Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][CH:10]1[C:16](=[O:17])[N:15]([CH2:18][C:19]([N:21]([CH:30]([CH3:32])[CH3:31])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:20])[C:14]2[CH:33]=[CH:34][CH:35]=[CH:36][C:13]=2[N:12]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:11]1=[O:43])C1C=CC=CC=1>[Cl-].[Na+].O.C(OCC)(=O)C.[Pd]>[OH:8][CH2:9][CH:10]1[C:16](=[O:17])[N:15]([CH2:18][C:19]([N:21]([CH:30]([CH3:32])[CH3:31])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:20])[C:14]2[CH:33]=[CH:34][CH:35]=[CH:36][C:13]=2[N:12]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:11]1=[O:43]
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(COCc3ccccc3)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(CO)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.6 %

Procedure:
To a stirring solution of 460 mg (0.80 mmol) of 2-[3-(Benzyloxymethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide in 10 mL of DMF/CHCl3 1/1 is added 200 mg of 10% Pd/C. The resulting mixture is stirred at RT over an atmosphere of H2 gas (balloon) for 6 h. The reaction mixture is filtered through a pad of Celite to remove the catalyst, rinsing with EtOAc. The filtrate is diluted further with 20 mL of EtOAc and extracted with H2O (2×40 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by trituration with EtOAc/Et2O 1/1 afforded 365 mg of the title compound as a white solid: mp 136°-139° C.; 1H NMR (CDCl3, 400 MHz) δ7.40-7.19 (m, 8H), 7.10 (m, 2H), 6.94 (m, 3H), 4.99 (m, 1H), 4.28 (m, 2H), 4.15 (m, 2H), 3.84 (s, 3H), 3.65 (t, 1H, J=6.9), 2.37 (t, 1H, J=7.3), 1.06 (2×d, 6H, J=6.3); low resolution MS (FAB)m/e 488 (MH+), 323, 277; Anal. (C28H29N3O5) Calcd. C, 68.98; H, 6.00; N, 8.62 Found C, 67.05; H, 5.99; N, 8.33.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([CH3:38])[C:29]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=1>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:37][S:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH3:38])(=[O:36])=[O:35])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccccc2C)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and o-toluenesulfonamide in accordance with Procedure 1, Method B described hereinabove. Yield (37%); 1H NMR (CD3OD) δ 11.63 (br s, 1H), 7.54 (d, J=15.7 Hz, 2H), 7.39-7.09 (m, 15H), 6.87 (d, J=8.0 Hz, 2H), 6.81 (s, 1H), 6.41 (d, J=15.7 Hz, 1H), 3.02-2.73 (s, 3H), 2.37 (q, J=7.3 Hz, 2H), 0.83 (t, J=7.3 Hz, 3H); APcI m/z: 508 (M+H+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:16]=3[N:15]=2)[CH2:9]1)C1C=CC=CC=1.Cl.C(Cl)Cl>CO.[Pd]>[Cl:23][C:21]1[CH:20]=[CH:19][C:17]2[NH:18][C:14]([CH:10]3[O:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[N:15][C:16]=2[CH:22]=1
Reactant: Clc1ccc2[nH]c(C3CN(Cc4ccccc4)CCO3)nc2c1
Agent: [Pd]
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Clc1ccc2[nH]c(C3CNCCO3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.3 %

Procedure:
To a solution of 4-benzyl-2-(5-chloro-1H-benzo[d]imidazol-2-yl)morpholine (2.1 g, 6.41 mmol), and hydrogen chloride (0.234 g, 6.41 mmol) in CH3OH (50 mL) stirred under nitrogen at room temperature was added palladium on carbon (0.068 g, 0.641 mmol). The reaction mixture was stirred under hydrogen at 25° C. for 3 hours. CH2Cl2 was added and the mixture was filtered. The filtrate was evaporated in vacuo and the residue was dissolved in water (10 mL). The crude product was purified via reverse phase chromatography, eluting with 5˜50% of CH3OH in water, to afford the title compound (400 mg) as a white solid. LC-MS (ES) m/z=238 [M+H]+.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+]>>[OH:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:7]
Reactant: CCCCOC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O
Reactant: NCCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCCNC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O
Yield: 91.5 %

Procedure:
A mixture of 4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (50 mg, 0.14 mmol) (prepared according to WO 2004108681), 4-aminobutyric acid (730 mg, 7.08 mmol) and NaOMe (11 mL, 5.31 mmol, 0.5 M in MeOH) was refluxed for 3 days, then partitioned between EtOAc and water. 1 M HCl was added with stirring until pH was ˜1. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-60% EtOAc/hexanes+2% AcOH) to give 49 mg of the title compound. MS: (+) m/z 383.09 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:53]1[C:61]2[C:56](=[CH:57][C:58]([C:62]3[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=3)=[CH:59][CH:60]=2)[CH:55]=[CH:54]1>CN(C=O)C>[NH:53]1[C:61]2[C:56](=[CH:57][C:58]([C:62]3[CH:63]=[C:64]([NH:68][C:24]([C:19]4[C:20](=[O:23])[O:21][C:22]5[C:17]([CH:18]=4)=[CH:16][CH:15]=[CH:14][C:13]=5[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:65]=[CH:66][CH:67]=3)=[CH:59][CH:60]=2)[CH:55]=[CH:54]1
Reactant: Nc1cccc(-c2ccc3[nH]ccc3c2)c1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
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: O=C(Nc1cccc(-c2ccc3[nH]ccc3c2)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 75 %

Procedure:
DIEA (0.014 mL, 0.073 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.020 g, 0.066 mmol) and HATU (0.030 g, 0.073 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-Indol-5-yl)-phenylamine (0.015 g, 0.066 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected were collected and the solvent removed under vacuum to give 0.023 g of product in 68% yield: LCMS (ESI) m/z 465 (MH+).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH3:39])[CH:33]=1>CN(C=O)C.O>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH3:39])[CH:33]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(CBr)ccc1F
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2c(ccn2Cc2ccc(F)c(C)c2)c1-c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
Methyl 2-(tert-butoxy)-2-(6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (15 mg, 0.036 mmol) was dissolved in DMF (2 mL) and cooled to 0° C. Sodium hydride (0.175 mmol, 7 mg, 60% dispersion in oil) was added followed by dropwise addition of 4-(bromomethyl)-1-fluoro-2-methylbenzene. The reaction was stirred at ambient temperature 15 minutes, diluted with water and extracted with ethyl acetate, dried over sodium sulfate and purified by silica-gel chromatography (0-50% ethyl acetate/hexanes gradient elution) to give the title compound as a colorless oil 17 mg, 85%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.52-7.46 (m, 1 H), 7.42-7.35 (m, 1 H), 7.34-7.26 (m, 2 H), 7.16 (d, J=7.2 Hz, 1 H), 7.11 (td, J=2.3, 5.3 Hz, 1 H), 7.02-6.92 (m, 2 H), 6.15 (d, J=3.5 Hz, 1 H), 5.44-5.39 (m, 2 H), 3.77 (s, 3 H), 2.74 (s, 3 H), 2.47 (s, 3 H), 2.26 (d, J=1.4 Hz, 3 H), 1.67 (s, 1 H), 0.93 (s, 9 H); LCMS (m/z) ES+=489 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[C:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:12]([O:11][C:4]1[CH:3]=[C:2]([N:25]2[CH2:26][CH2:27][N:22]([C:19](=[O:21])[CH3:20])[CH2:23][CH2:24]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)CC1

Procedure:
The compound obtained in Step 1 above (300 mg), N-acetylpiperazine (300 mg), and potassium carbonate (500 mg) were dissolved in dimethylformamide (3 mL) and reacted at 80° C. overnight. The dimethylformamide of the reaction mixture was removed under reduced pressure, and added with water to form a solid. The solid was filtered to obtain a target compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CS(C)=O.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:13][CH2:14][CH2:2][CH2:3][CH2:4][CH2:12][CH2:11][CH3:10])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: CCCCCCCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 80 °C
Reaction time: 20 h

Procedure:
10.0 g (31.0 mmol) of 2,7-dibromofluorene, 19.7 g (89.0 mmol) of 1-bromooctane, 25 ml of dimethylsulfoxide, 24.9 g (623 mmol) of sodiumhydroxide and 50 ml of water were added to a 200 ml three-necked flask equipped with a reflux condenser, and this mixture was heated to 80° C. After the dissolution of the 2,7-dibromofluorene was confirmed, 608 mg (2.66 mmol) of benzyltriethylammonium chloride was added, and the resulting mixture was heated and agitated for 20 hours.
Reaction SMILES: CC[N:3]([CH2:6][CH3:7])[CH2:4][CH3:5].Br[C:9]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:10]=1C=O.C#CC.N.CO.C1C2C(=CC=CC=2)C=CN=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[F:17][C:15]1[CH:14]=[C:13]2[C:5](=[CH:9][CH:16]=1)[CH:4]=[N:3][C:6]([CH3:7])=[CH:10]2
Reactant: O=Cc1ccc(F)cc1Br
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#CC
Solvent: c1ccc2cnccc2c1
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc2cc(F)ccc2cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.4 %

Procedure:
DMF (50 mL) and NEt3 (10.30 mL, 73.9 mmol) were added to 2-bromo-4-fluorobenzaldehyde (10 g, 49.3 mmol) under argon in a 300 mL stainless steel reactor. The vessel was sparged with propyne and chilled in dry ice, then propyne (18.22 mL, 296 mmol) was distilled in. Bis(triphenylphosphine)palladium(II) chloride (0.173 g, 0.246 mmol) and copper(I) iodide (0.047 g, 0.246 mmol) were added, and the reactor was sealed and stirred for 4 hours at room temperature. The mixture was chilled and sampled. HPLC analysis indicated 90% conversion. 2 M NH3/MeOH (150 mL) was added to the chilled (and solidified) mixture, and the resulting solution was stirred 1.5 hours at 85° C. HPLC indicated complete conversion of alkyne to isoquinoline. The mixture was cooled and concentrated. Water (200 mL) and EtOAc (200 mL) were added, the layers were separated, and the organic layer was washed with brine (2×50 mL). The organic portion was extracted with 2N HCl (100 mL) and water (100 mL), then the aqueous layer was basified with 2N NaOH (120 mL). The mixture was extracted with EtOAc (2×100 mL) and the organic layer was washed with brine (50 mL), dried (Na2SO4), and concentrated, giving the title compound (6.87 g, 42.6 mmol, 87% yield). MS (DCI/NH3) m/z 162 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]2[N:7]([C@@H](C3C=CC=CC=3)C)[CH2:8][CH2:9][C@@H:4]2[CH2:3]1>[Pd].C(O)C>[CH3:1][N:2]1[CH2:3][C@@H:4]2[C@@H:5]([NH:7][CH2:8][CH2:9]2)[CH2:6]1
Reactant: C[C@H](c1ccccc1)N1CC[C@@H]2CN(C)C[C@@H]21
Agent: [Pd]
Solvent: CCO
Product: CN1C[C@H]2CCN[C@H]2C1

Procedure:
Palladium on carbon (10 g) was added to a solution of (3aR,6aR)-5-methyl-1-[(1R)-1-phenylethyl]-2,3,3a,4,6,6a-hexahydropyrrolo[3,2-c]pyrrole (Intermediate 38, 20 g, 0.087 mol) in ethanol (500 mL) under N2. The resulting mixture was hydrogenated at 70° C./45 psi for 24 h. The mixture was then filtered and the filtrate was concentrated in vacuo to give the title compound as a (10.9 g, 99%) solid; 1H NMR: 1.59-1.66 (1H, m), 1.86-1.95 (1H, m), 2.18 (s, 3H), 2.28-2.34 (2H, m), 2.46-2.47 (1H, m), 2.73 (2H, d), 3.00 (2H, m), 3.90 (2H, m).
Reaction SMILES: [NH2:1][C:2]([CH2:21][OH:22])([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1)[CH2:3][OH:4].[CH2:23](C(CC)(CC)C([O-])([O-])[O-])[CH3:24].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][C:24]1[O:22][CH2:21][C:2]([CH2:3][OH:4])([CH2:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH:12]=2)[N:1]=1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: CCCCCCCCc1ccc(CCC(N)(CO)CO)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCc1ccc(CCC2(CO)COC(C)=N2)cc1
Yield: 88.5 %

Procedure:
A solution of 450 mg (1.5 mmol) of 2-amino-2-hydroxymethyl-4-(4-(octyl)phenyl)butanol, 0.32 mL (1.75 mmol) of triethylorthoacetate and 0.56 mL (3.2 mmol) of DIEA in 6 mL of DMF was stirred at 75° C. for 2 h. The mixture was cooled, partitioned between 40 mL of 3:1 v/v ether/EtOAc and water and the layers were separated. The organic layer was washed with water and dried. Flash chromatography on silica gel using 4:1 v/v CH2Cl2/EtOAc as the eluant afforded 440 mg (91%) of the title compound: Mass spectrum (NH3—CI) 332 (M+H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][CH2:12][C@@H:13]([NH:17][C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[CH:25][C:26]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4[N:34]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH:35]=[CH:36][N:37]=4)=[CH:29][CH:28]=3)=[C:20]2[N:19]=1)[CH:14]([CH3:16])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:56](OC(Cl)(Cl)Cl)=[O:57]>ClCCl>[Si:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:12][C@H:13]([CH:14]([CH3:16])[CH3:15])[N:17]([C:18]2[CH:23]=[CH:22][N:21]3[N:24]=[CH:25][C:26]([C:27]4[CH:28]=[CH:29][C:30]([C:33]5[N:34]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:44])([CH3:45])[CH3:43])[CH:35]=[CH:36][N:37]=5)=[CH:31][CH:32]=4)=[C:20]3[N:19]=2)[C:56]1=[O:57])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H](CNCCO[Si](C)(C)C(C)(C)C)Nc1ccn2ncc(-c3ccc(-c4nccn4COCC[Si](C)(C)C)cc3)c2n1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H]1CN(CCO[Si](C)(C)C(C)(C)C)C(=O)N1c1ccn2ncc(-c3ccc(-c4nccn4COCC[Si](C)(C)C)cc3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
To a stirred solution of (S)—N1-(2-(tert-butyldimethylsilyloxy)ethyl)-3-methyl-N2-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)butane-1,2-diamine (0.055 mmol) in dichloromethane (1 mL) was added diisopropylethylamine (0.019 mL, 0.14 mmol). Trichloromethyl chloroformate (0.010 mL, 0.083 mmol) was added dropwise at 0° C. under N2. The reaction mixture was stirred at 0° C. for 30 minutes, then diluted with dichloromethane, washed with aqueous saturated NaHCO3 and brine, dried and concentrated. The residue was purified by silica gel chromatography (dichloromethane:MeOH, 100:1) to give (S)-1-(2-(tert-butyldimethylsilyloxy)ethyl)-4-isopropyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (15 mg, 40% for two steps). LCMS (APCI+) m/z 676.9 [M+H]
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[I:12].[H-].[Na+].[CH2:15](Br)[CH:16]=[CH2:17]>CN(C=O)C>[CH2:17]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[I:12])[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(O)c(I)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C(=O)OC)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Methyl 4-hydroxy-3-iodobenzoate (1.85 g, 6.65 mmol) is dissolved in anhydrous DMF (15 mL) in a dry flask under nitrogen, treated with NaH (60% dispersion in oil, 265 mg, 6.65 mmol) and stirred for 1 h at RT. Allyl bromide (633 μL, 7.32 mmol) is added and the mixture is stirred for 16 h. The mixture is concentrated and the residue is partitioned between EtOAc (25 mL) and H2O (25 mL). The organic layer is washed with a 50% saturated mixture of 1:1 NaC/NaHCO3 (2×10 mL), dried (MgSO4) and concentrated to a yellow oil which solidified to a white solid upon standing (2.12 g). The crude material is chromatographed over 100 g slurry-packed silica gel, eluting with 10% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 1.27 g (60%) of methyl 4-(allyloxy)-3-iodobenzoate as a colorless oil which solidified on standing. MS for C11H11IO3 (EI) m/z: 318 (M)+.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Cl:5][C:6]1[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=1[C:8]([N:10]1[CH2:17][C@@H:16](F)[CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9]>C1C=CC=CC=1>[Cl:5][C:6]1[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=1[C:8]([N:10]1[CH2:17][C@H:16]([C:6]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:7]=2)[CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9]
Reactant: O=C(O)[C@@H]1C[C@H](F)CN1C(=O)c1ccccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(O)[C@@H]1C[C@@H](c2ccccc2)CN1C(=O)c1ccccc1Cl

Procedure:
A suspension of aluminum trichloride (100 mg, 0.75 mmole) in benzene (3.7 ml) was stirred under argon and treated with (cis)-1-o-chloro- benzoyl-4-fluoro-L-proline (60 mg, 0.22 mmole). After stirring overnight, the reaction was cooled, quenched with 1N HCl and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried and concentrated in vacuo. The residue consisted of
Reaction SMILES: O.[OH-].[Na+].[OH:4][C:5]1[CH:18]=[CH:17][C:8]2[O:9][C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=3[C:7]=2[CH:6]=1.[ClH:19].[N:20]1([CH2:26][CH2:27][CH2:28][Cl:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[ClH:29].[ClH:19].[N:20]1([CH2:26][CH2:27][CH2:28][O:16][C:13]2[CH:14]=[CH:15][C:10]3[O:9][C:8]4[CH:17]=[CH:18][C:5]([O:4][CH2:28][CH2:27][CH2:26][N:20]5[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]5)=[CH:6][C:7]=4[C:11]=3[CH:12]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: ClCCCN1CCCCC1
Reactant: Oc1ccc2oc3ccc(O)cc3c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: c1cc2oc3ccc(OCCCN4CCCCC4)cc3c2cc1OCCCN1CCCCC1
Reaction time: 24 h

Procedure:
To 200 ml of water containing 13.0 g (0.33 mole) of sodium hydroxide and 12.0 g (0.06 mole) of 2,8-dihydroxydibenzofuran are added 250 ml of toluene and 29.7 g (0.15 mole) of 3-piperidinopropyl chloride hydrochloride, and the heterogeneous reaction mixture is heated to reflux with stirring for 24 hours. When cool, the organic layer is washed with water, dried over magnesium sulfate then concentrated in vacuo. The remaining oily residue is dissolved in ether and treated with ethereal HCl to give the desired product which is recrystallized twice from methanol-ethyl acetate yielding 2,8-bis(3-piperidonopropoxy)dibenzofuran dihydrochloride, M.P. 245°-246.5°C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([F:19])=[CH:4][N:3]=1.[F:20][C:21]1[CH:22]=[C:23]2[C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][N:27]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[C:24]2=[N:25][CH:26]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.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].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[CH3:16][C:15]([CH3:18])([CH3:17])[C@H:9]([NH:8][C:6]1[C:5]([F:19])=[CH:4][N:3]=[C:2]([C:29]2[C:23]3[C:24](=[N:25][CH:26]=[C:21]([F:20])[CH:22]=3)[N:27]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:40])=[O:41])[CH:28]=2)[N:7]=1)[CH2:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Reactant: CC(C)(C)[C@@H](CS(C)(=O)=O)Nc1nc(Cl)ncc1F
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H](CS(C)(=O)=O)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Temperature: 120 °C

Procedure:
A solution of (S)-2-chloro-N-(3,3-dimethyl-1-(methylsulfonyl)butan-2-yl)-5-fluoropyrimidin-4-amine, 79a, (0.15 g, 0.48 mmol), 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.24 g, 0.58 mmol), and K3PO4 (0.25 g, 1.16 mmol) in 2-methyl THF (5 mL) and water (1 mL) was purged with nitrogen for 30 minutes. X-Phos (0.015 g, 0.031 mmol) and Pd2(dba)3 (0.007 g, 0.008 mmol) were added and the reaction mixture was heated at 120° C. in a pressure vial for 2 hours. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-40% EtOAc/Hexanes gradient) to afford 210 mg of the desired product as a white foamy solid: 1H NMR (400 MHz, CDCl3) δ 8.54-8.43 (m, 2H), 8.24 (d, J=1.3 Hz, 1H), 8.09 (s, 1H), 8.03 (d, J =8.2 Hz, 2H), 7.23 (s, 1H), 4.99 (dt, J=20.3, 10.1 Hz, 2H), 3.37 (d, J=14.4 Hz, 1H), 3.07 (dt, J=31.3, 15.7 Hz, 1H), 2.83 (s, 3H), 2.33 (d, J=19.0 Hz, 3H), 0.98 (d, J=20.7 Hz, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA, C4) m/z 564.20 (M+H) RT=3.70 minutes.
Reaction SMILES: [NH2:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[C:4]([CH3:20])[CH:3]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>C1(C)C=CC=CC=1>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30]([NH:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:15])([CH3:16])[C:11]([O:13][CH3:14])=[O:12])=[C:4]([CH3:20])[CH:3]=1)=[O:31]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COC(=O)C(C)(C)CCCOc1cc(C)c(N)cc1C
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)CCCOc1cc(C)c(NC(=O)Nc2ccc(F)cc2F)cc1C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
5-(4-Amino-2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, methyl ester as the free base (Example 2) (4.15 g, 15 mmol) in 50 mL of toluene, 2.33 g (15 mmol) of 2,4-difluorophenyl isocyanate is added and the solution is stirred at 50° C. for 18 hours overnight. The solid mixture is evaporated on a rotary evaporator; the precipitate is taken up in acetonitrile, treated with charcoal, filtered, evaporated, and the residual, crystalline precipitate is recrystallized from 70 mL of toluene: 50 mL of isooctane to afford 5.7 g of the title compound as a slight pink solid; mp 152°-153° C.