH2:13][CH2:12][NH:11][C:10]2[N:16]=[CH:17][C:18](/[CH:20]=[CH:21]/[C:22]([OH:24])=O)=[CH:19][C:9]=2[CH2:8]1.C1C=CC2N(O)N=NC=2C=1.[CH3:35][O:36][C:37]1[C:38]([O:46][CH2:47][CH2:48][CH3:49])=[C:39]([CH2:43][NH:44][CH3:45])[CH:40]=[CH:41][CH:42]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C.C(#N)CC.C(OCC)(=O)C>[CH3:35][O:36][C:37]1[C:38]([O:46][CH2:47][CH2:48][CH3:49])=[C:39]([CH:40]=[CH:41][CH:42]=1)[CH2:43][N:44]([CH3:45])[C:22](=[O:24])/[CH:21]=[CH:20]/[C:18]1[CH:17]=[N:16][C:10]2[NH:11][CH2:12][CH2:13][C:14](=[O:15])[N:7]([CH3:6])[CH2:8][C:9]=2[CH:19]=1
Reactant: CCCOc1c(CNC)cccc1OC
Reactant: CN1Cc2cc(/C=C/C(=O)O)cnc2NCCC1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCC#N
Solvent: CCOC(C)=O
Product: CCCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(C)C(=O)CCN3)cccc1OC
Temperature: 40 °C
Reaction time: 17 h

Procedure:
EDC (54 mg, 0.28 mmol) was added to a suspension of (E)-3-(5-methyl-4-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-b][1,5]diazocin-8-yl)acrylic acid hydrochloride (70 mg, 0.23 mmol), HOBt (34 mg, 0.25 mmol), (3-methoxy-2-propoxyphenyl)-N-methylmethanamine (52 mg, 0.25 mmol) and (i-Pr)2EtN (0.20 mL, 1.2 mmol) in 5 mL of DMF:propionitrile (4:1). The mixture was allowed to stir for 17 h at 40° C. The mixture was cooled to room temperature and diluted with ethyl acetate (40 mL) and washed with water (50 mL) and NaHCO3 (50 mL), dried over MgSO4 and dried under high vacuum. The solid was then subjected to purification on Prep HPLC to obtain the product as a fluffy white solid. Yield 64 mg (62%); 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.73 (s, 1H), 7.50 (m, 2H), 7.05 (m, 1H), 6.86 (m, 2H), 6.73 (d, J=7.6 Hz, 1H), 4.72 (s, 3H), 4.00 (m, 2H), 3.89 (s, 5H), 3.14 (m, 5H), 2.83 (s, 3H), 1.82 (q, J=6.8 Hz, 2H), 1.06 (t, J=7.6 Hz, 3H); ESI MS m/z 453 [C25H32N4O4+H]+
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]([CH3:4])[CH3:3].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>>[CH2:1]([N:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)CNCC(C)C
Product: COC(=O)CN(CC(C)C)CC(C)C

Procedure:
Following a procedure similar to that described in Preparation 47(a) 5.17 g (40 mmole) of N,N-diisobutylamine and 3.06 g (20 mmole) of methyl bromoacetate were reacted together, to give 4.02 g of the title compound as a white powder.
Reaction SMILES: [F:1][CH2:2][CH:3]([C:5]1[C:6]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][CH:8]=[CH:9][CH:10]=1)[OH:4].[C:19](OC(=O)C)(=[O:21])[CH3:20].O.OS(O)(=O)=O>C1COCC1>[C:19]([O:4][CH:3]([C:5]1[C:6]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][F:1])(=[O:21])[CH3:20]
Reactant: OC(CF)c1cccnc1SCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)OC(CF)c1cccnc1SCc1ccccc1
Yield: 92.7 %

Procedure:
A solution of 3-(2-fluoro-1-hydroxyethyl)-2-(phenylmethylthio)pyridine (16 g) in dry THF and acetic anhydride (7.4 g) is stirred with a catality amount of4-dimethylaminopyridine at room temperature for 12 hours. The reaction mixture is then poured into water and neutralized with dilute H2SO4. The mixture is extracted three times with methylene chloride, the combined extracts are dried (MgSO4), evaporated to obtain the desired product (oil, 17.2 g, Yield: 93%).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([C:8]([C:10]2[NH:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl>CN(C=O)C>[N+:1]([C:4]1[CH:16]=[CH:15][C:7]([C:8]([C:10]2[N:11]([CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:27])([CH3:26])[CH3:19])[CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cccc1C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-(4-nitrobenzoyl) pyrrole (White et al., J. Org. Chem., 42 4284 [1977]; 2 g. 9.26 mM) in DMF (5 ml) was added dropwise to a stirred suspension of sodium hydride (0.42 g of a 60% dispersion in mineral oil, 1.05 mM) in DMF (15 ml). After 10 minutes, the mixture was cooled to 5° C. and 2-trimethylsilylethoxymethyl chloride (1.7 ml) was added dropwise and the mixture stirred for 10 minutes. The cooling bath was removed and stirring continued for 1.5 hours. The mixture was poured into aqueous sodium carbonate solution and extracted into EtOAc. The organic layer was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography in dichloromethane, eluting with a gradient increasing in polarity from 2% to 5% MeOH/dichloromethane to give 2-(4-nitrobenzoyl)-1-(2-trimethylsilylethoxymethyl)pyrrole as an oil (2.3 g). MS: 347 (MH+) NMR: −0.1 (9H, s); 0.82 (2H, t) 3.5 (2H, t); 5.71(2H, s); 6.28 (1H, m); 6.84 (1H, m); 7.52 (1H, m), 7.92 (2H, d); 8.36 (2H, d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][NH:14][C:15]3[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([N:23]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)[CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:16]=3[NH2:42])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:43](OCC)(OCC)OCC.Cl.Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][N:14]3[C:15]4[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]=[C:17]([N:23]([CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)[CH2:33][C:34]5[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=5)[C:16]=4[N:42]=[CH:43]3)[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)c(C)c(NCc3cc(-c4ccc(F)cc4)no3)c2N)cc1
Reactant: CCOC(OCC)OCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)c(C)c3c2ncn3Cc2cc(-c3ccc(F)cc3)no2)cc1
Temperature: 25 °C
Yield: 32.7 %

Procedure:
N4-{[3-(4-Fluorophenyl)isoxazol-5-yl]methyl}-N2,N2-bis(4-methoxybenzyl)-5,6-dimethylpyridine-2,3,4-triamine (6.00 g, 10.6 mmol), triethyl orthoformate (2.6 mL, 16 mmol), concentrated hydrochloride acid (0.2 mL), and toluene (30 mL) were combined at heated at reflux for 24 hours. An analysis by HPLC indicated the reaction was incomplete. Therefore, pyridine hydrochloride (0.25 g) was added, and the reaction vessel was fitted with a Dean-Stark trap. The reaction was heated at reflux for an additional 1.8 days, and additional triethyl orthoformate (1 mL) was added and heating was resumed. After the reaction was heated for a total of three days, it was allowed to cool to room temperature, and concentrated under reduced pressure. The residue was dissolved in dichloromethane, and the resulting solution was washed sequentially with aqueous potassium carbonate, water, and brine; dried over magnesium sulfate; and filtered. The solution was purified by column chromatography on silica gel (eluting with 5% ethyl acetate in dichloromethane) to provide 2.0 g of 1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-N,N-bis(4-methoxybenzyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]([CH2:14][OH:15])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:7][C@@H:8]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:14][O:15][S:17]([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H](CC(C)(C)C)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
To a stirred solution of ((S)-1-hydroxymethyl-3,3-dimethyl-butyl)-carbamic acid tert-butyl ester (3.0 g, 13.0 mmol, 1.0 equiv.) in dry pyridine (14.8 mL) was added tosyl chloride (3.7 g, 19.4 mmol, 1.5 equiv) portionwise at 0° C. under nitrogen. After 4 hours of stirring at room temperature, the reaction mixture was extracted with ethyl acetate (200 mL), washed with water (3×200 mL) followed by brine (2×100 mL), and dried over anhydrous sodium sulfate to give a crude residue. The residue was purified by silica gel column chromatography (100-200 mesh) using a gradient of 5-10% ethyl acetate/hexanes to give toluene-4-sulfonic acid(S)-2-tert-butoxycarbonylamino-4,4-dimethyl-pentyl ester (3 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:11](O)[CH3:12].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][CH3:12])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(Cl)nc1

Procedure:
A mixture of 15.75 g (0.1 mol) 6-chloronicotinic acid, 6.9 g (0.15 mol) ethanol, 22.7 g (0.11 mol) dicyclohexylcarbodiimide and 3.7 g 0.03 mol) dimethylaminopyridine in 200 ml methylene chloride was heated at reflux for 2 hours. The mixture was allowed to cool, solvent removed in vacuo and residue subjected to flash chromatography to give the title compound as a low-melting white solid. PMR (CDCl3): δ1.44 (3 H, t, J~6.2 Hz) 4.44 (2 H, q, J~6.2 Hz), 7.44 (1 H, d, J~8.1 Hz), 8.27 (1 H, dd, J~8.1 Hz, 3 Hz), 9 02 (1 H, d, J3 Hz).