Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[CH2:9][O:10][C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([C:24]#[N:25])[N:22]=[CH:23][C:17]=3[N:16](COCC[Si](C)(C)C)[C:15]=2[N:14]=[CH:13][CH:12]=1)[CH3:2].Br.[OH-].[Na+].Cl>O1CCOCC1>[CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[CH2:9][O:10][C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([C:24]#[N:25])[N:22]=[CH:23][C:17]=3[NH:16][C:15]=2[N:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCN1CCCC[C@@H]1COc1ccnc2c1c1cc(C#N)ncc1n2COCC[Si](C)(C)C
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN1CCCC[C@@H]1COc1ccnc2[nH]c3cnc(C#N)cc3c12
Temperature: 75 °C
Yield: 31.9 %

Procedure:
(R)-4-((1-ethylpiperidin-2-yl)methoxy)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (64 mg, 0.14 mmol) was dissolved in 1,4-dioxane (0.5 mL) and then treated with 48% HBr(aq) (0.5 mL) and heated at 75° C. for 15 minutes. The cooled reaction mixture was then basified to pH ˜12 by dropwise addition of 6N sodium hydroxide and then immediately acidified to pH ˜8-9 by dropwise addition of concentrated hydrochloric acid, producing a cloudy precipitate. The solid was collected by centrifugation, dissolved in dimethylsulfoxide (2 mL), and purified by preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as a solid (15 mg, 32%). 1H NMR (500 MHz, d6-DMSO) δ 12.81 (s, 1H), 8.98 (s, 1H), 8.55 (d, J=5.7, 1H), 8.43 (s, 1H), 7.05 (d, J=5.8, 1H), 4.27 (m, 3H), 3.05 (m, 1H), 2.77 (m, 1H), 2.36 (m, 1H), 2.25 (m, 1H), 1.99 (m, 1H), 1.83 (m, 1H), 1.70 (m, 1H), 1.57 (m, 1H), 1.23 (m, 1H), 1.03 (t, J=7.1, 3H), 0.92 (d, J=6.6, 1H). LCMS (Method D): RT=6.63 min, M+H+=336.2.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:29]=1[CH3:35]>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:34][C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[C:29]([CH3:35])[CH:30]=2)=[N:3][CH:4]=1
Reactant: Cc1cc(O)ccc1Cl
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Product: Cc1cc(Oc2ncc(Cl)cc2C(=O)N[C@@H](C)c2ccc(C(=O)OC(C)(C)C)cc2)ccc1Cl

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 4-chloro-3-methylphenol: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.6 Hz), 8.15 (1H, d, J=2.6 Hz), 8.09 (1H, d, J=7.3 Hz), 7.95 (2H, d, J=8.3 Hz), 7.47–7.37 (3H, m), 7.03 (1H, d, J=2.8 Hz), 6.96 (1H, dd, J=8.6, 2.8 Hz), 5.36 (1H, dq, J=7.3, 7.0 Hz), 2.41 (3H, s), 1.60 (3H, d, J=7.0 Hz), 1.58 (9H, s); MS (ESI) m/z 501 (M+H)+, 499 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14](=[O:15])[CH:13](C(OC)=O)[CH2:12][N:6]3[C:7]=2[CH:8]=[C:9]([F:11])[CH:10]=1.Cl.O>CCO>[Br:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14](=[O:15])[CH2:13][CH2:12][N:6]3[C:7]=2[CH:8]=[C:9]([F:11])[CH:10]=1
Reactant: COC(=O)C1Cn2c(cc3c(Br)cc(F)cc32)C1=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C1CCn2c1cc1c(Br)cc(F)cc12
Yield: 88.2 %

Procedure:
To a solution of the ketoester of Step 5 (4 g) in EtOH (150 mL) r.t. was added 40 mL of concentrated HCl. The reaction mixture was stirred at reflux for 1 hour and water was added. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were concentrated The residue was swished in EtOAc/Hexanes to provide 2.9 g of the title compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:22]([C:21]2[CH:20]=[N:19][N:16]3[CH:17]=[CH:18][C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@@H:8]4[C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:14][C:15]=23)=[O:24])[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Product: O=C(NC1CC1)c1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Yield: 54 %

Procedure:
Prepared by the method as described in Example 1 using (R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation E) and cyclopropylamine to yield the title compound as a white solid (23 mg, 54% yield). MS (apci) m/z=366.1 (M+H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[C:18](Br)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:25][N:26]([CH3:38])[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[C:18]([C:32]5[CH:33]=[CH:34][C:29]([C:27]([N:26]([CH3:38])[CH3:25])=[O:28])=[CH:30][CH:31]=5)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Nc1ccc(CO)c(Br)c1)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2CO)cc1
Temperature: 80 °C
Yield: 34.9 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(hydroxymethyl)-phenyl)cyclopropanecarboxamide (39 mg, 0.10 mmol), 4-(dimethylcarbamoyl)-phenylboronic acid (29 mg, 0.15 mmol), 1 M K2CO3 (0.3 mL, 0.3 mmol), Pd-FibreCat 1007 (8 mg, 0.1 mmol), and N,N-dimethylformamide (1 mL) were combined. The mixture was heated at 80° C. for 3 h. After cooling, the mixture was filtered and purified by reverse phase HPLC to yield 5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(hydroxymethyl)-N,N-dimethylbiphenyl-4-carboxamide (16 mg, 34%). ESI-MS m/z calc. 458.5, found 459.5 (M+1)+; Retention time 2.71 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH:5](O)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.S(Cl)([Cl:19])=O>C(Cl)Cl.N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH:5]([Cl:19])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OC(c1ccc(Cl)cc1)c1cccc(Br)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Clc1ccc(C(Cl)c2cccc(Br)c2)cc1
Reaction time: 8 h
Yield: 103 %

Procedure:
A solution of the above benzhydryl alcohol (13.0 g, 43 mmol) in 100 mL of methylene chloride and 5 mL of pyridine was stirred at room temperature during dropwise addition of 4.7 mL (64 mmol) of thionyl chloride in 20 mL of methylene chloride. After stirring overnight, the reaction solution was washed with two 60 mL portions of 1M hydrochloric acid and 50 mL of water and dried over magnesium sulfate. Evaporation of the solvent gave 14.0 g of 3-bromo-4'-chlorobenzhydryl chloride as a pale yellow oil. A portion was purified by chromatography on silica gel with hexane to give a colorless oil. Calc. for C13H9BrCl2 : C, 49.41; H, 2,87; Br, 25.28; Cl, 22.44. Found: C, 49.50; H, 2.82; Br, 25.27; Cl, 22.48.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CC1C=CC(S(O[CH2:23][CH2:24][CH2:25][NH:26][C:27]2[C:28](=[O:44])[N:29]([C:40]([CH3:43])([CH3:42])[CH3:41])[S:30](=[O:39])(=[O:38])[C:31]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=O)=O)=CC=1>>[C:40]([N:29]1[C:28](=[O:44])[C:27]([NH:26][CH2:25][CH2:24][CH2:23][O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[C:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[S:30]1(=[O:38])=[O:39])([CH3:41])([CH3:42])[CH3:43]
Reactant: COC(=O)c1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Product: COC(=O)c1cccc(OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)c1
Yield: 54 %

Procedure:
The title compound was prepared as described for Example 12 from methyl 3-hydroxybenzoate and 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate with a reaction time of 15 mins. The reaction mixture was evaporated and the residue purified by silica gel column chromatography (Horizons Biotage) using DCM as eluent to give the title compound (0.077 g, 54%). 1H NMR (500 MHz CDCl3): δ 7.66 (d, 1H), 7.54-7.48 (m, 3H), 4.47-7.42 (m, 3H), 7.36 (t, 1H), 7.07 (dd, 1H), 5.70 (t, 1H), 3.94-3.90 (m, 5H), 3.13-3.08 (m, 2H), 1.90-1.84 (m, 2H), 1.75 (s, 9H); 13C NMR (125 MHz CDCl3): δ 167.1, 159.8, 158.5, 135.3, 131.8, 131.7, 129.8, 129.7, 128.8, 125.3, 122.6, 120.2, 114.6, 107.3, 66.2, 61.7, 52.4, 42.3, 28.9, 27.8; Mass Spectrum M+H+ 473.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([OH:10])[C:2]1=2.[CH3:11][C:12]1[O:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:13]=1[CH2:23][CH2:24]OS(C)(=O)=O>>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH2:24][CH2:23][C:13]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[O:16][C:12]=3[CH3:11])[C:2]1=2
Reactant: Oc1cccc2ccsc12
Reactant: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1cccc2ccsc12

Procedure:
In analogy to the procedures described in example 91 a] and b], benzo[b]thiophen-7-ol [J. Chem. Soc., Perkin Trans. 1 (1983), (12), 2973-7] was reacted with methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester [PCT Int. Appl. (2000) WO0008002]) to yield 4-[2-(benzo[b]thiophen-7-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole. Treatment of 4-[2-(benzo[b]thiophen-7-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole with dichloromethyl methyl ether and titanium tetrachloride then gave 7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophene-4-carbaldehyde as a yellow solid. NMR: (CDCl3, 1H, δ, TMS, 300 MHz) 2.45 (s, 3H), 3.12 (t, J=6, 2H), 4.55 (t, J=6, 2H), 6.92 (d, J=8, 1H), 7.39-7.46 (m, 3H), 7.66 (d, J=5, 1H), 7.80 (d, J=8, 1H), 7.95-7.99 (m, 2H), 8.35 (d, J=5, 1H), 10.1 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1C=CC=CC=1>[C:21]1([NH:27][C:28]([N:1]2[CH2:2][CH2:3][CH:4]([CH:7]3[C:13]4=[CH:14][CH:15]=[CH:16][N:12]4[CH2:11][C:10]4[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=4[O:8]3)[CH2:5][CH2:6]2)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Reactant: O=C=Nc1ccccc1
Solvent: c1ccccc1
Product: O=C(Nc1ccccc1)N1CCC(C2Oc3ccccc3Cn3cccc32)CC1
Yield: 89.6 %

Procedure:
A solution of 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (4.8 g, 0.018 mole) and phenylisocyanate (2.14 ml, 0.02 mole) in 140 ml benzene was heated at 65° C. for 1 hour. The reaction mixture was then cooled. The product was filtered and dried to yield 6.25 g (90%) of a solid, m.p. 184°-192° C. This was recrystallized from tetrahydrofuran/diethyl ether (1:4) to yield 5.9 g (85%) of an analytically pure solid, m.p. 167°-170° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]2[C:10]=1[C:11]([C:19](=O)[C:20](OC)=[O:21])=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]2[C:10]=1[C:11]([CH2:19][CH2:20][OH:21])=[CH:12][NH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1c[nH]c2cc(F)cc(OCc3ccccc3)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: OCCc1c[nH]c2cc(F)cc(OCc3ccccc3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
A crude of 26-1 (2.32 mmol) and LiAlH4 (1.32 g, 34.8 mmol) in 100 mL dioxane was heated at reflux for 2 h. The reaction mixture was cooled to 0° C. and quenched by water, 15% NaOH and then water. The resulting suspension was stirred for 30 min, and then filtered. After dried over Na2SO4, the organic phase was concentrated to give a brown oil, which was purified by flash column chromatography, eluting with hexanes/EtOAc (8:1 to 1:1) to afford 26-2 as a white solid (259 mg, 39%). 1H NMR (CDCl3) (ppm): 7.98 (bs, 1H), 7.35-7.48 (m, 5H), 6.91 (d, J=2.5 Hz, 1H), 6.68 (dd, J1=1.9 Hz, J2=9.2 Hz, 1H), 6.39 (dd, J1=1.9 Hz, J2=11.5 Hz, 1H), 5.14 (s, 2H), 6.81 (q, J=6.3 Hz, 2H), 3.07 (t, J=6.3 Hz, 2H), 1.47 (t, J=6.0 Hz, 1H).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[CH2:4][C:3](=O)[CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>ClCCl>[CH:25]([NH:28][C:3]1[CH2:2][O:1][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[CH:4]=1)([CH3:27])[CH3:26]
Reactant: CC(C)N
Reactant: O=C1COc2ccccc2C(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)NC1=CC(=O)c2ccccc2OC1
Temperature: 25 °C

Procedure:
A solution of 17.6 g (0.1 mole) 2,3,4,5-tetrahydro-1-benzoxepin-3,5-dione and a spatula tip of p-toluene sulfonic acid in 200 ml dichloromethane are mixed while stirring with 6 g (0.1 mole) isopropylamine and subsequently stirred to the end of the reaction at room temperature. After concentration of the solution a product is obtained by filtering off under suction and by recrystallizing from butylacetate. 13.5 g (62% of the theoretical yield) of 3-isopropylamino-1-benzoxepin-5(2H)-one are obtained.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:6]([O:19][CH3:20])=[CH:5][CH:4]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C.O.COCCOC>[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:2][C:3]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[C:6]([O:19][CH3:20])=[CH:5][CH:4]=2)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1ccc(CBr)nc1-c1cccc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: COc1ccc(Cc2ccc(F)cc2)nc1-c1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 20 h
Yield: 22 %

Procedure:
To the 6-bromomethyl-3-methoxy-2-(3-trifluoromethyl-phenyl)-pyridine synthesized above (0.2 g, 0.58 mmol), 4-fluorophenylboronic acid (0.12 g, 0.87 mmol), PPh3 (0.03 g, 0.12 mmol), K3PO4 (0.37 g, 1.73 mmol) and Pd(OAc)2 (0.013 g, 0.058 mmol) was added DME (4.0 mL), and EtOH—H2O (1:1, 1.0 mL). The reaction was stirred at 80° C. for 20 h. The reaction was cooled to room temperature, concentrated. The residue was purified by silica gel column chromatography using 1:1 dichloromethane-hexanes then dichloromethane to afford 0.056 g (22%) of 6-(4-fluoro-benzyl)-3-methoxy-2-(3-trifluoromethyl-phenyl)-pyridine (P-065) as a clear viscous liquid. 1H NMR (CDCl3, 400 MHz): 8.24 (s, 1H), 8.14 (d, J=8.0 Hz, 1H), 7.6-7.64 (m, 1H), 7.52-7.65 (m, 1H), 7.2-7.34 (m, 4H), 6.96-7.05 (m, 2H), 4.14 (s, 2H), 3.85 (s, 3H); MS (APCI+): 362.1 (M+1), LC-MS: 97.2%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:26]([F:27])=[CH:25][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16](C)[C:17](=O)OC(C)(C)C)=[CH:10][C:9]=2[F:28])=[C:6]([CH:29]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[N:5]2[N:36]=[CH:37][N:38]=[C:4]2[N:3]=1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[C:26]([F:27])=[CH:25][C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:16][CH3:17])=[CH:10][C:9]=2[F:28])=[C:6]([CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[N:5]2[N:36]=[CH:37][N:38]=[C:4]2[N:3]=1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]
Reactant: CN(CCCOc1cc(F)c(-c2c(Cl)nc3ncnn3c2C2CCCCCC2)c(F)c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCCOc1cc(F)c(-c2c(Cl)nc3ncnn3c2C2CCCCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 3-[4-(5-chloro-7-cycloheptyl [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy]propyl(methyl)carbamate (452 mg, 0.82 mmol) in 4 mL of methylene chloride is added 2.3 mL of trifluoroacetic acid. The mixture is stirred at room temperature for 18 h, and concentrated in vaccuo, yielding 3-[4-(5chloro-7-cycloheptyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy]-N-methylpropan-1-amine as a trifluoroacetic acid salt as a yellow semi-solid (400 mg). MS: m/z 450.2 (M+H).
Reaction SMILES: [NH:1]([C:18]([O:20]C(C)(C)C)=O)[C@H:2]([C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:25]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@H:26](C(O)=O)[CH2:27][S:28][CH2:29][C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1.C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:25]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@H:26]([C:18]([NH:1][C@H:2]([C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:20])[CH2:27][S:28][CH2:29][C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCCC(=O)O
Reactant: Cc1ccc(CSC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Product: Cc1ccc(CSC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccccc2)C(=O)NCCC(=O)O)cc1

Procedure:
Using Boc-Phe-βAla-OH (prepared with 1.31 g Boc-Phe-βAla-OH.CHA), 1.02 g Boc-Cys(MBzl)-OH, 0.60 g HONB and 0.68 g DCC, the desired product was obtained in exactly the same manner as in Example 1-(XX), and was then crystallized with ether and collected by filtration.
Reaction SMILES: [OH-:1].[K+].[CH2:3]([C:5]([C:26]1[CH:39]=[CH:38][C:29]([O:30][CH2:31][C@@H:32]2[O:36][C:35](=[O:37])[CH2:34][CH2:33]2)=[C:28]([CH3:40])[CH:27]=1)([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]([C:19]([CH2:23][CH3:24])([OH:22])[CH2:20][CH3:21])=[CH:17][CH:18]=2)=[C:10]([CH3:25])[CH:9]=1)[CH2:6][CH3:7])[CH3:4]>O1CCCC1CO>[CH2:6]([C:5]([C:26]1[CH:39]=[CH:38][C:29]([O:30][CH2:31][C@H:32]([OH:1])[CH2:33][CH2:34][C:35]([OH:36])=[O:37])=[C:28]([CH3:40])[CH:27]=1)([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]([C:19]([CH2:20][CH3:21])([OH:22])[CH2:23][CH3:24])=[CH:17][CH:18]=2)=[C:10]([CH3:25])[CH:9]=1)[CH2:3][CH3:4])[CH3:7]
Reactant: [OH-]
Reactant: CCC(O)(CC)c1ccc(-c2ccc(C(CC)(CC)c3ccc(OC[C@H]4CCC(=O)O4)c(C)c3)cc2C)o1
Agent: [K+]
Solvent: OCC1CCCO1
Product: CCC(O)(CC)c1ccc(-c2ccc(C(CC)(CC)c3ccc(OC[C@H](O)CCC(=O)O)c(C)c3)cc2C)o1
Temperature: 65 °C
Yield: 89.9 %

Procedure:
A 1 N potassium hydroxide aqueous solution (0.083 mL, 0.083 mmol) was added to a solution of 5(R)-[4-(1-ethyl-1-{4-[5-(1-ethyl-1-hydroxy-propyl)-furan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one (Example 21-(1); 8.6 mg, 0.017 mmol) in tetrahydrofuran-methanol=10:1 (1.1 mL), and the mixture was stirred at 65° C. for one and half hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform/methanol=10/1, saturated with water) to give the title compound as a colorless oil (8.2 mg, 90%).
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][N:9]=1.BrC1C=C(C)C=CN=1.[F:24][C:25]([F:53])([F:52])[C:26]1[CH:27]=[C:28]([NH:36][C:37]([N:39]2[CH2:44][CH2:43][N:42]([C:45]3[C:50](Cl)=[N:49][CH:48]=[CH:47][N:46]=3)[CH2:41][CH2:40]2)=[O:38])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>C(O)(C)(C)C>[F:53][C:25]([F:24])([F:52])[C:26]1[CH:27]=[C:28]([NH:36][C:37]([N:39]2[CH2:44][CH2:43][N:42]([C:45]3[C:50]([O:15][CH2:14][C:12]4[CH:11]=[CH:10][N:9]=[C:8]([Br:7])[CH:13]=4)=[N:49][CH:48]=[CH:47][N:46]=3)[CH2:41][CH2:40]2)=[O:38])[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nccnc2Cl)CC1
Reactant: OCc1ccnc(Br)c1
Agent: CC(C)(C)[O-]
Agent: Cc1ccnc(Br)c1
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nccnc2OCc2ccnc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of potassium t-butoxide (0.073 g, 0.66 mmol) and t-butanol (0.5 mL) was added dropwise with stirring (2-bromo-pyridin-4-yl)-methanol (0.082 g, 0.44 mmol, prepared in the similar fashion as Example 16a from 2-Bromo-4-methyl-pyridine), followed by 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide (0.100 g, 0.22 mmol; prepared in Example 16b). The mixture was stirred at room temperature overnight. LC/MS analysis indicated formation of the desired product. The mixture was concentrated in vacuo, and the crude product was purified on preparative HPLC to afford N-[3,5-bis(trifluoromethyl)phenyl]-4-(3-{[(2-bromopyridin-4-yl)methyl]-oxy}pyrazin-2-yl)piperazine-1-carboxamide (5 mg). 1H NMR (CDCl3) 8.40 (s, 1H), 7.95 (s, 2H), 7.8 (s, 1H), 7.6 (s, 1H), 7.58 (m, 2H), 7.24 (m, 1H), 6.62 (s, 1H), 5.4 (s, 2H), 3.6 (m, 4H), 1.6 (m, 4H) ppm.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:11][N:10]2[C:12]3[CH:13]=[C:14]([C:25]([O:27][CH3:28])=[O:26])[CH:15]=[CH:16][C:17]=3[C:18]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:9]2[C:8]2[CH:29]=[CH:30][CH:31]=[CH:32][C:7]=2[O:6][CH2:5]1)#[N:2]>CO.[Pt](=O)=O>[NH2:2][CH2:1][CH2:3][CH:4]1[CH2:11][N:10]2[C:12]3[CH:13]=[C:14]([C:25]([O:27][CH3:28])=[O:26])[CH:15]=[CH:16][C:17]=3[C:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[C:9]2[C:8]2[CH:29]=[CH:30][CH:31]=[CH:32][C:7]=2[O:6][CH2:5]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CC#N)COc1ccccc1-3
Agent: O=[Pt]=O
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCN)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 4 h
Yield: 12 %

Procedure:
Platinum(IV) oxide (0.5 eq) was added to a solution of methyl 7(R,S)-(cyanomethyl)-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.20 M) in MeOH. The atmosphere in the reaction vessel was exchanged for H2 and the reaction stirred vigorously at RT for 4 h. The reaction vessel was flushed with N2 and the reaction mixture filtered through a plug of celite (washing well with MeOH and EtOAc). Volatiles were removed in vacuo to afford the crude product which was purified by FC (EtOAc/MeOH/Et3N 93:5:2) affording the product as a yellow oil (12%). (ES+) m/z 433 (M+H)+.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12](=[O:22])[C:13]1[CH:18]=[C:17](I)[C:16]([OH:20])=[C:15](I)[CH:14]=1>COCCOC.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:10][O:11][C:12](=[O:22])[C:13]1[CH:18]=[C:17]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]([OH:20])=[C:15]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(I)c(O)c(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
To a stirred solution of phenylboronic acid (4.95 g, 40.57 mmol), Ba(OH)2.H2O (10.48 g, 55.33 mmol), and Pd(OAc)2 (0.414 g, 1.84 mmol) in DME/H2O (110 mL/20 mL) was added 3,5-diiodo-4-hydroxybenzoic acid methyl ester (7.45 g, 18.44 mmol). The mixture was stirred at 85° C. for 3 h and was then cooled and concentrated. The residue was partitioned between ethyl acetate/2N HCl. The organic phase was dried (MgSO4) and concentrated to give a solid which was triturated with diethyl ether/petroleum ether to give 3.51 g (62.5%) of product as a white solid. 1H NMR (DMSO-d6) δ9.27 (s, 1H), 7.27 (s, 2H), 7.25-7.40 (m, 10H), 3.81 (s, 3H).