Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([S:36]([F:41])([F:40])([F:39])([F:38])[F:37])[CH:35]=1)[C:30](O)=[O:31])(=[O:26])=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:30](=[O:31])[C:29]2[CH:33]=[C:34]([S:36]([F:38])([F:39])([F:40])([F:41])[F:37])[CH:35]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:28]=2)=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cc(S(C)(=O)=O)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
66 mg (0.228 mmol) of the compound of Example 6A and 74 mg (0.228 mmol) of the compound of Example 32A were dissolved in 1.5 ml of anhydrous DMF, and 104 mg (0.273 mmol) of HATU and 48 μl (0.273 mmol) of N,N-diisopropylethylamine were added in succession. The reaction mixture was stirred at RT for 4 h and then separated completely into its components by preparative HPLC (Method 9). The product fractions were combined and concentrated to dryness on a rotary evaporator. This gave the title compound in the form of its formic acid salt. For conversion into the salt-free form, the formate was dissolved in about 5 ml of methanol and passed over a bicarbonate cartridge (from Polymerlabs, Stratospheres SPE, PL-HCO3 MP SPE, capacity 0.9 mmol). After re-evaporation, the residue was triturated with a little diisopropyl ether at RT. Filtration with suction and drying of the solid under high vacuum gave 72.6 mg (53% of theory) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([N:14]=[C:15]([NH2:17])[N:16]=2)[CH:13]=1)([O-:3])=[O:2].[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1.O>CN(C)C(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([N:14]=[C:15]([NH:17][C:24]([CH:21]3[CH2:23][CH2:22]3)=[O:25])[N:16]=2)[CH:13]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)C1CC1
Reactant: Nc1nc2ccc(Oc3cccc([N+](=O)[O-])c3)cn2n1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(Nc1nc2ccc(Oc3cccc([N+](=O)[O-])c3)cn2n1)C1CC1
Yield: 88.2 %

Procedure:
To a solution of 6-(3-nitrophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-amine (3.49 g, 12.9 mmol) in N,N-dimethylacetamide (20 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (2.46 mL, 27.0 mmol), and the mixture was stirred at room temperature for 15 hr. Water (40 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water and dried to give the title compound (3.86 g, 88%) as a white solid.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5](O)[CH:4]=1.CN(C)[CH:14]=[O:15].C(=O)([O-])[O-].[K+].[K+].[CH2:23]1[CH:27]2C[CH:29](Br)[CH:25]([CH2:26]2)[CH2:24]1>O>[CH:27]12[CH2:26][CH:25]([CH2:24][CH2:23]1)[CH2:29][CH:14]2[O:15][C:4]1[CH:5]=[C:7]([O:8][CH3:9])[CH:10]=[CH:11][C:3]=1[CH:2]=[O:1]
Reactant: BrC1CC2CCC1C2
Reactant: CN(C)C=O
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(C=O)c(OC2CC3CCC2C3)c1
Temperature: 80 °C

Procedure:
Isovanillin (50 g, 0.328 mol) is placed in a 1 liter round bottom flask which is equipped with a stir bar and reflux condensor and is charged with 500 ml of dimethylformamide. Potassium carbonate (45.3 g, 0.328 mol) is added to the reaction mixture which is heated to 80° C. At this temperature exo-2-bromonorbornane (12.57 g, 0.072 mol, 0.219 equivalents) is added and the reaction mixture is heated to 120° C. for 48 hours. The reaction is then cooled to room temperature and poured into 300 ml of water. The aqueous layer is extracted with ethyl ether (3×100 ml). The ethereal layer is washed with 1N sodium hydroxide solution (4×100 ml), water (3×100 ml) and saturated sodium chloride solution (3×100 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield 15.47 g of a green/brown oil. The crude product is purified by flash chromatography using a gradient eluent system of ethyl acetate/hexane [10% ethyl acetate/hexane→20% ethyl acetate/hexane] to yield 7.76 g (14.4%) of the aldehyde as a white solid. MP: 75.5° C.-79.5° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[O:22])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.I[CH2:39][CH2:40][OH:41]>C(Cl)(Cl)Cl.CO>[OH:41][CH2:40][CH2:39][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:21]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)=[O:22])=[O:10])[CH2:5][CH2:4]1
Reactant: OCCI
Reactant: N[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cc3)oc3ccccc23)CC1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(Cl)cc1)c1oc2ccccc2c1NC(=O)[C@H]1CC[C@H](NCCO)CC1
Temperature: 25 °C

Procedure:
Trans-3-[4-aminocyclohexylcarbonylamino]-N-(4-chlorophenyl)benzofuran-2-carboxamide hydrochloride (150 mg) obtained in Example 225 is suspended in acetonitrile/methanol (5/1, 6 ml), and thereto is added triethylamine (93 μl), and the mixture is stirred at room temperature for several minutes. The reaction solution is cooled with ice, and thereto is added 2-iodo-ethanol (29 μl), and the mixture is stirred at 50° C. for 3 hours. 2-Iodo-ethanol (58 μl) is further added thereto, and the mixture is stirred at 50° C. for 3 hours. Again, 2-iodo-ethanol (58 μl) is added thereto, and the mixture is further stirred at 50° C. for 15 hours. The reaction solution is concentrated under reduced pressure, and to the residue are poured water and a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is washed with water and a saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: ethyl acetate, then ethyl acetate/methanol=20/1) to give trans-3-[4-(2-hydroxyethylamino)cyclohexylcarbonylamino]-N-(4-chlorophenyl)benzofuran-2-carboxamide (104 mg). This product (104 mg) is dissolved in chloroform/methanol (5/1, 6 ml), and thereto is added 4N hydrogen chloride in ethyl acetate (1 ml). The solvent is evaporated under reduced pressure, and the resulting residue is suspended in diethyl ether, and collected by filtration to give the title compound (95 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=O)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.F[C:24](F)(F)[C:25]([OH:27])=O.C([SiH2]OC(C)(C)[CH:37]1[CH2:42][CH2:41][N:40]([NH2:43])[CH2:39][CH2:38]1)(C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:43][N:40]3[CH2:41][CH2:42][CH:37]([CH2:24][CH2:25][OH:27])[CH2:38][CH2:39]3)=[O:22])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1CCN(N)CC1
Product: O=C(NN1CCC(CCO)CC1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1018782-82-5) and 4-(t-butyl-dimethyl-silanyloxymethyl)-piperidin-1-ylamine trifluoroacetate (1:1) as starting materials; the silyl protecting group was lost during reaction and work-up; LC-MS (UV peak area/ESI) 96.6%, 444.1292 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:13](O)[CH3:14]>>[C:1]1([CH:7]([CH3:11])[C:8]([O:10][CH2:13][CH3:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C(=O)O)c1ccccc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(C)c1ccccc1
Reaction time: 60 h

Procedure:
Dissolve 2-phenylpropionic acid (30 g) in 2B ethanol (100 mL and add anhydrous HCl (10 g). Allow to sit for 48-72 hours, evaporate the solvent in vacuo and purify by distillation to give ethyl 2-phenylpropionate (31 g); bp 100 C at 6 mm.
Reaction SMILES: Br[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[CH:18][CH:17]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[CH3:31][C:32]1([CH3:66])[C:56]2[C:36]([CH:37]=[C:38]3[CH:55]=[C:54]4[C:41]([C:42]5[C:47]([C:48]6[C:53]4=[CH:52][CH:51]=[CH:50][CH:49]=6)=[CH:46][CH:45]=[CH:44][CH:43]=5)=[CH:40][C:39]3=2)=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33]1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.C1(C)C=CC=CC=1>[CH3:66][C:32]1([CH3:31])[C:56]2[C:36]([CH:37]=[C:38]3[C:39]=2[CH:40]=[C:41]2[C:54]([C:53]4[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=4[C:47]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=42)=[CH:55]3)=[CH:35][C:34]([C:2]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)=[CH:18][CH:17]=3)=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[CH:7]3)=[CH:33]1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Reactant: Brc1c2ccccc2c(-c2ccc(-c3cccs3)c3ccccc23)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)C=C(c2c3ccccc3c(-c3ccc(-c4cccs4)c4ccccc34)c3ccccc23)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Temperature: 90 °C
Yield: 62.7 %

Procedure:
A mixture of 6.5 g (14 mmol) of 2-(4-(10-bromoanthracen-9-yl)naphthalene-1-yl)thiophene, 7.53 g (16 mmol) of 2-(10,10-dimethyl-10H-indeno[1,2-b]triphenylen-12-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 0.16 g (0.14 mmol) of tetrakis(triphenylphosphine)palladium, 11 ml of 2M Na2CO3, 30 ml of EtOH and 65 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 4 h. After finishing the reaction, the mixture was allowed to cool to room temperature. Than 500 ml MeOH was added, while stirring and the precipitated product was filtered off with suction. To give 6.4 g (yield 63%) of yellow product which was recrystallized from toluene. MS (m/z, FAB+): 728.1; 1H NMR (CDCl3, 400 MHz): chemical shift (ppm) 9.13 (s, 1H), 8.64˜8.56 (m, 3H), 8.31˜8.05 (m, 5H), 7.95˜7.83 (m, 9H), 7.68˜7.61 (m, 2H), 7.55 (d, J=8.00 Hz, 1H), 7.49˜7.40 (m, 6H), 7.18 (d, J=6.20 Hz, 1H), 7.02 (t, J=6.20 Hz, 1H), 6.55 (d, J=8.00 Hz, 1H), 1.81 (s, 6H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:2].[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH2:1]([CH:3]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][C:14]([C:31]([C:30]3[CH:34]=[CH:35][C:27]([F:26])=[CH:28][CH:29]=3)=[O:32])=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:2]
Reactant: CCCCC(CC)Cn1c2ccccc2c2ccc3ccccc3c21
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC(CC)Cn1c2ccccc2c2cc(C(=O)c3ccc(F)cc3)c3ccccc3c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 11-(2-ethylhexyl)-11H-benzo[a]carbazole (10.0 g, 30.6 mmol) in CH2Cl2 (150 mL) are added 4-fluorobenzoyl chloride (5.03 g, 31.7 mmol) and AlCl3 (4.58 g, 34.3 mmol) at 0° C. After stirring for 0.5 hour, the reaction mixture is stirred for 2 hours at room temperature. The reaction mixture is poured into ice-water, and the crude product is extracted with CH2Cl2. The organic layer is washed with water and brine, dried over MgSO4. After concentration, the crude product is purified by column chromatography on silica gel eluting with a mixed solvent of n-hexane and CH2Cl2 (1:1) to obtain an off-white solid (8.14 g; 57%). The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 0.83 (t), 0.89 (t), 1.18-1.52 (m), 2.24-2.31 (m), 4.68-4.80 (m), 7.16 (t), 7.31 (t), 7.50 (t), 7.55-7.60 (m), 7.65 (t), 7.97 (dd), 8.06 (d), 8.31 (s), 8.50 (d), 8.65 (d); 19F-NMR spectrum (CDCl3). δ [ppm]−106.30.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.CC(C)([O-])C.[K+].[NH2:17]Cl>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH2:17])[CH:6]=[CH:5]2
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: NCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Nn1ccc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
A solution of 5-fluoro-1H-indole (16.9 mmol) and potassium tert-butoxide (33.8 mmol) in DMF (76 mL) is stirred at rt under N2 for 2 h. 0.15 M NH2Cl. in ether (169.2 mL) is added drop-wise for 15 minutes at rt. The reaction mixture is stirred at rt for 2 h, then quenched with 10% Na2S2O3 aqueous solution and extracted with ether. The organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 60-80% EtOAc in heptane to afford 5-fluoro-indole-1-ylamine (751 mg, 30%) as a solid. 1H NMR (300 MHz, CDCl3): δ 4.80 (br, 2N—H), 6.38 (d, H), 7.00 (m, H), 7.19-7.43 (m, 3H).
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[CH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7].[CH3:13][NH:14][CH3:15]>C(O)C>[CH3:13][N:14]([CH3:15])[C:3]([S:2][CH3:1])=[CH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7]
Reactant: CNC
Reactant: CSC(=CC(=O)C(F)(F)F)SC
Solvent: CCO
Product: CSC(=CC(=O)C(F)(F)F)N(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
The product of Example 1, 1,1-bismethylthio-4,4,4-trifluoro-1-buten-2-one, (2.16 g, 0.01 mol) and dimethylamine (0.45 g, 0.01 mol) were dissolved in ethanol (30 ml). The resulting solution was heated to 50° C. and maintained at that temperature with stirring for 1 hour. After this time, the resulting mixture was cooled to ambient temperature (20° C.) and the solvent was removed by evaporation under reduced pressure yielding a yellow residue. Chromatographic purifications of the solid using a silica column eluted with dichloromethane/methanol (30:1) gave the product, 1-dimethylamino-1-methylthio-4,4,4-trifluoro-1-buten-3-one, as a yellow oil in a yield of 2.1 g (98%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C@H:12]([CH3:15])[CH2:13]I)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[CH2:18]([CH:23]1[CH2:29][CH:28]2[NH:30][CH:25]([CH2:26][CH2:27]2)[CH2:24]1)[CH2:19][CH2:20][CH2:21][CH3:22]>CCCCCCC.CCOC(C)=O>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C@H:12]([CH3:15])[CH2:13][N:30]3[CH:25]4[CH2:26][CH2:27][CH:28]3[CH2:29][CH:23]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:24]4)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: C[C@H](CI)CN1C(=O)COc2cc(F)ccc21
Reactant: CCCCCC1CC2CCC(C1)N2
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2cc(F)ccc21
Yield: 30 %

Procedure:
The compound (S)-7-Fluoro-4-(3-iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (111MF20) (0.208 g, 0.59 mmol) and 3-Pentyl-8-azabicyclo[3.2.1]octane (0.106 g, 0.58 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) and prep HPLC gave the title compound (111MF30) (0.070 g, 29%). 1H NMR (CDCl3) δ 7.23-7.19 (m, 1H), 6.66-6.60 (m, 2H), 4.60-4.46 (m, 2H), 4.05-3.99 (m, 1H), 3.95-3.90 (m, 1H), 3.06-3.03 (m, 1H), 2.99-2.96 (m, 1H), 2.24-2.19 (m, 1H), 2.07-1.94 (m, 3H), 1.90-1.73 (m, 3H), 1.60-1.45 (m, 3H), 1.33-1.25 (m, 2H), 1.24-1.12 (m, 8H), 0.83-0.78 (m, 6H); 13C NMR (CDCl3) δ 164.1, 158.8 (d, J=243.3 Hz), 146.4 (d, J=11.5 Hz), 125.1 (d, J=3.1 Hz), 116.6 (d, J=9.3 Hz), 108.9 (d, J=22.8 Hz), 105.0 (d, J=25.7 Hz), 67.7, 60.9, 58.8, 58.1, 45.4, 38.3, 36.8, 36.6, 32.1, 31.6, 28.5, 28.4, 28.1, 27.0, 22.8, 17.0, 14.2.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Br[CH2:10][CH2:11][O:12][CH2:13][CH3:14].[C:15]12([C:25](O)=[O:26])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2>>[CH2:11]([O:12][CH2:13][CH2:14][N:3]1[C:2]([CH3:1])=[C:6]([CH3:7])[S:5]/[C:4]/1=[N:8]\[C:25]([C:15]12[CH2:24][CH:19]3[CH2:18][CH:17]([CH2:23][CH:21]([CH2:20]3)[CH2:22]1)[CH2:16]2)=[O:26])[CH3:10]
Reactant: Cc1nc(N)sc1C
Reactant: CCOCCBr
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Product: CCOCCn1c(C)c(C)s/c1=N\C(=O)C12CC3CC(CC(C3)C1)C2

Procedure:
4,5-Dimethylthiazol-2-ylamine, 1-bromo-2-ethoxyethane and 1-adamantane carboxylic acid were processed as described in Example 47 to afford the title compound. 1H NMR (CDCl3, 500 MHz) δ ppm 1.05 (t, J=7.02 Hz, 3 H) 1.61-1.76 (m, 6 H) 1.84 (d, J=2.50 Hz, 6 H) 1.95-2.03 (m, 3 H) 2.16 (s, 3 H) 2.21 (s, 3 H) 3.43 (q, J=7.07 Hz, 2 H) 3.69 (t, J=5.46 Hz, 2 H) 4.24 (t, J=5.46 Hz, 2 H); MS (ESI) m/z 363 (M=H)+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][C:37]1[CH:38]=[C:39]([CH:64]=[CH:65][CH:66]=1)[CH2:40][CH:41]1[CH2:45][C:44](=[O:46])[O:43][CH:42]1[C:47]1[O:48][C:49]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[C:50]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[N:51]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1>[C:52]1([C:50]2[N:51]=[C:47]([CH:42]3[CH:41]([CH2:40][C:39]4[CH:64]=[CH:65][CH:66]=[C:37]([OH:36])[CH:38]=4)[CH2:45][C:44](=[O:46])[O:43]3)[O:48][C:49]=2[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: CC(C)(C)[Si](Oc1cccc(CC2CC(=O)OC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1CC(Cc2cccc(O)c2)C(c2nc(-c3ccccc3)c(-c3ccccc3)o2)O1
Reaction time: 5 h
Yield: 80.8 %

Procedure:
A 1.0M solution of tetrabutylammonium fluoride in tetrahydrofuran (THF) (0.75 ml) was added to a solution of 3-[3-(tert-butyldiphenylsilyloxy)benzyl]-2-(4,5-diphenyl-2-oxazolyl)-5-oxotetrahydrofuran (0.26 g) in THF (0.75 ml) at room temperature. The resulting mixture was stirred at the same temperature for 5 hours and partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel to afford 2-(4,5-diphenyl-2-oxazolyl)-3-(3-hydroxybenzyl)-5-oxotetrahydrofuran (133 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=O)[CH:12]=2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][C@@H:52]([CH2:66][C:67]1[CH:72]=[C:71]([F:73])[CH:70]=[C:69]([F:74])[CH:68]=1)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=1.C(Cl)[Cl:76]>C(N(CC)CC)C>[ClH:76].[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([NH:51][C@@H:52]([CH2:66][C:67]3[CH:68]=[C:69]([F:74])[CH:70]=[C:71]([F:73])[CH:72]=3)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=3)=[O:16])[CH:12]=2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCN1CCc2ccc(C(=O)O)cc21
Reactant: ClCCl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CCCCN1CCc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Product: Cl
Temperature: 40 °C
Reaction time: 5 h

Procedure:
To a mixture of 1-butylindoline-6-carboxylic acid (0.2 g) in methylene chloride was added triethylamine (0.0.27 g), HOBT (0.125 g) and, HATU (0.347 g). The mixture was stirred at 40° C. for 15 minutes at which time (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (0.346 g) was added. The resulting mixture was stirred at 40° C. for 5 h then partitioned between water and methylene chloride. The layers were separated and the organic layer washed with water followed by brine and dried over anhydrous magnesium sulfate. Column chromatography on silica gel (100 mL) using 5% methanol in methylene chloride as eluent to give 0.100 g of the title compound: MS (ESI+) for C32H39F2N3O2 m/z 535.9 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[C:20]([O-])([O-])=O.[K+].[K+].[CH3:26][O:27][C:28](=[O:31])[CH2:29]Br>CC(C)=O>[CH3:26][O:27][C:28](=[O:31])[CH2:29][N:9]1[C:8]([C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[CH:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([CH3:20])[CH:14]=2)=[N:10]1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(-c2cc(-c3ccc(F)cc3)[nH]n2)cc1
Reactant: COC(=O)CBr
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Cn1nc(-c2ccc(F)c(C)c2)cc1-c1ccccc1

Procedure:
3.6 g 3,5-Bis-(4-fluoro-phenyl)-1H-pyrazole, 8.8 g K2CO3 and 1.34 mL 2-bromoacetic acid methyl ester were dissolved in 100 mL acetone and stirred over night under reflux. K2CO3 was filtered and the solvent was removed. The residue was purified by HPLC (method 1) to yield 2.6 g of the desired product.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:12]=2)=[O:9])=[C:6]([Cl:26])[CH:5]=1.[NH:27]1[CH2:31][CH2:30][N:29]=[C:28]1N1C(C)=CC(C)=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:26][C:6]1[CH:5]=[C:4]([CH2:3][NH:2][C:28]2[NH:29][CH2:30][CH2:31][N:27]=2)[CH:25]=[CH:24][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:12]=1)=[O:9]
Reactant: Cc1cc(C)n(C2=NCCN2)n1
Reactant: NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CNC2=NCCN2)cc1Cl

Procedure:
100 mg of the crude HCl salt of 4-(aminomethyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was reacted with 72 mg of 1-(4,5-dihydro-1H-imidazol-2-yl)-3,5-dimethyl-1H-pyrazole and 100 SL of DIPEA in 500 μL of DMF in the microwave at 150° C. for 5 minutes. The crude product was concentrated to dryness and purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4,5-dihydro-1H-imidazol-2-ylamino)methyl)benzamide. MS (Q1) 440 (M)+.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]2[O:36][C:35](=[O:37])[N:34]([CH2:38][C:39]([OH:41])=O)[C:33]=2[CH:42]=1.[C:43]1([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:48]=[CH:47][C:46]([C:49]([NH:57][CH3:58])([CH3:56])[CH2:50][N:51]2[CH2:55][CH2:54][CH2:53][CH2:52]2)=[CH:45][CH:44]=1.CCN(CC)CC>CN(C=O)C>[C:43]1([C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:48]=[CH:47][C:46]([C:49]([N:57]([CH3:58])[C:39](=[O:41])[CH2:38][N:34]2[C:33]3[CH:42]=[C:29]([Cl:28])[CH:30]=[CH:31][C:32]=3[O:36][C:35]2=[O:37])([CH3:56])[CH2:50][N:51]2[CH2:55][CH2:54][CH2:53][CH2:52]2)=[CH:45][CH:44]=1
Reactant: CNC(C)(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)Cn1c(=O)oc2ccc(Cl)cc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C(=O)Cn1c(=O)oc2ccc(Cl)cc21)C(C)(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
BOP (133 mg, 0.30 mmol) was added to a mixture containing (5-chloro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetic acid (68 mg, 0.30 mmol), 2-(4-biphenylyl)-N-methyl-1-(1-pyrrolidinyl)-2-propanamine (74 mg, 0.25 mmol) and Et3N (0.042 ml, 0.30 mmol) in DMF (3 ml) and the resulting mixture was stirred at room temperature for 16 h. The crude reaction mixture was purified by preparative HPLC (Xterra PrepRP 30×100 mm, 45 mL/min, A: acetonitrile B: water, PH 10, A: 50 to 90% over 12 min, UV detection at 214 nm) to give 17.5 mg (13.9%) as a white solid. MS (ES) m/e 504.4 [M+H]+.