Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]([O:17]CC1C=CC=CC=1)=[O:16])[C:10]([CH3:14])([CH2:12][OH:13])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>ClCCl.CN(C)C1C=CN=CC=1>[C:25]([O:13][CH2:12][C:10]([CH3:11])([CH3:14])[C@@H:9]([C:15]([OH:17])=[O:16])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)OCc1ccccc1)C(C)(C)CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
To a solution of the product of Example 174D (0.175 g, 0.519 mmol) in dichloromethane (5.0 mL) were added 4-(dimethylamino)pyridine (0.070 g, 0.573 mmol) and acetic anhydride (0.054 mL, 0.571 mmol) and the mixture was stirred at room temperature for 30 minutes. The reaction was extracted with ethyl acetate and the organic layer was washed with 10% citric acid, dilute NaHCO3, and brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in a mixture of ethyl acetate (4.0 mL) and methanol (1.0 mL) and 20% Pd(OH)2 on carbon (0.10 g) was added, and the reaction was stirred under an atmosphere of hydrogen (balloon pressure) for 1 hour. The mixture was filtered through celite and the solvent was evaporated to give the title compound (0.15 g), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[Cl:18])=[O:22])=[N:15][CH:16]=2)=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1ccc(-c2cc3c(cc2Cl)CCO3)cn1
Product: O=C(Nc1ccc(-c2cc3c(cc2Cl)CCO3)cn1)c1ccccc1Cl
Yield: 69.7 %

Procedure:
Similarly, N-[5-(5-chloro(2,3-dihydrobenzo[3,4-b]furan-6-yl))(2-pyridyl)](2-chlorophenyl)carboxamide (154) (16.1 mg, yield 69.7%, purity>90%) was prepared from 5-(5-chloro-2,3-dihydrobenzo[3,4-b]furan-6-yl)-2-pyridylamine (151) (15 mg, 0.06 mmol) and 2-chlorobenzoyl chloride (11 μl).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH2:8][N:9]([C:13]1[C:18]([N+:19]([O-])=O)=[CH:17][N:16]=[C:15]([Cl:22])[N:14]=1)[CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:23])[CH2:7][CH2:8][N:9]([C:13]1[C:18]([NH2:19])=[CH:17][N:16]=[C:15]([Cl:22])[N:14]=1)[CH:10]([CH3:12])[CH3:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)N(CCC(=O)OC(C)(C)C)c1nc(Cl)ncc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)N(CCC(=O)OC(C)(C)C)c1nc(Cl)ncc1N
Yield: 98.8 %

Procedure:
A mixture of 1.6 g (0.0045 mole) of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-isopropyl-amino]-propanoic acid tert-butyl ester (IV-43) in 50 mL of ethyl acetate and 0.5 g of 5% palladium on carbon catalyst was stirred under an atmosphere of hydrogen until hydrogen uptake was complete. The mixture was filtered through a pad of Celite, washing the filter pad with dichloromethane. Concentration of the filtrate under reduced pressure gave 1.4 g of 3-[(5-amino-2-chloro-pyrimidin-4-yl)-isopropyl-amino]-propanoic acid tert-butyl ester (V-43). This material was used directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:10])(S(F)(=O)=O)C(O)=O.[OH:11][CH2:12][C:13]1[N:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[CH:15][CH:14]=1>CC#N.[Cu]I>[F:1][CH:2]([F:10])[O:11][CH2:12][C:13]1[N:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cccc(CO)n1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: [Cu]I
Solvent: CC#N
Product: CCOC(=O)c1cccc(COC(F)F)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 11.7 %

Procedure:
2,2-Difluoro-2-(fluorosulfonyl)acetic acid (495 mL, 4.79 mmol) was added dropwise to a solution of ethyl 6-hydroxymethylpyridine-2-carboxylate (800 mg, 4.79 mmol) and CuI (91 mg, 0.479 mmol) in MeCN (10 mL) at room temperature at a rate to maintain the internal temperature <30° C. The mixture was stirred for a further 20 min at room temperature, poured onto brine/water and extracted with EtOAc (×3). The combined extracts were dried (MgSO4), filtered, evaporated and purified by column chromatography (4:1 to 2:1, isohexane:EtOAc) to give the title compound (130 mg, 13%) as a colorless oil; NMR δH (400 MHz, CDCl3) 8.01 (1H, d, J 7.5 Hz), 7.89 (1H, t, J 7.5 Hz), 7.66 (1H, d, J 7.5 Hz), 6.41 (1H, t, J 74.0 Hz), 5.14 (2H, s), 4.49 (2H, q, J 7.0 Hz), 1.44 (3H, t, J 7.0 Hz); (M+H)+ 232.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1.[Cu]I>[C:9]1([C:15]#[C:16][C:2]2[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C#Cc1ccccc1
Reactant: O=Cc1ccc(Br)o1
Agent: [Cu]I
Solvent: C1CCOC1
Product: O=Cc1ccc(C#Cc2ccccc2)o1
Reaction time: 48 h
Yield: 68.3 %

Procedure:
To a solution of 5-bromofuraldehyde (1.0 g, 5.71 mmol, 1 eq), copper (I) iodide (0.163 g, 0.857 mmol, 0.15 eq), trans-dichlorobis(triphenylphosphine) palladium(II) (0.20 g, 0.287 mmol, 0.05 eq), and TEA (3.98 mL, 28.6 mmol, 5 eq) in THF (45 mL) is added dropwise phenyl acetylene (1.25 mL, 11.4 mmol, 2 eq). After 48 hr, the reaction appears complete. The reaction is filtered over a pad of celite, and the solvent is removed under reduced pressure. The reaction is purified by silica gel chromatography using a Biotage Flash 40M column (10% EtOAc/heptane) to give 5-phenylethynyl-furan-2-aldehyde as a yellow orange crystalline solid (0.765 g, 68.3%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[N:21]=[CH:20][N:19]=[C:18]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH:17]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[CH:6][C:5]=1[C:16]1[N:21]=[CH:20][N:19]=[C:18]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[CH:25]=2)[CH:17]=1
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(NCc2cccc(C(F)(F)F)c2)ncn1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCCCC2)cc1-c1cc(NCc2cccc(C(F)(F)F)c2)ncn1
Reaction time: 1 h

Procedure:
A mixture of 6-(2-nitro-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)pyrimidin-4-amine (184 mg) and 5% Pd/C (35 mg) in ethanol was stirred for 1 h under an atmosphere of hydrogen. The mixture was filtered and the solvent was evaporated.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:30][N:21]4[N:22]=[C:23]5[C:28]([CH:27]=[CH:26][CH:25]=[C:24]5Br)=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:39]([NH2:43])(=[O:42])[CH:40]=[CH2:41].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:30][N:21]4[N:22]=[C:23]5[C:28]([CH:27]=[CH:26][CH:25]=[C:24]5/[CH:41]=[CH:40]/[C:39]([NH2:43])=[O:42])=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)=[O:38])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(N)=O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5cccc(Br)c5nn4cc3-c3ccccc3)cc2)CCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5cccc(/C=C/C(N)=O)c5nn4cc3-c3ccccc3)cc2)CCC1
Yield: 143 %

Procedure:
200 mg (0.351 mmol) {1-[4-(7-Bromo-3-phenylpyrimido[1,2-b]indazol-2-yl)phenyl]-cyclobutyl}carbamic acid tert-butyl ester (intermediate example Int-2-1), 49.9 mg (0.7 mmol) acrylamide, 18.2 mg (0.06 mmol) tri-2-tolylphosphane and 7.9 mg (0.035 mmol) palladium(II) acetate were treated in 2.47 mL degassed acetonitrile as described in example 13 (step 1). After the work-up 281 mg (>100%) of the crude product were obtained and used in the next step without further purification.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27]O)=[CH:22][CH:21]=1>>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][O:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:18])=[O:17])=[CH:15][CH:14]=2)=[CH:22][CH:21]=1
Reactant: Cc1ccc(CCO)cc1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Product: Cc1ccc(CCOc2ccc(C(=O)NCC(=O)O)cc2)cc1
Yield: 89.6 %

Procedure:
The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (275 mg, 1.09 mmol) prepared in Example 1 (1a) and 2-(4-methylphenyl)ethanol (159 μL, 1.14 mmol) to give 306 mg of the title compound (colorless crystalline solid, yield: 90%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[F:15][C:14]([F:17])([F:16])[C:12]1[CH:11]=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:32]3[CH:31]=[N:30][C:29]([NH2:28])=[CH:34][CH:33]=3)[CH:7]=2)[N:13]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cc1
Product: Nc1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)cn1

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.6) (0.202 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.18 g, 80%). MS (ISP) 462.0 [(M+H)+]; mp 226° C.
Reaction SMILES: CC1(C)[O:7][C:6](=O)[CH:5]([CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)C(=O)O1.[CH3:27][NH2:28]>N1C=CC=CC=1>[CH3:27][NH:28][C:6](=[O:7])[CH2:5][CH:9]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:10]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1
Reactant: CN
Reactant: CC1(C)OC(=O)C(C(c2ccccc2)c2c[nH]c3ncccc23)C(=O)O1
Solvent: c1ccncc1
Product: CNC(=O)CC(c1ccccc1)c1c[nH]c2ncccc12
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A sealed tube loaded with 2,2-dimethyl-5-[phenyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-[1,3]dioxane-4,6-dione (700 mg), methylamine (2M in THF, 3 ml) and pyridine (5 ml) was stirred at 120° C. for 2 hours. The reaction mixture was cooled to RT and partitioned between H2O and EtOAc. The organic layer was separated, dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) affording N-Methyl-3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:4]2[N:3]=1.[CH2:17]1[NH:22][CH2:21][CH2:20][N:19]2[CH2:23][C@H:24]([CH2:27][OH:28])[CH2:25][CH2:26][C@@H:18]12.[F-].[Cs+]>CS(C)=O>[NH2:8][C:6]1[N:5]2[N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:4]2[N:3]=[C:2]([N:22]2[CH2:21][CH2:20][N:19]3[CH2:23][CH:24]([CH2:27][OH:28])[CH2:25][CH2:26][CH:18]3[CH2:17]2)[CH:7]=1
Reactant: Nc1cc(Cl)nc2nc(-c3ccco3)nn12
Reactant: OC[C@@H]1CC[C@H]2CNCCN2C1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: Nc1cc(N2CCN3CC(CO)CCC3C2)nc2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 18 h

Procedure:
5-chloro-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrimidin-7-ylamine (1 eq; see WO 99/43678 A1), cis-(octahydro-pyrido[1,2-a]pyrazin-7-yl)-methanol (1-2 eq), and CsF (1-2 eq) were dissolved in DMSO. The mixture was stirred at around 100° C. for 18 hours. The solution was then cooled to room temperature, filtered, and purified by preparative HPLC using aqueous CH3CN (buffered with 0.1% TFA) to give the desired compound as a white solid. Alternatively, for scale up synthesis, the DMSO solvent was removed and the crude product was chromatographed on silica gel column using 5-10% MeOH/CH2Cl2 as eluant to afford the desired product: 1H NMR (400 Hz, CD3OD) δ 7.69 (d, J=2.3 Hz, 1H), 7.10 (d, J=3.5 Hz, 1H), 6.61 (dd, J=3.5, 2.3 Hz, 1H), 5.73 (s, 1H), 4.32 (d, J=13.5 Hz, 1H), 4.24 (d, J=13.5 Hz, 1H), 3.82 (dd, J=10.5, 7.5 Hz, 1H), 3.74 (dd, J=10.5, 7.5 Hz, 1H), 3.10 (dt, J=12.5, 3.2 Hz, 1H), 2.94 (d, J=11.5 Hz, 1H), 2.79 (d, J=11.5 Hz, 1H), 2.67 (dd, J=13.0, 10.5 Hz, 1H), 2.21 (m, 2H), 1.96 (m, 1H), 1.85 (brd, 12.0 Hz, 2H), 1.60 (m, 1H), 1.47 (m, 2H). MS m/z: 370 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[CH:17]=[C:16]([N:29]3[CH2:38][CH2:37][C:32]4(OCC[O:33]4)[CH2:31][CH2:30]3)[N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:15]=[C:16]([N:29]3[CH2:30][CH2:31][C:32](=[O:33])[CH2:37][CH2:38]3)[CH:17]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[N:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(Nc2cc(N3CCC4(CC3)OCCO4)nc(N3CCN(Cc4ccccc4)CC3)n2)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: O=C1CCN(c2cc(Nc3ccc(Cl)c(Cl)c3)nc(N3CCN(Cc4ccccc4)CC3)n2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 10.9 %

Procedure:
A mixture of 2-(4-benzyl-1-piperazinyl)-N-(3,4-dichlorophenyl)-6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-4-pyrimidinamine (100 mg, 0.18 mmol) and 4M HCl (10 mL) in dioxane (20 mL) was stirred at room temperature for 24 hours. The crude product was purified by preparative thin-layer chromatography [eluent: EtOAc/hexane (2:3) with 1% NH3 in methanol], giving the desired product (10 mg, 11%).
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[H][H]>CC(O)=O.C(OCC)(=O)C.O=[Pt]=O>[N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]2[CH2:6][NH:7][CH2:8][CH2:9][CH:4]2[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)n1ccc2ccncc21
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2CCNCC21
Temperature: 25 °C
Reaction time: 12 h
Yield: 101.8 %

Procedure:
To a solution of tert-butyl 1H-pyrrolo[2,3-c]pyridine-1-carboxylate (0.5 g, 2.3 mmol) in AcOH (15 mL) was added PtO2 (0.25 g, 1.1 mmol). The mixture was treated with an atmosphere of hydrogen atmosphere (60 psi) and stirred for 12 h at rt. The suspension was filtered through a pad celite and concentrated in vacuo to afford a residue. The crude material was diluted with ethyl acetate (50 mL) and washed with sat. NaHCO3 (100 mL), the organic phase was separated, dried (Na2SO4) filtered and concentrated in vacuo to afford the title compound (0.53 g, 99% yield). 1H NMR (400 MHz, CDCl3) δ=6.07-5.58 (m, 1H), 4.03-3.68 (m, 1H), 3.57-3.22 (m, 3H), 3.05-2.66 (m, 2H), 2.49-2.19 (m, 1H), 1.96 (s, 4H), 1.77-1.64 (m, 1H), 1.45 (s, 9H). LC/MS (m/z): calc; d. For C12H22N2O2 (M+1H) 227. found 227.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[OH:28])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][C:2]2[CH:3]=[C:4]([NH:8][CH2:9][C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: Brc1cccc(NCc2cccnc2)c1
Product: c1ccc(-c2ccccc2Oc2cccc(NCc3cccnc3)c2)cc1

Procedure:
Using the procedure of Example 342 using N-(3-bromophenyl)pyridin-3-ylmethylamine and 2-phenylphenol (Aldrich) and purifying via preparative HPLC eluting with 90:10 to 80:20 DCM/ethyl acetate gave N-(3-(2-phenylphenoxy)phenyl)pyrid-3-ylmethylamine. Anal Calcd for C24H20N2O.0.2H2O: C, 80.96; H, 5.78; N, 7.87. Found: C, 81.07; H, 5.73; N, 7.63. MS found 353.1 [M+H]+
Reaction SMILES: C([O:4][C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8]([O:21][CH3:22])=[CH:9][C:10]([O:19][CH3:20])=[CH:11][C:12]=1[C:13]2=[O:18])(C)C.B(Cl)(Cl)Cl>C(Cl)Cl>[CH3:20][O:19][C:10]1[CH:9]=[C:8]([O:21][CH3:22])[C:7]2[C:6]3[C:14](=[CH:15][CH:16]=[CH:17][C:5]=3[OH:4])[C:13](=[O:18])[C:12]=2[CH:11]=1
Reactant: COc1cc(OC)c2c(c1)C(=O)c1cccc(OC(C)C)c1-2
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COc1cc(OC)c2c(c1)C(=O)c1cccc(O)c1-2
Temperature: 0 °C
Yield: 68.8 %

Procedure:
Prepare a solution of 5-isopropoxy-2,4-dimethoxy-fluoren-9-one (0.48 g, 1.6 mmole) in 25 mL CH2Cl2 and stir at 0° C. under argon. Dropwise, add boron trichloride (1.0 M in 1.8 mL CH2Cl2, 1.8 mmole) and stir the reaction for 1 hour. Quench with 20 mL water and stir vigorously. Filter and wash twice the resulting precipitate with 100 mL methylene chloride. Separate the organic layer from the filtrate and wash with brine. Dry with MgSO4, filter and strip off the solvent. Recrystallize the solid from CH2Cl2 /hexane (4:6) to obtain the title compound (0.28 g, 1.1 mmole, 69%). Rf =0.3.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][CH:9]([O:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([O:27][CH3:28])[N:18]2C2CCCCO2)=[C:14]([NH2:29])[N:13]=1)[CH3:10]>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:10][CH:9]([O:11][C:12]1[NH:13][C:14]([NH2:29])=[C:15]2[C:19]([N:20]=1)=[N:18][C:17]([O:27][CH3:28])=[N:16]2)[CH3:8]
Reactant: COc1nc2c(N)nc(OC(C)C)nc2n1C1CCCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1nc2nc(OC(C)C)[nH]c(N)c-2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Trifluoroacetic acid (1 ml, 12.98 mmol) was added to a stirred solution of 2-[(1-methylethyl)oxy]-8-(methyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6- amine (568 mg, 1.848 mmol) in methanol (10 ml) and the mixture was stirred at room temperature overnight. More trifluoroacetic acid (0.2 ml) was added and the reaction mixture stirred at room temperature for a further 1.5 hours and then evaporated in vacuo. The solid residue was triturated with ethyl acetate, collected by filtration, washed with ethyl acetate and dried in vacuo overnight to give the title compound as a white solid (405 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]>C(O)CCC>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:3][CH2:2][CH2:7][CH3:6])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Solvent: CCCCO
Product: CCCCOC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and n-butanol according to Method E. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94 (t, J=7.38 Hz, 3H), 1.12-1.55 (m, 9H), 1.66-1.75 (m, 3H), 1.83 (ddd, J=25.91, 13.02, 4.03 Hz, 1H), 2.01-2.11 (m, 1H), 2.20-2.27 (m, 1H), 2.85-2.96 (m, 1H), 3.07-3.15 (m, 1H), 3.61 (ddd, J=13.63, 9.33, 4.70 Hz, 1H), 4.29 (t, J=6.44 Hz, 2H), 4.97 (dd, J=9.53, 5.77 Hz, 1H), 7.21 (dd, J=8.86, 1.88 Hz, 1H), 7.42 (d, J=2.15 Hz, 1H), 7.69 (d, J=8.86 Hz, 1H), 7.83 (dd, J=8.32, 1.34 Hz, 1H), 7.87 (s, 1H), 8.12 (d, J=8.32 Hz, 1H); ES-MS m/z 476 (M+H).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH:7]([CH2:9][CH:10]=[CH2:11])[OH:8])[CH2:4][O:3]1.Cl.C(Cl)(Cl)Cl>O1CCCC1>[CH2:4]([OH:3])[CH:5]([OH:6])[CH:7]([OH:8])[CH2:9][CH:10]=[CH2:11]
Reactant: C=CCC(O)C1COC(C)(C)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: C=CCC(O)C(O)CO

Procedure:
A solution of 11 g of [R-(R*,R*)]-2,2-dimethyl-alpha-2-propenyl-1,3-dioxolane-4-methanol, prepared by the procedure described in J. Am. Chem. Soc., 1985, 107(26), 8186-8190, in 300 ml of 1:1 tetrahydrofuran: 2N hydrochloric acid is heated at the reflux temperature of the solvents for 2 hours. Chloroform is added and the layers are separated. The aqueous layer is re-extracted 2× with chloroform. The aqueous layer is neutralized with potassium carbonate and exhaustively extracted with 80% chloroform/iso-propanol. The combined organic layers are concentrated in vacuo to give 7.51 g of the desired product.
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22](=[O:28])/[CH:23]=[CH:24]/[CH2:25][CH2:26][CH3:27]>>[CH2:24]([CH:23]1[C:22](=[O:28])[O:13][C:12]2[NH:11][C:10]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[F:21])=[N:9][C:8]=2[CH:1]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCC/C=C/C=O
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Product: CCCCC1C(=O)Oc2[nH]c(-c3cc(F)ccc3F)nc2C1c1ccccc1
Yield: 90 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and (E)-hex-2-enal. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 17 as an off-white solid (103 mg, 90%). Analytical data for 17: 1H NMR (500 MHz, CDCl3) δ 9.54 (d, J=8.5 Hz, 1H), 7.88 (ddd, J=9.2, 6.1, 3.2 Hz, 1H), 7.35-7.27 (m, 2H), 7.12-7.03 (m, 3H), 7.01-6.93 (m, 1H), 4.29 (d, J=6.8 Hz, 1H), 3.18-3.08 (m, 1H), 1.86-1.73 (m, 1H), 1.46-1.36 (m, 2H), 1.36-1.15 (m, 4H), 0.86 (t, J=7.3 Hz, 3H); 13C NMR (CDCl3, 126 MHz) δ 169.2, 159.1 (d, JCF=243.5 Hz), 155.4 (d, JCF=240.4 Hz), 149.2, 137.2, 136.3, 129.2, 128.1, 127.7, 118.5 (dd, JCF=12.8, 9.0 Hz), 117.1 (dd, JCF=25.6, 8.8 Hz), 116.5 (dd, JCF=24.7, 9.4 Hz), 114.5 (dd, JCF=27.1, 3.8 Hz), 110.6 (d, JCF=3.8 Hz), 46.0, 39.3, 29.3, 26.7, 22.4, 13.9; IR (film) cm−1 3084, 3030, 2957, 1773, 1619, 1528, 1482, 1464, 1238, 1174, 1138, 1118, 1094, 1068, 874, 812, 766, 699; LRMS (ESI): Mass calcd for [M+H]+ C22H21F2N2O2: 383.2. found 383.4; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 0-30 min: isocratic 12% IPA/hexanes; 30-45 min: 20% IPA/hexanes 1.0 mL/min, 280 nm), Rt1 (major)=16.8, Rt2 (minor)=37.6 min; er=>99:1.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:53])[CH2:10][C:11]1[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:46]=[CH:45][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)=[CH:28][CH:27]=2)[N:16]=1>C(Cl)Cl>[NH:35]1[CH2:36][CH2:37][CH:32]([C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:17]3[N:16]=[C:15]([CH2:14][CH2:13][C:12]4[CH:45]=[CH:46][C:47]([C:49]([F:50])([F:51])[F:52])=[CH:48][C:11]=4[CH2:10][C:9]([NH2:8])=[O:53])[C:20]([C:21]([F:24])([F:22])[F:23])=[CH:19][N:18]=3)=[CH:27][CH:28]=2)[CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccc(C(F)(F)F)cc4CC(N)=O)n3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Cc1cc(C(F)(F)F)ccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.7 %

Procedure:
TFA (1.0 mL) was added to a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)-4-(trifluoromethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A109) (0.121 g, 0.185 mmol) in DCM (10 mL) and the resulting mixture stirred for 24 hours at room temperature. The volatiles were evaporated under reduced pressure and the residue was dissolved in DCM. Cyclohexane was added and the resultant precipitate was collected by vacuum filtration to give the title compound 25 as a cream solid (0.065 g, 68%); 1H NMR (400 MHz, d4-MeOH) δ 8.55 (s, 1H), 7.61 (d, J=8.5 Hz, 2H), 7.57 (s, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 7.22 (d, J=8.6 Hz, 2H), 4.73-4.49 (m, 2H), 3.74 (s, 2H), 3.28-3.21 (m, 2H), 3.17-3.09 (m, 2H), 2.95 (m, 2H), 2.84-2.71 (m, 1H), 1.96 (d, J=13.6 Hz, 2H), 1.79 (m, 2H). LCMS-A: rt 4.679 min; m/z 552.3 [M+H]+.