Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([OH:33])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@@H:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][C@H:36]1[OH:48]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([NH:34][C@H:35]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[CH2:37][C@@H:36]4[OH:48])=[O:33])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Product: Cc1c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2O)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c2) and tert-butyl (3R*,4R*)-4-amino-3-hydroxy-piperidine-1-carboxylate (example C2) the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [C:1]([C:4]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]#[C:14][C:15]2[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])=[CH:28][CH:27]=3)[N:16]=2)[CH2:6][CH2:5]1)(=[O:3])[NH2:2]>CCOC(C)=O.CN(C=O)C.[Pd]>[C:1]([C:4]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][CH2:14][C:15]2[C:20]([C:21]([F:22])([F:24])[F:23])=[CH:19][N:18]=[C:17]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])=[CH:28][CH:27]=3)[N:16]=2)[CH2:6][CH2:5]1)(=[O:3])[NH2:2]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3C3(C(N)=O)CC3)n2)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cc1
Yield: 55.9 %

Procedure:
A solution of tert-butyl 1-(4-(4-((2-(1-carbamoylcyclopropyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)ethylcarbamate (0.25 g, 0.44 mmol) in EtOAc (12 mL) and DMF (2.0 mL) was stirred with Pd/C 10% (0.15 g) under an atmosphere of hydrogen for 16 hours at ambient temperature. The reaction mixture was diluted with EtOAc, filtered through a plug of Celite and washed with EtOAc. The solvents were removed in vacuo and the crude residue was purified by silica gel column chromatography (Combiflash Rf 0-100% EtOAc in cyclohexane) to give the title compound 70 as a colourless oil (0.14 g, 56%). LCMS-C: rt 5.88 min; m/z 570 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([CH:14]([O:18][C:19]2[CH:24]=[C:23]([CH3:25])[C:22]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[C:21]([CH3:36])[CH:20]=2)[CH:15](C)[CH3:16])=[CH:12][CH:13]=1)=[O:8].[OH-].[Li+].Cl>C1COCC1>[CH3:25][C:23]1[CH:24]=[C:19]([O:18][CH:14]([C:11]2[S:10][C:9]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[O:8])=[CH:13][CH:12]=2)[CH2:15][CH3:16])[CH:20]=[C:21]([CH3:36])[C:22]=1[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][CH:27]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(Oc2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)C(C)C)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(Oc1cc(C)c(-c2ccc(C(F)(F)F)cc2)c(C)c1)c1ccc(C(=O)NCCC(=O)O)s1
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a solution of 3-({5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxy)-2-methyl-propyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.0390 mg, 0.0731 mmol) in THF (2.0 mL) is added lithium hydroxide (1N aqueous, 2.0 mL) at rt and stirred overnight. The reaction mixture is acidified with 1 N HCl (2.4 mL), extracted with EtOAc (3×10 mL), dried over MgSO4, filtered, and conc. to provide the title compound (0.0356 g, 94%). MS (ES): 520.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([CH2:16][N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)=[CH:15][C:9]=2[N:8]=1>C(O)C.C(=O)([O-])[O-].[K+].[K+]>[N:1]1([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([CH2:16][N:17]4[CH:21]=[CH:20][N:19]=[CH:18]4)=[CH:15][C:9]=3[N:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Clc1nc2cc(Cn3ccnc3)ccc2[nH]1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: c1cn(Cc2ccc3[nH]c(-n4ccnc4)nc3c2)cn1
Reaction time: 1 h
Yield: 17 %

Procedure:
A mixture of 4.4 parts of 1H-imidazole and 5 parts of 2-chloro-5-(1H-imidazol-1-ylmethyl)-1H-benzimidazole was molten together for 1 hour at 140° C. The sticky mixture was taken up in a mixture of ethanol and potassium carbonate. The supernatant liquid was decanted and evaporated to dry. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and ammonium hydroxide (90:10:0.1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was taken up in 15 parts of water. The product was filtered off and crystallized from a mixture of methanol and ethyl acetate, yielding 0.95 parts (17%) of 2-(1H-imidazol-1-yl)-5-(1H-imidazol-1-ylmethyl)-1H-benzimidazole; mp. 226.2° C. (compound 258).
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.[CH:6]1([CH2:12][CH:13]=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:13][CH2:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: BrC(Br)(Br)Br
Reactant: O=CCC1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=CCC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
A solution of 76.36 g of tetrabromomethane in 100 ml of CH2Cl2 is added dropwise at -10° C. to a solution of 0.2 mol of cyclohexylacetaldehyde and 104.8 g of triphenylphosphine in 150 ml of CH2Cl2. After stirring at room temperature for 30 min, the mixture is filtered with suction, concentrated and purified on silica gel using petroleum ether as the eluent. 48 g of the title compound are obtained as an oil.
Reaction SMILES: [CH3:1][Si:2]([CH3:40])([CH3:39])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:28]([OH:30])[CH3:29])[CH:9]=1.C(N(CC)CC)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>C(Cl)Cl>[CH3:48][S:49]([O:30][CH:28]([C:10]1[CH:9]=[C:8]([N:7]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:39])([CH3:1])[CH3:40])[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=1)[CH3:29])(=[O:51])=[O:50]
Reactant: CC(O)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
To a solution of 1-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)ethanol (6.1 g, 10.4 mmol) in methylene chloride (100 mL) and triethylamine (7.1 mL, 50.9 mmol) under nitrogen was added methanesulfonyl chloride (2.4 mL, 31.0 mmol) dropwise. After 15 minutes the reaction was complete by HPLC. The contents of the flask were transferred to a separatory funnel, washed twice with water and twice with brine. The organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford 1-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)ethyl methanesulfonate (6.8 g; 98% yield) as a dark yellow oil that was used as is for the following step. HPLC: 6.18 min (Method D). LCMS: ESI+ m/z of 662 (M+H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.C(OC(N[C@@H](C1C=CC=C([N+]([O-])=O)C=1)CC(OCC)=O)=O)C1C=CC=CC=1>[Fe]>[NH2:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:15][C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C[C@H](NC(=O)OCc1ccccc1)c1cccc(N)c1
Agent: [Fe]
Agent: CCOC(=O)C[C@@H](NC(=O)OCc1ccccc1)c1cccc([N+](=O)[O-])c1
Product: CCOC(=O)C[C@@H](NC(=O)OCc1ccccc1)c1cccc(N)c1
Yield: 95 %

Procedure:
Using a procedure analogous to that used to prepare 34C, 39B (3.1 g, 8.3 mmol) was reacted with Fe to afford 39C (2.7 g, 95%) as a white solid. MS (ESI) m/z 343.35 (M+H)+.
Reaction SMILES: [CH:1]1[C:6]([C:7](/[C:9](/Cl)=[N:10]/[OH:11])=[O:8])=[CH:5][CH:4]=[C:3]([Cl:13])[CH:2]=1>C(O)CCCC#C>[Cl:13][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH:2]=[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][OH:8])[O:11][N:10]=2)=[O:8])=[CH:1][CH:2]=1
Reactant: O=C(/C(Cl)=N/O)c1ccc(Cl)cc1
Agent: C#CCCCCO
Product: O=C(c1ccc(Cl)cc1)c1cc(CCCCO)on1
Yield: 233.8 %

Procedure:
A solution of 12 g of 4-chlorophenylglyoxylohydroxamyl chloride in 30 g of 5-hexyn-1-ol was refluxed under N2 for 2.5 hours. Concentration of the product on a rotovapor under high vacuum gave 18 g of an oil. Purification by high pressure liquid chromatography with 5% ethyl acetate/CH2Cl2 used as a eluent yielded 12.0 g (78%) of an oil which solidified on standing, m.p. 48°-51°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:66]=[CH:65][C:53]2[NH:54][C:55]([C@@H:57]([NH2:64])[CH2:58][C:59]3[N:60]=[CH:61][S:62][CH:63]=3)=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:66]=[CH:65][C:53]2[NH:54][C:55]([C@@H:57]([NH:64][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][C:59]3[N:60]=[CH:61][S:62][CH:63]=3)=[N:56][C:52]=2[CH:51]=1
Reactant: N[C@@H](Cc1cscn1)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(C(=O)N[C@@H](Cc2cscn2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-(thiazol-4-yl)ethylamine in tetrahydrofuran. Yield: %; Rf value: 0.29 (silica gel: dichloromethane/ethanol=9:1); C25H24ClN5O2S (494.02); mass spectrum: (M+H)+=494/496 (chlorine isotope).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([CH:17]=[O:18])=[CH:11][C:10]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)([CH3:7])[CH3:6])C.CO.[OH-].[Li+]>O1CCCC1.O>[CH:17]([C:12]1[C:13]([O:15][CH3:16])=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:24])=[O:3])=[C:10]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:11]=1)=[O:18]
Reactant: CCOC(=O)C(C)(C)Oc1cc(OC)c(C=O)cc1-c1cccs1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC(C)(C)C(=O)O)c(-c2cccs2)cc1C=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.9 %

Procedure:
Ex-47D: To a solution of 2-(4-formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propionic acid ethyl ester (0.29 g, 0.83 mmol) in a mixture of tetrahydrofuran, water and methanol (9 mL, 4:1:1) was added lithium hydroxide (0.10 g, 2.49 mmol) and the resulting yellow slurry was stirred at rt for 5 h. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (1×5 mL). The aqueous layer was acidified with a 1 N HCl solution and extracted with ethyl acetate (3×15 mL). The combined organic layers was dried over sodium sulfate and concentrated to afford 0.13 g (87%) of 2-(4-formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propionic acid as a pale green solid, mp 183–184° C. 1H-NMR (300 MHz, CDCl3) δ 10.32 (s, 1H), 8.12 (s, 1H), 7.40 (d, 1H, J=3.6 Hz), 7.32 (d, 1H, J=4.8 Hz), 7.08 (dd, 1H, J=4.8, 3.6 Hz), 6.47 (s, 1H), 3.86 (s, 3H), 1.78 (s, 6H). MS (EI) m/z=320 ([M]+, 100%). Anal. Calcd. for C16H16O5S: C, 59.99; H, 5.03; S, 10.01. Found: C, 60.04; H, 5.26; S, 9.70.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH3:17])=[C:5]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7].C[N+]1([O-])CC[O:22]CC1.Cl>C(#N)C>[CH:2]([C:3]1[C:4]([CH3:17])=[C:5]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7])=[O:22]
Reactant: C[N+]1([O-])CCOCC1
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1C
Agent: Cl
Solvent: CC#N
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1C
Temperature: 25 °C
Yield: 76.9 %

Procedure:
18.90 g of methyl 3-bromomethyl-4-methylsulfonyl-2-methylbenzoate was dissolved in 180 ml of acetonitrile, and 20.67 g of N-methylmorpholine oxide was added over 10 minutes at room temperature. The resulting solution was stirred at room temperature for an hour, poured into ice water, acidified with concentrated hydrochloric acid, and extracted with benzene. The organic layer was washed with water, then with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure to give 11.59 g of the title compound as white crystals. The crude product was washed with ethanol to give white crystals of the title compound. m.p. 108~110° C.
Reaction SMILES: [C:1]([O:10][CH3:11])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[H-].[Na+].Cl[CH2:15][C:16]([C:18]1[C:23]([O:24][CH3:25])=[CH:22][C:21]([O:26][CH3:27])=[CH:20]C=1F)=[O:17].O>CN(C=O)C>[CH3:27][O:26][C:21]1[CH:22]=[C:23]([O:24][CH3:25])[C:18]2[C:16](=[O:17])[C:15]3[S:4][C:3]4[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=4[C:1]=3[O:10][C:11]=2[CH:20]=1
Reactant: COC(=O)c1ccccc1S
Reactant: COc1cc(F)c(C(=O)CCl)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)c3sc4ccccc4c3oc2c1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 40.8 %

Procedure:
A solution consisting of methyl thiosalicylate 28 (0.67 g, 4.0 mmol) in DMF was treated with NaH (0.19 g, 4.8 mmol as a 60% dispersion in mineral oil) and stirred at rt for approximately 5-10 minutes and then Example 27 (1 g, 4.3 mmol) was added followed by additional NaH (0.4 g, 10 mmol, as a 60% dispersion in mineral oil) and the reaction was heated at 100° C. for 30 minutes. The crude reaction mixture was poured into water, filtered, and the solid product washed with additional water, MeOH and hexanes. The product thus obtained was triturated with MeOH to yield 29 (0.51 g): 1H NMR (DMSO-d6) δ 8.16 (d, 2H, J=2.3 Hz), 7.71-7.61 (m, 2H), 6.91 (d, 1H, J=2.3 Hz), 6.63 (d, 1H, J=2.3 Hz), 3.95 (s, 3H), 3.89 (s, 3H); MS 335 (M+Na)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH3:7])[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[CH2:7][Br:18])[CH3:2]
Reactant: CCOC(=O)C=C(C)Oc1ccc(OC)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=C(CBr)Oc1ccc(OC)cc1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
A solution of 3-(4-methoxy-phenoxy)-but-2-enoic acid ethyl ester (0.98 g, 4.17 mmol) in carbon tetrachloride (23.2 mL) was treated with N-bromosuccinimide (0.81 g, 4.59 mmol) and benzoyl peroxide (81 mg, 0.33 mmol). The reaction was then heated to reflux for 5 h. At this time, the reaction was cooled to 25° C. and then was placed in the freezer over the weekend. At this time, the reaction was removed from the freezer and allowed to thaw. The resulting precipitate was removed by filtration and was rinsed with carbon tetrachloride (5 mL). The filtrate was concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 1-4% ethyl acetate/hexanes) afforded impure 4-bromo-3-(4-methoxy-phenoxy)-but-2-enoic acid ethyl ester (1.03 g, 78%) as a pale, yellow oil. The material was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+](=[CH2:15])=[N-].CO>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:15])=[O:9])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Nitrobenzoic acid (5 g; 29.92 mmol; 1 eq.) is dissolved in toluene (37.5 ml). Timethylsilyl diazomethane in toluene and MeOH (1/1)(45 ml; 2 M; 89.76 mmol; 3 eq.) is added dropwise. The solution is stirred at rt for 2 h. Solvents are removed affording methyl 4-nitrobenzoate as a yellow powder (5.42 g; 100%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14](O)[CH2:15]OC1C=CC=CC=1F)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].BrCCCCOCC1C=CC=CC=1.[Cu](C#N)C#N.FC1C=CC(C(OC(C2C=CC(F)=CC=2)C2OC2)C2OC2)=CC=1>C1COCC1.C(OCC)(=O)C.CCCCCC>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(CCCCCOCc1ccccc1)COc1ccccc1F
Agent: N#C[Cu]C#N
Agent: BrCCCCOCc1ccccc1
Agent: Fc1ccc(C(OC(c2ccc(F)cc2)C2CO2)C2CO2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Part 1: (±)-7-Benzyloxy-1-(fluorophenoxy)-heptane-2-ol (Scheme VIII; 42) Magnesium (2.4 g, 98 mmol) was added to a 250 ml flask and flame dried. Dry THF, 25 ml, and 1 ml of dibromoethane were then added. 1-Bromo-4-benzyloxy-butane 41 (12 g, 49.4 mmol) dissolved in 50 ml of dry THF was added dropwise and the reaction mixture was stirred at room temperature. After 1 hour, the reaction mixture is cooled in an ice-water bath and 90 mg of copper cyanide is added. After 10 minutes in an ice-bath, 4-fluorophenyl-glycidyl ether (5 g, 29.6 mmol) dissolved in 30 ml of dry THF is added slowly. The reaction is monitored by TLC (ethyl acetate:hexane 3:7). After 15 minutes, the reaction is quenched with saturated aqueous ammonium chloride, concentrated and partitioned between water-ethyl acetate. The ethyl acetate layer is then washed with brine, dried over Na2SO4 and concentrated to give the desired benzyloxy-heptane 42. The structure was confirmed by 1H-NMR.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=3)[C:11]2=[O:15])[CH2:3][CH2:2]1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: FC(F)(F)c1nccc(Cl)n1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2ccnc(C(F)(F)F)n2)CCN1c1cnccc1C1CC1
Yield: 11.6 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 100 mg, 0.492 mmol) was reacted with 4-chloro-2-(trifluoromethyl)pyrimidine (108 mg, 0.591 mmol), 1,4-dioxane (5 mL), copper iodide (9.3 mg, 0.049 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (6.9 mg, 0.049 mmol) and potassium phosphate (313 mg, 1.47 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3), followed by preparative HPLC afforded 20 mg of the product (12% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:10]=1.[NH2:35][C:36]1[C:44]([CH3:45])=[CH:43][C:42](I)=[CH:41][C:37]=1[C:38]([OH:40])=[O:39].C(=O)(O)[O-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>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].O.ClCCl.C(#N)C>[NH2:35][C:36]1[C:44]([CH3:45])=[CH:43][C:42]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])[C:12]3=[N:13][CH:14]=2)=[CH:41][C:37]=1[C:38]([OH:40])=[O:39]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Cc1cc(I)cc(C(=O)O)c1N
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cc(C)c(N)c(C(=O)O)c3)cc12
Yield: 80.7 %

Procedure:
650 mg (1.35 mmol) of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine, 449 mg (1.35 mmol max.) of 2-amino-5-iodo-3-methyl-benzoic acid and 55 mg (67 μmol) of dichloro[1,1′-bis(diphenylphoshino)ferrocene]palladium(II) dichloromethane adduct were placed in a vial. 10 mL of acetonitrile and 10 mL of a saturated aqueous solution of sodium bicarbonate were added. The vial was closed and the mixture irradiated in a Personal Chemistry® Optimizer to 120° C. for 20 min. The crude mixture was distributed between dichloromethane and water, adjusting the pH to 4-5 by addition of 10% aqueous citric acid. The aqueous layer was extracted three times with ethyl acetate. The combined organic phases were washed with a saturated aqueous solution of sodium bromide, dried over sodium sulfate and evaporated. The crude was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes to afford 551 mg (1.09 mmol, 81%) of 2-amino-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-3-methyl-benzoic acid as a beige solid. MS: m/z 505.1 (M+H+), 528.1 (M+Na+).
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:24][OH:25])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[OH:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NC(N=NC(NC(C)C)=O)=O)(C)C>ClCCl>[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[O:36][C:24](=[O:25])[C@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: Oc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCCNC(=O)OCc1ccccc1
Agent: CC(C)NC(=O)N=NC(=O)NC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)Oc1ccc2ccccc2c1
Yield: 65.1 %

Procedure:
Solution of Nα-Boc-Nδ-Cbz-ornithinol (587 mg), dichloromethane (17 ml), 2-naphthol (288 mg), triphenylphosphine (524 mg) and N,N′-diisopropylazodicarboxamide (393 μl) was stirred for 12 hrs at 25° C., under nitrogen. The reaction mixture was poured into dichloromethane and washed successively with saturated sodium bicarbonate and brine. The organic phase was then dried over anhydrous sodium sulfate and concentrated in vacuo. Further purification by flash chromatography gave the titled product (534 mg) as a glassy solid: 1H NMR (400 MHz, CDCl3) δ1.41 (s, 9H), 1.60-1.73 (m, 4H), 3.20 (m, 2H), 4.01 (m, 3H), 5.07 (s, 2H), 7.09 (s, 1H), 7.11 (d, J=8.3 Hz, 1H), 7.28 (m, 6H), 7.40 (t, J=8.4 Hz, 1H), and 7.71 (m, 3H).