Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH3:25])=[CH:17][C:16]=1[C:26]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH3:43][Mg]Br.Cl.C(OCC)(=O)C>C1COCC1>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH3:25])=[CH:17][C:16]=1[C:26]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)([OH:27])[CH3:43])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cc1cc(C(=O)C2CCCCC2)c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)cc1C(F)(F)F
Reactant: C[Mg]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(C)(O)C2CCCCC2)c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To a solution of (2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-5-methyl-4-(trifluoromethyl)phenyl)(cyclohexyl)methanone (52 mg, 0.085 mmol) in anhydrous THF (10 mL) under nitrogen at 0° C. was added methylmagnesium bromide (3.0 M solution in THF, 25.6 mg, 0.114 mL, 0.342 mmol). The solution was stirred at 0° C. for 30 minutes, then warmed to room temperature and stirred for 1.5 hours. The solution was then poured into a mixture of 2 N hydrochloric acid (10 mL) and ethyl acetate (20 mL). The solution was stirred at room temperature for 10 minutes then the layers were separated and the aqueous layer was extracted with ethyl acetate (3×15 mL). The combined organics layer was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on a 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 1-50% ethyl acetate in heptane) to yield the title compound (97.2%). 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H) 7.68 (s, 2H) 7.33 (s, 1H) 7.17 (s, 1H) 5.39 (d, J=16.17 Hz, 1H) 4.82 (d, J=15.76 Hz, 1H) 4.77(s, 2H) 4.15(s, 3H) 2.39 (s, 3H) 1.62 (m, 6H) 1.24 (s, 3H) 1.04 (m, 5H). LC-MS calc. 623.5, found 624.6 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.Cl.[N:22]1([CH2:27][CH2:28][CH2:29]Cl)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:29][CH2:28][CH2:27][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: Oc1ccc2ncnc(Nc3ccc(F)c(Cl)c3)c2c1
Reactant: ClCCCN1CCCC1
Agent: Cl
Product: Fc1ccc(Nc2ncnc3ccc(OCCCN4CCCC4)cc23)cc1Cl
Temperature: 100 °C
Yield: 45 %

Procedure:
Using an analogous procedure to that described in Example 1 except that the reaction mixture was heated to 100° C. for 16 hours, 4-(3'-chloro-4'-fluoroanilino)-6-hydroxyquinazoline was reacted with 3-(pyrrolidin-1-yl)propyl chloride hydrochloride (Chem. Abs., 82, 57736) to give 4-(3'-chloro-4'-fluoroanilino)-6-(3-pyrrolidin-1-ylpropoxy)quinazoline in 45% yield; NMR Spectrum: 1.73 (m, 4H), 2.03 (m, 2H), 2.58 (m, 4H), 2.69 (t, 2H), 4.22 (t, 2H), 7.44 (t, 1H), 7.51 (m, 1H), 7.73 (d, 1H), 7.85 (m, 1H), 7.9 (d, 1H), 8.17 (m, 1H), 8.52 (s, 1H), 9.72 (broad s, 1H); Elemental Analysis: Found C, 62.3; H, 5.9; N. 13.7; C21H22ClFN4O 0.25H2O requires C, 62.2; H, 5.6; N, 13.8%.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]([CH2:29][O:30][C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])=[C:27]3[C:22]([NH:23][C:24]([CH3:42])([CH3:41])[C:25](=[O:40])[N:26]3[CH3:39])=[CH:21][CH:20]=2)=[C:15]([O:43][CH3:44])[CH:14]=1)=[O:11])=O)(C)(C)C.[ClH:45]>O1CCOCC1.CCCCCC>[ClH:45].[NH2:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]([CH2:29][O:30][C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])=[C:27]3[C:22]([NH:23][C:24]([CH3:42])([CH3:41])[C:25](=[O:40])[N:26]3[CH3:39])=[CH:21][CH:20]=2)=[C:15]([O:43][CH3:44])[CH:14]=1)=[O:11]
Reactant: COc1cc(NC(=O)CNC(=O)OC(C)(C)C)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCCC
Product: COc1cc(NC(=O)CN)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
7-(4-tert-Butoxycarbonylaminoacetylamino-2-methoxyphenyl)-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 15-31, 10.5 mg, 0.0173 mmol) was dissolved in 1,4-dioxane (0.2 mL), 4N 1,4-dioxane solution of hydrochloride (41.3% L. 0.165 mmol) was added thereto. After the reaction mixture was stirred for 4 hours at room temperature, it was diluted with hexane (10 mL). The precipitated solid was filtered to give the titled compound (7.8 mg) as a pale yellow solid. (Yield 83%)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][C:26]=3[O:40][CH3:41])[N:15]=2)=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12].[C:42]([O:46][C:47](=[O:55])[CH2:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)([CH3:45])([CH3:44])[CH3:43]>>[CH2:32]([O:31][P:30]([CH2:29][C:28]1[CH:38]=[CH:39][C:25]([NH:24][C:16]2[N:15]=[C:14]([NH:13][C:5]3[CH:4]=[CH:3][C:2]([N:52]4[CH2:51][CH2:50][N:49]([CH2:48][C:47]([O:46][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:55])[CH2:54][CH2:53]4)=[C:10]4[C:6]=3[C:7](=[O:12])[N:8]([CH3:11])[CH2:9]4)[C:19]([C:20]([F:23])([F:21])[F:22])=[CH:18][N:17]=2)=[C:26]([O:40][CH3:41])[CH:27]=1)([O:34][CH2:35][CH3:36])=[O:37])[CH3:33]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CC(C)(C)OC(=O)CN1CCNCC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCN(CC(=O)OC(C)(C)C)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 199 using Diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl) pyrimidin-2-yl}amino)-3-methoxybenzyl]phosphonate and piperazine-1-acetic acid tert-butyl ester.MS (ES+): m/z 778.42 (100) [MH+]; HPLC: tR=0.86 min (UPLC, purity).
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([OH:17])=O)[CH:9]=[CH:8]2)([CH3:4])[CH3:3].Cl.Cl.[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C@H:27]([NH2:29])[CH3:28])[CH:23]=[N:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([CH:27]([NH:29][C:15]([C:10]2[CH:9]=[CH:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[CH:6]=3)[CH:11]=2)=[O:17])[CH3:28])[CH:23]=[N:22]1
Reactant: CC(C)(O)c1ccc2cc(C(=O)O)ccc2c1
Reactant: Cc1c([C@@H](C)N)cnn1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(C(C)NC(=O)c2ccc3cc(C(C)(C)O)ccc3c2)cnn1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.2 %

Procedure:
To a DMF (3 ml) solution of 6-(1-Hydroxy-1-methyl-ethyl)-naphthalene-2-carboxylic acid (U.S. Pat. No. 4,638,087, published 20 Jan. 1987, 95 mg, 0.413 mmol), Amine 9 (1-(5-Methyl-1H-pyrazol-4-yl)ethanamine dihydrochloride, 95 mg, 0.352 mmol), HBTU (188 mg, 0.495 mmol) and triethylamine (0.173 ml, 1.24 mmol) were added and the mixture was stirred for 24 hours at room temperature. The reaction was quenched with sat. NaHCO3 aq and water, and the product extracted with EtOAc 3 times. The combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (Ethylacetate:Hexane=2:1) to give the title product as a white solid (84.4 mg, 58.2% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.46-1.49 (3H, d), 1.50-1.53 (6H, s) 2.22-2.24 (3H, s) 3.67-3.68 (3H s) 5.13-5.20 (2H, m) 7.38-7.39 (1H, s) 7.69-7.72 (1H, d) 7.81-8.00 (4H, m) 8.39-8.40 (1H, s) 8.68-8.72 (1H, d). MS (ESI) m/z 352 (M+H)+.
Reaction SMILES: [H][H].[N:3]([CH:6]([F:25])[C:7]([NH:9][C:10]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:11]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)=[O:8])=[N+]=[N-]>[Pd].C(OCC)(=O)C>[F:25][CH:6]1[N:3]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:10]=2[NH:9][C:7]1=[O:8]
Reactant: [H][H]
Reactant: [N-]=[N+]=NC(F)C(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1F

Procedure:
Hydrogen is passed into a solution of 3.33 g. of 2-(α-azido-α-fluoro-acetamido)-5-chlorobenzophenone in 100 ml. of ethyl acetate in the presence of 0.3 g. of 5% palladium-on-charcoal for 4 hours. After filtering off the catalyst, evaporation and working up in the customary manner, there is obtained 3-fluoro-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one, m.p. 235° (decomposition).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[C:7]1(=O)[O:12][C:10](=[O:11])[CH:9]2[CH2:13][CH2:14][CH2:15][CH2:16][CH:8]12>C(O)C>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][N:1]1[C:10](=[O:11])[CH:9]2[CH2:13][CH2:14][CH2:15][CH2:16][CH:8]2[C:7]1=[O:12]
Reactant: NCC(O)CO
Reactant: O=C1OC(=O)C2CCCCC12
Solvent: CCO
Product: O=C1C2CCCCC2C(=O)N1CC(O)CO
Yield: 81 %

Procedure:
A 500-ml, two necked flask was equipped with a magnetic stirring bar, heating mantle and condenser. The flask was charged with 46 g of 3-amino-1,2-propanediol (0.50 mol.) and 300 ml of ethanol. Next, 77 g of hexahydrophthalic anhydride (0.50 mol.) was slowly added to the flask after which the reaction was refluxed for 12 hours. The imide formation was confirmed by IR. The ethanol was removed by a rotoevaporator to yield 92 g (81%) of the N-(2,3-dihydroxypropyl)hexahydrophthalimide.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[F:15][C:14]([F:17])([F:16])[C:10]1[CH:9]=[C:8]([C:7]2[C:2]([O:31][C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=4)=[CH:30][CH:29]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Reactant: Fc1ncccc1-c1ccnc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: FC(F)(F)c1cc(-c2cccnc2Oc2ccc(Nc3ccccn3)cc2)ccn1
Temperature: 80 °C

Procedure:
A mixture of 2-fluoro-2′-(trifluoromethyl)-3,4′-bipyridine (200 mg, 0.83 mmol), 4-(pyridin-2-ylamino)phenol (185 mg, 0.99 mmol) and cesium carbonate (323 mg, 0.99 mmol) in DMSO (3.3 mL) was heated to 80° C. for 4 h. The mixture was cooled to room temperature, diluted with H2O and filtered. The solids were washed with H2O and air-dried. The solids were suspended in sat aq. NaHCO3 and extracted with CH2Cl2 (3×). The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified using column chromatography (EtOAc/Hexanes=0→40%) to give the title compound. MS (ESI, pos. ion) m/z: 409 (M+1). IC50 (uM) 0.022.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CO.O.[Pd]>[CH:15]1([CH2:14][CH2:13][NH:12][C:10]([NH:9][CH2:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:11])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=C(NCCC1=CCCCC1)NCCC1=CCCCC1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: O=C(NCCC1CCCCC1)NCCC1CCCCC1
Yield: 97.7 %

Procedure:
1,3-Bis[2-(1-cyclohexen-1-yl)ethyl]urea (from step (a) example 8, 10.82 g, 39.14 mmol) was dissolved in methanol (400 mL)-water (12 mL) and shaken with 10% palladium on carbon (600 mg) under hydrogen (55 psi) on a Parr apparatus for 7.5 h. The catalyst was filtered off (Celite) and volatiles were removed in vacuo to leave 1,3-bis(2-cyclohexylethyl)urea as white crystals (10.72 g, 98%), m.p. 150°-151.5° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:6]=2[N:7]=1.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=1.O(C(C)(C)C)[Na]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1>[CH3:26][C:22]1[CH:21]=[C:20]([NH:1][C:2]2[N:3]=[CH:4][C:5]3[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:6]=3[N:7]=2)[CH:25]=[CH:24][N:23]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: CC(C)(C)OC(=O)N1CCc2cnc(N)nc2C1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(Nc2ncc3c(n2)CN(C(=O)OC(C)(C)C)CC3)ccn1
Temperature: 90 °C
Yield: 33.2 %

Procedure:
A tube was charged with 187 (300 mg, 1.20 mmol), Pd(dba)2 (34.5 mg, 0.0599 mmol), Binap-rac (74.6 mg, 0.120 mmol), 4-chloro-2-methylpyridine (229 mg, 1.80 mmol), and NaO-tert-Bu (230 mg, 2.40 mmol) and toluene (3 mL), sealed, degassed with nitrogen for 5 min then heated to 90° C. for 4 h. The reaction was cooled and filtered through a plug of CELITE®. The filtrate was concentrated and purified by reverse phase column chromatography (SP4) eluting with a MeCN/H2O gradient (5 to 85% MeCN) to afford 136 mg (33.2%) of tert-butyl 2-(2-methylpyridin-4-ylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (188).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([CH2:25][O:26][C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[N:21]([CH2:34][CH2:35][CH2:36][CH:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].[C:49]1([CH2:55][CH2:56][CH2:57]Br)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN(C)C=O>[CH:8]1([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([CH2:25][O:26][C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)[N:21]([CH2:34][CH2:35][CH2:36][CH:37]4[CH2:38][CH2:39][N:40]([CH2:57][CH2:56][CH2:55][C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)[CH2:41][CH2:42]4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: Clc1ccc(OCc2nc3c(OCC4CCCCC4)cccc3n2CCCC2CCNCC2)cc1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Clc1ccc(OCc2nc3c(OCC4CCCCC4)cccc3n2CCCC2CCN(CCCc3ccccc3)CC2)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 4-(cyclohexylmethoxy)-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]benzimidazole trifluoroacetate (0.29 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was treated with potassium carbonate (120 mg, 0.87 mmol, 3 eq) and 3-phenylpropyl bromide (87 mg, 0.43 mmol, 1.5 eq). The resulting mixture was stirred at 80° C. for six hours. The reaction was quenched by the addition of water (5 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (3×10 ml), and brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by column chromatography to yield the title product as a white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]([P:14](=[O:19])([O:17][CH3:18])[O:15][CH3:16])[P:8](=[O:13])([O:11][CH3:12])[O:9][CH3:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Br:28][CH2:29][C:30](Br)=[O:31]>C(Cl)Cl>[Br:28][CH2:29][C:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([P:14](=[O:19])([O:17][CH3:18])[O:15][CH3:16])[P:8](=[O:13])([O:11][CH3:12])[O:9][CH3:10])=[CH:20][CH:21]=1)=[O:31]
Reactant: O=C(Br)CBr
Reactant: COP(=O)(OC)C(Cc1ccc(N)cc1)P(=O)(OC)OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COP(=O)(OC)C(Cc1ccc(NC(=O)CBr)cc1)P(=O)(OC)OC
Yield: 68.2 %

Procedure:
A solution of 13 (0.959 g, 2.87 mmol) and pyridine (349 μL, 4.31 mmol) in CH2Cl2 was cooled in an ice-bath while stirring. A solution of bromoacetylbromide (250 μL, 2.87 mmol) in CH2Cl2 (5 mL) was added drop-wise and the resulting mixture was stirred for 4 h at that temperature. The reaction was quenched by the addition of water and the product was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude yellow solid was purified by silica gel chromatography resulting in 14 as a colorless solid (0.897 g, 67%). 1H NMR (400 MHz, CDCl3) δ 2.65 (tt, J=6.2, 24.4, 1H), 3.22 (dt, J=6.2, 17.4, 2H), 3.72 (d, J=3.7, 6H), 3.75 (d, J=3.7, 6H), 4.01 (s, 2H), 7.26 (d, J=8.6, 2H), 7.47 (d, J=8.6, 2H), 8.15 (bs, 1H): 31P (162 MHz, CDCl3) δ 26.33 (s, 2P).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15]Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:12][N:13]([CH2:14][CH2:15][O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1])[CH3:17]
Reactant: CN(C)CCCl
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc([N+](=O)[O-])ccc1OCCN(C)C
Yield: 20.5 %

Procedure:
Acetonitrile (30 mL) solution of 2 g of 2-methyl-4-nitrophenol, 1.87 g of 2-dimethylaminoethyl chloride and 5.4 g of potassium carbonate was stirred at 120° C. for 23 hours. The reaction liquid was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The organic layer was washed with water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the crude product was purified through silica gel column chromatography (chloroform/methanol) to obtain 600 mg of the entitled compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:7]([CH2:22]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:6]2.[CH3:34][C:35]1[CH:48]=[CH:47][C:38]([CH2:39][C:40]2([OH:46])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:37][CH:36]=1.Cl>C1(C)C=C(C)C=C(C)C=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:13])=[O:14])[CH:7]([CH2:22][N:43]1[CH2:42][CH2:41][C:40]([CH2:39][C:38]3[CH:37]=[CH:36][C:35]([CH3:34])=[CH:48][CH:47]=3)([OH:46])[CH2:45][CH2:44]1)[CH2:6]2
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Reactant: COc1ccc2c(c1)CC(COS(=O)(=O)c1ccc(C)cc1)N2S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Solvent: Cc1cc(C)cc(C)c1
Product: COc1ccc2c(c1)CC(CN1CCC(O)(Cc3ccc(C)cc3)CC1)N2S(=O)(=O)c1ccc(C)cc1
Yield: 73.2 %

Procedure:
(RS)-Toluene-4-sulfonic acid 5-methoxy-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-2-ylmethyl ester (200 mg, 0.41 mmol) and 4-(4-methylbenzyl)-piperidin-4-ol (337 mg, 1.64 mmol) were heated in mesitylene (10 ml) for 20 hr at 140° C. After cooling 4N HCl was added to pHl and the mixture extracted with EtOAc (3×25 ml), the extracts dried (Na2SO4), filtered and evaporated. Purification of the crude material over SiO2 (Merck 230-400 mesh) eluting with EtOAc-cyclohexane-Et3N (9:10:1) afforded the title compound as a yellow oil (155.9 mg, 0.3 mmol, 73%), MS: m/e=521.4 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](O)=[O:8])([O-:3])=[O:2].S(Cl)([Cl:18])=O>C1C=CC=CC=1.C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([Cl:18])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1

Procedure:
Typically, the 3,4-dinitrobenzoic acid starting material is dissolved in an aprotic solvent such as benzene or toluene and refluxed with thionylchloride for a period of about 2-6 hours to form the desired 3,4-dinitrobenzoyl chloride.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([C:17]([OH:19])=O)[NH:15][N:16]=2)=[C:8]([CH3:20])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].FC1C=CC(C2C(CO[C:35]3[CH:36]=[C:37]([C:40](O)=O)[NH:38][N:39]=3)=C(C)ON=2)=CC=1>>[N:39]1([NH:38][C:17]([C:14]2[NH:15][N:16]=[C:12]([O:11][CH2:10][C:9]3[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=3[CH3:20])[CH:13]=2)=[O:19])[CH2:40][CH2:37][CH2:36][CH2:35]1
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)O)[nH]n1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)[nH]n1
Product: CCCCc1noc(C)c1COc1cc(C(=O)NN2CCCC2)[nH]n1
Yield: 48 %

Procedure:
As described for example 10b, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid (140 mg, 0.5 mmol), instead of 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid, was converted, to the title compound (83 mg, 48%), which was obtained as a white solid. MS: m/e=348.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]1[S:18][C:17]([Cl:19])=[N:16][CH:15]=1>>[Cl:19][C:17]1[S:18][C:14]([CH2:13][O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=2)=[CH:15][N:16]=1
Reactant: Clc1ncc(CBr)s1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Product: O=[N+]([O-])c1cc(OCc2cnc(Cl)s2)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 5-Bromomethyl-2-chloro-thiazole (prepared according to the method of Kim, H.-J., Liu, S., Keum, Y.-S., Qing, X. J. Agric. Food Chem. 2003, 51, 1823-1830) using the conditions described in Example 10C to provide 2-Chloro-5-(4-chloro-3-nitro-phenoxymethyl)-thiazole which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:14].[CH:15]1([CH2:18][NH:19][C:20](=[O:37])[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[C:23](B3OC(C)(C)C(C)(C)O3)[CH:22]=2)[CH2:17]C1>CN(C=O)C>[CH:18]1([NH:19][C:20]([C:21]2[CH:22]=[C:23]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[N:12]=[C:11]([CH3:13])[O:10][N:9]=4)=[CH:4][C:3]=3[CH3:14])[C:24]([CH3:27])=[CH:25][CH:26]=2)=[O:37])[CH2:15][CH2:17]1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nc(-c2ccc(Br)c(C)c2)no1
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)c(C)c2)no1

Procedure:
Example 29 was prepared using 3-(4-bromo-3-methylphenyl)-5-methyl-[1,2,4]oxadiazole and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 17) using DMF as the solvent.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:15]([CH3:19])[C:16]([NH2:18])=[O:17])[C:7]2=[O:14].[F:20][C:21]([F:33])([F:32])[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN(C)C=O>>[CH3:13][O:12][C:11]1[C:2]([NH:1][C:29](=[O:30])[CH2:28][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:32])([F:20])[F:33])=[CH:27][CH:26]=2)=[C:3]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:14])[N:6]([C@H:15]([CH3:19])[C:16]([NH2:18])=[O:17])[CH:5]=[CH:4]2
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc2c(=O)n([C@H](C)C(N)=O)ccc2c1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(=O)n([C@H](C)C(N)=O)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-2-(5-amino-6-methoxy-1-oxoisoquinolin-2(1H)-yl)propanamide (98.34 mg, 0.0003764 mol), 2-(4-(trifluoromethyl)phenyl)acetic acid (115.2 mg, 0.0005646 mol), N,N-diisopropylethylamine (163.9 μL, 0.0009409 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (357.8 mg, 0.0009409 mol) and N,N-dimethylformamide (2 mL, 0.02 mol) was stirred at room temperature overnight. The reaction was only 40% complete. The solvent was removed and the residue purified by preparative HPLC (reverse phase) to obtain the pure product as a light yellow solid. MS m/z=448.3 (M+H). 1H NMR (400 MHz; DMSO-d6) δ 9.71 (s, 1H), 8.17 (d, J=8.87 Hz, 1H), 7.74 (d, J=7.76 Hz, 2H), 7.62 (d, J=7.76 Hz, 2H), 7.34-7.29 (m, 2H), 7.20 (s, 1H), 6.28 (d, J=8.48 Hz, 1H), 5.45 (q, J=7.07 Hz, 1H), 3.90 (s, 3H), 3.84 (s, 2H), 1.49 (d, J=7.39 Hz, 3H).