Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(O)C>[O:10]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]=2[CH:8]=[CH:9]1
Reactant: Oc1cccc2occc12
Reactant: CCOC(=O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CCCCCOc1cccc2occc12

Procedure:
4-Hydroxybenzofuran (1.3 g, 0.0097 M), ethyl 6-bromohexanoate (2.17 g, 0.0097 M), anhydrous potassium carbonate (1.44 g), sodium iodide (60 mg) and 95% ethanol (10 ml) were reacted together to give ethyl 6-(4-benzofuranyloxy)-hexanoate which was subsequently hydrolysed, as previously described for the preparation of 5-(4-benzofuranyloxy)pentanoic awcid, to give 6-(4-benzofuranyloxy)hexanoic acid, m.p. 86°-87° C. (Found: C, 67.54; H. 6.48. C14H16O4 requires C, 67.73; H. 6.50%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:9][C:10]2[C:20]3[CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15][C:14]=3[CH:13]=[CH:12][C:11]=2[Cl:28])=[N:6][CH:7]=1.[Br-].[CH3:30][CH:31]([CH3:35])[CH2:32][CH2:33][Zn+]>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[C:24]([O:23][C:21]([N:17]1[CH2:18][CH2:19][C:20]2[C:10]([S:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([CH2:33][CH2:32][CH:31]([CH3:35])[CH3:30])=[CH:7][N:6]=3)=[C:11]([Cl:28])[CH:12]=[CH:13][C:14]=2[CH2:15][CH2:16]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Br)cn3)c2CC1
Reactant: CC(C)CC[Zn+]
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [Br-]
Solvent: ClCCl
Product: CC(C)CCc1ccc(CSc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To 6-(5-bromo-pyridin-2-ylmethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (219 mg, 0.452 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (18 mg, 0.022 mmol) under dry nitrogen add with stirring a solution of 0.5M 3-methylbutylzinc bromide in TIE (4.6 mL, 2.3 mmol). Degas, purge with dry nitrogen, and stir overnight at ambient temperature. Dilute with EtOAc, wash with water, dry over anhydrous MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (5:1) to give 3-tert-butoxycarbonyl-7-chloro-6-[5-(3-methyl-butyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (160 mg, 75%). MS (APCI+) m/z: 475 (M+H)+. Use a method similar to the General Procedure 1-4 to give the title compound as a tan solid. MS (APCI+) m/z: 375 (M+M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.OC=[C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17]>>[CH3:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][C:11]1[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][C:16]2=1
Reactant: O=C1CCCCC1=CO
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc2[nH]c3c(c2c1)CCCC3=O

Procedure:
6-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one was prepared from p-toluidine and 2-(hydroxymethylene)cyclohexanone in a similar manner as described in Example 1 to give a tan solid. 1H-NMR (CDCl3): δ 8.65 (s, 1H), 7.43 (s, 1H), 7.30 (d, 1H), 7.20 (d, 1H), 2.98 (t, 2H), 2.65 (t, 2H), 2.45 (s, 3H), 2.26 (quint, 2H); MS m/z 220 (M+1).
Reaction SMILES: C(OC([NH:8][CH:9]([C@@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=O)(C)(C)C.C(#N)C.[NH2:24][C:25]1[C:34]([F:35])=[C:33](F)[C:32]([F:37])=[C:31]2[C:26]=1[C:27](=[O:45])[C:28]([C:42]([OH:44])=[O:43])=[CH:29][N:30]2[C@@H:38]1[CH2:40][C@@H:39]1[F:41]>C(N(CC)CC)C>[NH2:24][C:25]1[C:34]([F:35])=[C:33]([N:18]2[CH2:19][CH2:20][C@@H:16]([CH:9]([NH2:8])[C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[CH2:17]2)[C:32]([F:37])=[C:31]2[C:26]=1[C:27](=[O:45])[C:28]([C:42]([OH:44])=[O:43])=[CH:29][N:30]2[C@@H:38]1[CH2:40][C@@H:39]1[F:41]
Reactant: CC(C)(C)OC(=O)NC(c1cccnc1)[C@@H]1CCNC1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1c(F)c(N2CC[C@@H](C(N)c3cccnc3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Yield: 32.8 %

Procedure:
3-(R)-[1-Tert-butoxycarbonylamino-1-(3-pyridyl)methyl]pyrrolidine [F2] (0.461 mmol) was added to an acetonitrile suspension (5 ml) of 5-amino-6,7,8-trifluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (156 mg, 0.493 mmol), and the mixture was heated under reflux for 19 hours in the presence of triethylamine (0.5 ml). After cooling, the solvent of the reaction solution was evaporated under a reduced pressure. The resulting residue was dissolved in chloroform (50 ml), this was washed with 10% citric acid (40 ml) and saturated brine (40 ml) and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was mixed with concentrated hydrochloric acid (5 ml) under ice-cooling, further mixed with 1 mol/l hydrochloric acid aqueous solution (5 ml) at room temperature and then washed with chloroform (50 ml×5). This hydrochloric acid aqueous solution was adjusted to an alkaline liquid property by adding 10 mol/l sodium hydroxide aqueous solution, further adjusted to a liquid property of pH 7.4 by adding concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then extracted with chloroform (150 ml×3). The resulting organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under a reduced pressure to obtain the crude title compound as light yellow crystals. This was purified by recrystallizing from ethanol to obtain 71.5 mg (32%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9](O)(=[O:11])[CH3:10]>S(Cl)(Cl)=O>[C:9]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])(=[O:11])[CH3:10]
Reactant: Oc1ccccc1F
Reactant: CC(=O)O
Solvent: O=S(Cl)Cl
Product: CC(=O)Oc1ccccc1F
Temperature: 150 °C

Procedure:
2-Fluorophenol (99.4 g, 886.7 mmol) was stirred in thionyl chloride (71.2 mL) and acetic acid (51 mL) added. After the initial reaction had subsided the mixture was heated to reflux for 4 hours. The solution was then heated at 150° C. overnight. The resulting dark solution was distilled under reduced pressure at an oil bath temperature of 190° C. to give the title compound as a pale yellow oil (120.9 g, 784.4 mmol).
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1.[CH3:28][O:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([CH2:36][C:37](O)=[O:38])[CH2:32][CH2:31]1>>[CH3:28][O:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([CH2:36][C:37]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:8]4[C:7]5[CH:6]=[CH:5][S:4][C:12]=5[CH:11]=[CH:10][N:9]=4)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:38])[CH2:32][CH2:31]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1
Reactant: CO[C@H]1CC[C@H](CC(=O)O)CC1
Agent: Cl
Product: CO[C@H]1CC[C@H](CC(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5sccc45)CC3)CC2)CC1

Procedure:
The title compound was prepared in analogy to example 4 starting from trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate B) (100 mg, 0.22 mmol) and (trans-4-methoxy-cyclohexyl)-acetic acid [CAS-Nr. 879877-61-9, US 2010/075985] (40 mg, 0.23 mmol). Purification by flash chromatography on silica gel (CH2Cl2/MeOH 95:5). White crystals (68 mg, 62%), MS (ISP) m/z=499.3 [(M+H)+].
Reaction SMILES: I[C:2]1[NH:6][C:5]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][CH:3]=1.[CH3:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[C:2]1[NH:6][C:5]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Ic1cnc(C2CCOCC2)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)c(-c2cnc(C3CCOCC3)[nH]2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
Into a 50-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 5-iodo-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole (compound 241.1, 400 mg, 1.44 mmol) in dioxane (15 mL). Methyl 4-methyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4, 397 mg, 1.44 mmol), potassium carbonate (993 mg, 7.18 mmol), water (1.5 mL) and Pd(dppf)Cl2 (105 mg, 0.14 mmol, 0.10 equiv) were added to the reaction. The reaction mixture was stirred overnight at 90° C., then diluted with 120 mL of EtOAc. The organic layer was washed with 3×40 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate as eluent to furnish 260 mg (60%) of the title compound as red oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[C:12](OC(=O)C)(=[O:14])[CH3:13]>O1CCCC1.C(O)(=O)C>[NH:1]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11])[C:12]([CH3:13])=[O:14]
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1C

Procedure:
349.6g (2.3 moles) of 4-amino-3-methyl-nitrobenzene were dissolved in 500g of tetrahydrofuran, 500g of acetic acid were added thereto, and 500g (3.5 moles) of acetic anhydride were added dropwise while stirring and heating at 70° to 80° C, and, after the completion of the acetic acid addition, the entire reaction system was reacted for 1 hour under reflux and then was allowed to cool whereby crystals were formed. The crystals were separated, filtered out and then dried.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9]2)=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:19][OH:20].C(=O)(O)[O-].[Na+]>CO>[OH:20]/[N:19]=[C:1](/[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:9][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:11]2)=[CH:16][CH:17]=1)\[NH2:2]
Reactant: NO
Reactant: COC(=O)C1CN(Cc2ccc(C#N)cc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Temperature: 25 °C
Yield: 54.1 %

Procedure:
A mixture of methyl 1-(4-cyanobenzyl)azetidine-3-carboxylate (760 mg, 3.30 mmol), hydroxylamine hydrochloride (459 mg, 6.60 mmol) and sodium bicarbonate (1109 mg, 13.20 mmol) in MeOH (4.9 mL) was heated to reflux for 2.5 hr. After cooling to rt, the reaction mixture was filtered and the filtrate was concentrated to a residue that was partitioned between EtOAc (75 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (75 mL) and the combined organic layers were dried (MgSO4) and concentrated to afford (Z)-methyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (470 mg, 1.785 mmol) as a colorless foam. MS:(M+H)=264.28. 1H NMR (400 MHz, CDCl3) δ ppm 3.30-3.39 (m, 3H) 3.54 (m, 2H) 3.64 (s, 2H) 3.71 (s, 3H) 4.86 (brs, 2H) 7.31 (d, J=8.3 Hz, 2H) 7.57 (d, J=8.3 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[CH3:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:8]([C:5]1[N:6]=[CH:7][C:2]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:3][CH:4]=1)=[O:9]
Reactant: O=Cc1ccc(Br)cn1
Reactant: CNC(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1ccc(C=O)nc1
Temperature: 110 °C
Yield: 51.3 %

Procedure:
A mixture of 5-bromo-2-pyridinecarbaldehyde (1.5 g, 8.064 mmol), 1,1-dimethylethyl methylcarbamate (D83) (1.267 g, 9.677 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.148 g, 0.161 mmol), xantphos (0,373 g, 0.645 mmol) and cesium carbonate (3.678 g, 11.289 mmol) in dioxane (35 mL) was heated at 110° C. overnight under an argon atmosphere. On cooling, the solvent was removed in vacuo and the residue partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, dried and concentrated to give the crude product which was purified by column chromatography. Elution with 0-50% ether/petroleum ether gave the title compound as a brown oil (0.977 g). δH (CDCl3, 400 MHz) 10.01 (1H, s), 8.79 (1H, d), 7.94 (1H, d), 7.86 (1H, dd), 3.40 (3H, s), 1.53 (9H, s). MS (ES+): 259.1 (MNa+), 181.2, no molecular ion (MH+) observed.
Reaction SMILES: C(O[C:4](=[O:21])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([NH:14][C:15](=[O:17])[CH3:16])=[C:7]([O:18][CH2:19][CH3:20])[CH:6]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1C[O:31]CC1>O=[Mn]=O>[C:15]1(=[O:17])[N:14]([C:8]2[C:7]([O:18][CH2:19][CH3:20])=[CH:6][C:5]([CH:4]=[O:21])=[CH:10][C:9]=2[O:11][CH2:12][CH3:13])[C:16]1=[O:31]
Reactant: CCOC(=O)c1cc(OCC)c(NC(C)=O)c(OCC)c1
Reactant: C1CCOC1
Agent: O=[Mn]=O
Agent: [Al+3]
Agent: [H-]
Product: CCOc1cc(C=O)cc(OCC)c1-n1c(=O)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of 4-acetylamino-3,5-diethoxy-benzoic acid ethyl ester (1.0 g, 3.56 mmol, 1.0 equiv; [CAS RN 142955-43-9] prepared as described in EP 488 861 A1, Rhone Poulenc Chimie) in anhydrous THF (40 mL) was added lithium aluminium hydride (0.283 g, 7.47 mmol, 2.1 equiv) and the reaction mixture stirred at rt for 2 h. The crude reaction mixture was filtered over Hyflo Super Cel, the filtrate extracted with ethyl acetate (3×50 mL) and the combined organic phases dried over MgSO4 providing 0.58 g (64%) of the benzyl alcohol. The crude reaction product (0.39 g, 1.54 mmol, 1.0 equiv) was dissolved in THF (20 mL) and activated MnO2 (1.34 g, 15.40 mmol, 10.0 equiv) was added. After stirring at 60° C. for 2 h, the reaction mixture was filtered over Hyflo Super Cel and the solvent removed by evaporation under reduced pressure providing 0.35 g (90%) of the title compound. MS (ISP): 252.1 [M+H]+.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[OH:12][C:13](C(F)(F)F)=O.OC(C(F)(F)F)=O.[OH:26]/[N:27]=[C:28](\[NH2:57])/[C:29]([CH3:56])([NH:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([NH:44][C:45]3[N:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:48]=[CH:47][N:46]=3)[CH:41]=[C:40]([CH3:55])[CH:39]=2)=[CH:34][N:33]=1)[CH3:30].C1N=CN(C(N2C=NC=C2)=O)C=1>O1CCOCC1>[CH3:55][C:40]1[CH:39]=[C:38]([C:35]2[CH:36]=[CH:37][C:32]([NH:31][C:29]([C:28]3[NH:57][C:13](=[O:12])[O:26][N:27]=3)([CH3:30])[CH3:56])=[N:33][CH:34]=2)[CH:43]=[C:42]([NH:44][C:45]2[N:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:48]=[CH:47][N:46]=2)[CH:41]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(NC(C)(C)/C(N)=N/O)nc2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(NC(C)(C)c3noc(=O)[nH]3)nc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DBU (10.0 μL, 0.066 mmol) was added to a mixture of (1Z)—N′-hydroxy-2-methyl-2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}propanimidamide bis-TFA salt (14.0 mg, 0.025 mmol) and CDI (4.26 mg, 0.026 mmol) in dioxane (100 μL). The reaction was stirred at room temperature overnight. The reaction mixture was filtered, diluted with DMF (500 μL), and directly purified by reverse phase HPLC. The isolated material was repurified by silica gel chromatography (0-100% ethyl acetate in hexanes with 1% triethylamine and then 20% methanol in dichloromethane) to yield 3-(2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}propan-2-yl)-1,2,4-oxadiazol-5(4H)-one. MS APCI calc'd for C22H21F3N7O2 [M+H]+ 472. found 472. 1H NMR (500 MHz, CDCl3) δ 8.67 (d, J=5.2 Hz, 1H), 8.34 (s, 1H), 7.79 (d, J=11.5 Hz, 2H), 7.41 (s, 1H), 7.31 (s, 1H), 7.05 (d, J=5.2 Hz, 2H), 6.64 (d, J=9.1 Hz, 1H), 2.43 (s, 3H), 1.80 (s, 6H).
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[C:5]([OH:25])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36]>CN(C)C=O.C(OCC)(=O)C.O>[F:26][CH:2]([F:1])[O:3][C:4]1[C:5]([O:25][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2O)nc2sccn12
Reactant: CC(C)(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2OCC(C)(C)C)nc2sccn12
Temperature: 110 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
To a stirred solution of Intermediate 6 (1.60 g, 4.209 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added cesium carbonate (2.74 g, 8.418 mmol) followed by 1-bromo-2,2-dimethylpropane (1.60 mL, 12.629 mmol) at room temperature. The resulting suspension was stirred at 110° C. overnight under nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (200 mL) and water (100 mL). The layers were separated. Aqueous layer was extracted with ethyl acetate (2×50 mL) and the combined organic layers were washed with brine (2×50 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure. The residue obtained after the evaporation of the solvent was purified by silica gel column chromatography using 10% ethyl acetate in petroleum ether to obtain 1.20 g of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.07 (s, 9H), 1.39 (t, J=6.9 Hz, 3H), 3.57 (s, 2H), 4.35-4.42 (m, 2H), 7.18 (t, J=74.7 Hz, 1H), 7.20-7.25 (m, 2H), 7.47 (d, J=3.9 Hz, 1H), 7.52-7.58 (m, 1H), 7.73 (d, J=16.2 Hz, 1H), 7.90 (d, J=16.2 Hz, 1H), 8.10-8.16 (m, 1H); APCI-MS (m/z) 451.10 (MH)+.
Reaction SMILES: FC(F)(F)[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[N:7]([CH:15]([CH3:17])[CH3:16])[CH:6]=1)=[O:4].[OH-:20].[Na+]>>[F:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([C:3]([OH:4])=[O:20])=[CH:6][N:7]2[CH:15]([CH3:17])[CH3:16])=[CH:12][CH:11]=1
Reactant: CC(C)n1cc(C(=O)C(F)(F)F)c2ccc(F)cc21
Reactant: [OH-]
Agent: [Na+]
Product: CC(C)n1cc(C(=O)O)c2ccc(F)cc21
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of 2,2,2-trifluoro-1-(6-fluoro-1-isopropyl-1H-indol-3-yl)-ethanone (1.65 g, 6.04 mmol) in a 20% aqueous sodium hydroxide solution (25 mL) was heated at 110° C. for 18 h. At this time, the reaction was cooled to 25° C., partitioned between water (50 mL) and ethyl acetate (50 mL), and treated with a 1N aqueous hydrochloric acid solution (50 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 6-fluoro-1-isopropyl-1H-indole-3-carboxylic acid (1.29 g, 96%) as a yellow solid: mp 177-180° C.; EI-HRMS m/e calcd for C12H12FNO2 (M+) 221.0852, found 221.0850.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][CH:16]=[CH:15]4)[C:9](=[O:11])[NH:10][C:5]2=[N:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30].C([O-])([O-])=O.[Na+].[Na+]>CC#N.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH:17]1[C:18]2[C:14](=[CH:13][C:12]([N:8]3[C:6]4=[N:7][C:2]([C:25]5[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=5)=[CH:3][N:4]=[C:5]4[NH:10][C:9]3=[O:11])=[CH:20][CH:19]=2)[CH:15]=[CH:16]1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: O=c1[nH]c2ncc(Br)nc2n1-c1ccc2[nH]ccc2c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(-c2cnc3[nH]c(=O)n(-c4ccc5[nH]ccc5c4)c3n2)cc(OC)c1OC
Temperature: 150 °C
Yield: 19.5 %

Procedure:
To a solution of 6-bromo-1-(1H-indol-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (27 mg, 0.08 mmol) in CH3CN (1 mL) in a Personal Chemistry microwave reaction vial was added 3,4,5-trimethoxyphenylboronic acid (17 mg, 0.08 mmol), bis(triphenylphosphine)-palladium(II)dichloride (6.0 mg, 0.008 mmol), and 1 M Na2CO3 (1 mL). The resulting mixture was de-gassed with Ar for 10 min, after which it was heated at 150° C. for 10 min in a Personal Chemistry Optimizer. The organic layer was separated, filtered, and concentrated in vacuo. The residue was purified by preparatory HPLC to yield the title compound (6.5 mg, 19%). 1H NMR (DMSO-d6, 300 MHz): δ 12.18 (s, 1H), 11.28 (s, 1H), 8.57 (s, 1H), 7.83 (d, J=1.8 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.42 (m, 1H), 7.37 (dd, J=1.8, 8.4 Hz, 1H), 7.20 (s, 2H), 6.51 (m, 1H), 3.78 (s, 6H), 3.66 (s, 3H); HPLC retention time: 2.30 minutes; MS ESI (m/z): 418.4 (M+1)+, calc. 417.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[CH3:8].CC1(C)C(C)(C)OB([C:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH:28]=2)O1>>[C:10]([NH:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([C:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:24]=2)[CH:3]=1)(=[O:14])[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1Br
Product: Cc1ccc(NC(=O)C(C)C)cc1C1=CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Prepared by Procedure W and Scheme AF using N-(3-bromo-4-methylphenyl)-2-methylpropanamide and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate: ESMS m/e: 259.1 (M−100)+.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].CCN=C=NCCCN(C)C.Cl.[CH3:21][O:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][O:28][CH3:29]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:21][O:22][CH2:23][CH2:24][N:25]([CH2:26][CH2:27][O:28][CH3:29])[C:1](=[O:8])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: COCCNCCOC
Reactant: C#CCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C#CCCCC(=O)N(CCOC)CCOC
Temperature: 25 °C

Procedure:
To a solution of hex-5-ynoic acid (7.11 g, 63.4 mmol), EDC.HCl (14.0 g, 72.9 mmol) and DMAP (387 mg, 3.17 mmol) in DCM (600 mL) at 0° C. was added bis(2-methoxyethyl)amine (9.3 mL, 63 mmol). The resulting mixture was warmed to RT for 20 hr and was then washed with hydrochloric acid (1 M, 2×500 mL) and water (500 mL). The organic layer was dried and evaporated in vacuo to afford the title compound, Intermediate B, as a yellow oil (16 g, 97%): 1H NMR (400 MHz, CDCl3) δ: 1.88 (3H, m), 2.26 (2H, m), 2.49 (2H, m), 3.32 (6H, s), 3.51 (4H, m), 3.55 (4H, m)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12](O)([CH3:15])([CH3:14])[CH3:13].C(N(C1C=CN=CC=1)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C)O
Reactant: Cc1ccc(CC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN(CC)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(CC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
450 g (3 mol) of 4-methylphenyl-acetic acid (Aldrich), 1.13 l (12 mol) of tert-butanol and 90 g (0.74 mol) of 4-(N,N-diethylamino)pyridine are dissolved in 2 l of dichloromethane. After addition of 680 g (3.3 mol of dicyclohexylcarbodiimide, dissolved in 400 ml of dichloromethane, the mixture is stirred at 25° C. for 20 h, the precipitated urea is filtered off with suction and washed with 200 ml of dichloromethane, and the organic phase is washed twice each with 500 ml of 2 M hydrochloric acid and water. The organic phase is concentrated and distilled.