Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[C:20]([C:24]1[CH:25]=[C:26]([S:32](Cl)(=[O:34])=[O:33])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31])([CH3:23])([CH3:22])[CH3:21].C(N(C(C)C)CC)(C)C.O>ClCCl>[C:20]([C:24]1[CH:25]=[C:26]([S:32]([N:17]2[CH2:16][CH2:15][N:14]3[CH2:19][C@H:11]([O:10][C:7]4[CH:6]=[N:5][C:4]([CH:1]5[CH2:3][CH2:2]5)=[CH:9][N:8]=4)[CH2:12][C@H:13]3[CH2:18]2)(=[O:34])=[O:33])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31])([CH3:23])([CH3:21])[CH3:22]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C(C)(C)C
Reactant: c1nc(C2CC2)cnc1O[C@@H]1C[C@H]2CNCCN2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCN3C[C@H](Oc4cnc(C5CC5)cn4)C[C@H]3C2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the product from Example 27B (30 mg, 0.115 mmol) in dichloromethane (1 mL) was added 3-tert-butyl-4-methoxybenzene-1-sulfonyl chloride (36 mg, 0.138 mmol) and diisopropylethylamine (0.040 mL, 0.23 mmol). The resulting mixture was stirred at room temperature for 90 minutes. Water (2 mL) was added, and the mixture was extracted with dichloromethane (2×2 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a crude product. Purification by column chromatography on silica gel eluting with a solvent gradient of 0-60% ethyl acetate in hexanes gave the titled compound. 1H NMR (300 MHz, CDCl3) δ ppm 0.87-1.00 (m, 4H), 1.38 (s, 9H), 1.73-1.87 (m, 1H), 1.91-2.03 (m, 2H), 2.08 (t, J=10.51 Hz, 1H), 2.31 (dd, J=10.17, 5.09 Hz, 1H), 2.37-2.48 (m, 2H), 2.48-2.60 (m, 1H), 2.91-3.05 (m, 1H), 3.63 (dd, J=10.17, 6.78 Hz, 1H), 3.68-3.76 (m, 1H), 3.83-3.90 (m, 1H), 3.90 (s, 3H), 5.23-5.35 (m, 1H), 6.94 (d, J=9.16 Hz, 1H), 7.57-7.66 (m, 2H), 7.91 (d, J=1.36 Hz, 1H), 8.02 (d, J=1.70 Hz, 1H); MS (ESI) m/z 487.1 (M+H)+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[C:11]=1[CH2:12][CH2:13][CH2:14][NH2:15].C(N(CC)CC)C.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>CN(C)C=O.ClCCl>[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[C:11]=1[CH2:12][CH2:13][CH2:14][NH:15][C:26]([CH:23]1[CH2:25][CH2:24]1)=[O:27]
Reactant: O=C(Cl)C1CC1
Reactant: NCCCc1c(Br)ccc2c1CCO2
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCc1c(Br)ccc2c1CCO2)C1CC1
Reaction time: 0.25 h
Yield: 77.6 %

Procedure:
A mixture of 3-(5-bromo-2,3-dihydro-benzofuran-4-yl)-propylamine hydrochloride (100 mg), dimethylformamide (3 drops), triethylamine (0.35 ml) and dichloromethane (3 ml) was stirred in ice for 15 minutes. Cyclopropanecarbonyl chloride (36 mg) was added and stirring continued for 2 hours. The mixture was purified by chromatography on silica to give the title compound as a white solid (86 mg).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:15](=O)[CH2:16][C:17](=O)[C:18]([F:21])([F:20])[F:19])[CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12].[NH2:26][C:27]1[C:31]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=2)=[CH:30][NH:29][N:28]=1>>[CH3:38][C:34]1[CH:33]=[C:32]([C:31]2[CH:30]=[N:29][N:28]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:15]([C:7]4[CH:8]=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:5]([O:4][CH2:3][C:2]([F:25])([F:24])[F:1])[CH:6]=4)=[N:26][C:27]=23)[CH:37]=[CH:36][N:35]=1
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)c(OCC(F)(F)F)c1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)nc23)ccn1
Yield: 53.8 %

Procedure:
Reaction of 1-[3-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-phenyl]-4,4,4-trifluoro-butane-1,3-dione (191 mg, 0.5 mmol), prepared from 4-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2-methyl-pyridine, as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (140 mg, 54%). MS (ISP) 521.4 [(M+H)+]; mp 201° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([F:24])=[CH:5][C:6]([O:22]C)=[C:7]([CH:21]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)=[O:9])#[N:2].B(Br)(Br)Br>ClCCl>[C:1]([C:3]1[C:4]([F:24])=[CH:5][C:6]([OH:22])=[C:7]([CH:21]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)=[O:9])#[N:2]
Reactant: COc1cc(F)c(C#N)cc1C(=O)NCc1cccc([N+](=O)[O-])c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1cc(C(=O)NCc2cccc([N+](=O)[O-])c2)c(O)cc1F
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 58.6 %

Procedure:
To a stirring solution of (5-cyano-4-fluoro-2-methoxy-N-(3-nitro-benzyl)-benzamide (1.5 g, 4.6 mmol) in dichloromethane (200 mL, 0.3 M) at −78° C. was added BBr3 (21.5 mL, 21.4 mmol). The mixture was allowed to stir for 45 min at −78° C. and the dry ice/acetone bath was then removed and tje solution was allowed to warm to room temperature. Then, the solution was cooled down again to −78° C. and was then quenched with 100 mL of methanol. The mixture was allowed to warm to room temperature and concentrated. Purification by MPLC (10–100% ethyl acetate, 23 mL/min, 75 min) provided 5-cyano-4-fluoro-2-hydroxy-N-(3-nitro-benzyl)-benzamide (0.85 g, 59%) as a beige powder: Rf 0.37 (70% ethyl acetate in heptane); 1H NMR (DMSO-d6, 300 MHz) δ 9.50 (bd s, 1 H), 8.39 (d, J=7.5 Hz, 1 H;), 8.20 (s, 1 H), 8.12 (d, J=9.3 Hz, 1 H), 7.80 (d, J=7.2 Hz, 1H), 7.63 (t, J=7.8 Hz, 1 H), 7.04 (d, J=11.1 Hz, 1 H), 4.62 (s, 2H).
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH2:13][C@H:14]2[CH2:16][C@@H:15]2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][N:18]=2)=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][CH:6]=2.[N:25]1[C:34]2[CH2:33][CH2:32][NH:31][CH2:30][C:29]=2[CH:28]=[CH:27][CH:26]=1.CC(C)([O-])C.[Na+].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C>C1(C)C=CC=CC=1.CCOC(C)=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]>[N:25]1[C:34]2[CH2:33][CH2:32][N:31]([C:2]3[C:3]([O:12][CH2:13][C@H:14]4[CH2:16][C@@H:15]4[C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][N:18]=4)=[N:4][C:5]4[C:10]([CH:11]=3)=[N:9][CH:8]=[CH:7][CH:6]=4)[CH2:30][C:29]=2[CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc([C@H]2C[C@@H]2COc2nc3cccnc3cc2Br)nc1
Reactant: c1cnc2c(c1)CNCC2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc([C@H]2C[C@@H]2COc2nc3cccnc3cc2N2CCc3ncccc3C2)nc1
Temperature: 100 °C

Procedure:
A mixture of 3-bromo-2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-1,5-naphthyridine (LL1) (25 mg, 0.07 mmol), 5,6,7,8-tetrahydro-1,6-naphthyridine (16.1 mg, 0.08 mmol), sodium t-butoxide (21.8 mg, 0.23 mmol), DavePhos (3.8 mg, 0.009 mmol) and tris(dibenzylideneacetone)dipalladium(0) (4.5 mg, 0.005 mol) in toluene (0.3 mL) was heated at 100° C. for 14 hours. The reaction mixture was allowed to cool to room temperature. The mixture was then diluted with EtOAc (5 mL), washed with sodium bicarbonate (1 mL) and brine (1 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by reverse phase chromatography (Waters Sunfire Prep C18 OBD, 5-60% acetonitrile in water with 0.1% TFA modifier) to afford the title compound. 1H NMR (500 MHz, DMSO): δ 8.69 (d, J=4.3 Hz, 1 H), 8.38 (d, J=4.8 Hz, 1 H), 8.14 (s, 1 H), 8.06 (d, J=8.3 Hz, 1 H), 7.61-7.53 (m, 2 H), 7.49 (dd, J=8.4, 4.4 Hz, 1 H), 7.27 (s, 2 H), 7.20 (dd, J=7.9, 4.9 Hz, 1 H), 4.63 (dd, J=11.2, 6.4 Hz, 1 H), 4.47-4.36 (m, 3 H), 3.79 (s, 3 H), 3.70-3.59 (m, 2 H), 2.93 (s, 2 H), 2.27-2.23 (m, 1 H), 1.85 (s, 1 H), 1.24 (m, 1 H), 1.12 (dd, J=8.7, 5.4 Hz, 1 H); LRMS m/z (M+H) 440.3 found, 440.2 required.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]([C:19]([O:21]CC)=O)([F:18])[CH2:13][CH2:14][C:15](O)=[O:16].C(C1NC=CN=1)(C1[NH:27]C=CN=1)=O.CN(C1N=CC=CN=1)C>O1CCCC1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1([F:18])[CH2:13][CH2:14][C:15](=[O:16])[NH:27][C:19]1=[O:21]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CCOC(=O)C(F)(CCC(=O)O)N1C(=O)c2ccccc2C1=O
Agent: CN(C)c1ncccn1
Solvent: C1CCOC1
Product: O=C1CCC(F)(N2C(=O)c3ccccc3C2=O)C(=O)N1
Reaction time: 0.17 h

Procedure:
A mixture of 4-(1,3-dioxoisoindolin-2-yl)-4-(ethoxycarbonyl)-4-fluorobutanoic acid (0.9 g, 2.8 mmol), carbonyl diimidazole (0.46 g, 2.8 mmol) and dimethylaminopyrimidine (0.68 g, 5.6 mmol) in tetrahydrofuran (30 mL) is heated at reflux for 18 hours. The solvent is removed in vacuo and the residue is stirred with methylene chloride (50 mL) for 10 minutes. The organic layer is washed with water and brine (40 mL each) and dried over sodium sulfate. The solvent is removed in vacuo to give 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidin-3-yl)isoindoline which is further purified by column chromatography.
Reaction SMILES: C([Mg:4][Br:5])(C)C.Cl[C:7]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:8]=1[F:17].BrC1C(F)=C(F)C(F)=C(F)C=1F>C(OCC)C>[C:7]1([Mg:4][Br:5])[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[C:9]([F:16])[C:8]=1[F:17]
Reactant: CC(C)[Mg]Br
Reactant: Fc1c(F)c(F)c(Cl)c(F)c1F
Agent: Fc1c(F)c(F)c(Br)c(F)c1F
Solvent: CCOCC
Product: Fc1c(F)c(F)c([Mg]Br)c(F)c1F
Temperature: 50 °C
Reaction time: 7.5 h

Procedure:
To a diethyl ether solution of isopropyl magnesium bromide, chloropentafluorobenzene was added at 0 to 40° C. under nitrogen with stirring in a period of thirty minutes, such that the isopropyl magnesium bromide was in 1.03 to 1.05 molar excess of the chloropentafluorobenzene. The mixture was stirred at 47 to 53° C.; after 5 to 10 hours, bromopentafluorobenzene was added to react with the excess isopropyl magnesium bromide, and the mixture was stirred at 25° C. for 1 hour. Any excess bromo-pentafluorobenzene was back-titrated in situ with isopropyl magnesium bromide to form more C6F5MgBr. The yield of C6F5MgBr was 96.1%, and 3.9% C6F5Cl remained, as determined by 19F NMR, using C6H5CF3 as a reference; no trace of iPrMgBr was seen with 1H NMR.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=2)[CH:3]=1.CCN(C(C)C)C(C)C.[NH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1>C1COCC1>[OH:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][NH:37][C:2]2[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]3[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:3]=2)=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2cc(Cl)nc(OCC(F)(F)F)n2)cc1
Reactant: NCc1ccc(O)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1ccc(Nc2cc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Yield: 45.9 %

Procedure:
To a solution of tert-butyl 4-((6-chloro-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzoate (210 mg, 0.52 mmol), and Hunig's Base (0.18 mL, 1.04 mmol) in THF (3 mL) was added 4-(aminomethyl)phenol (96 mg, 0.78 mmol). The resulting mixture was refluxed for 1 hour. After cooling to rt, the solvent was removed and the crude product was purified by silica gel chromatography using 20-40% EtOAc/Hexanes to give tert-butyl 4-((6-((4-hydroxybenzyl)amino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzoate (117 mg, 46%) as white solid.
Reaction SMILES: I[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.CN(C1CCCCC1)C1CCCCC1.[O:39]1[CH2:43][CH:42]=[CH:41][CH2:40]1>O1CCOCC1.CO.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[O:39]1[CH:40]=[CH:41][CH2:42][CH:43]1[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=CCOC1
Reactant: Ic1cccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: CO
Product: C1=COC(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of N-(4-(3-iodopyridin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (0.403 g, 0.905 mmol), N-methyldicyclohexylamine (0.400 mL, 1.886 mmol, Aldrich), bis(tri-tert-butylphosphine)palladium (0) (0.045 g, 0.088 mmol, Strem) and 2,5-dihydrofuran (0.500 mL, 6.78 mmol, Aldrich) in 5 mL of dioxane was capped under an atmosphere of argon and stirred at rt for 3 h and then heated at 45° C. overnight. The reaction mixture was diluted with MeOH, evaporated onto silica gel and purified by flash chromatography (Isco, (40 gram)) eluting with 2M NH3 in MeOH:CH2Cl2 (0:1→3:97) to give a white amorphous solid. MS (ESI, pos. ion) m/z: 386.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.[CH:26]1([CH:29]=[O:30])[CH2:28][CH2:27]1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[N:16]=[C:10]2[CH:9]1[CH:29]([CH:26]1[CH2:28][CH2:27]1)[OH:30])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CC1CC1
Reactant: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1
Agent: [Li]C(C)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1C(O)C1CC1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1.86 g (6.38 mmol) of 7-N-(tert-butoxycarbonyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazine (Ex. 2, Step A) in 20 mL of toluene at −78° C. was added 5.88 mL (7.65 mmol, 1.3 M solution in cyclohexane) of sec-butyllithium. The reaction mixture was stirred at −78° C. for 20 min, then 0.524 mL (7.01 mmol) of cyclopropanecarboxaldehyde was added dropwise. The reaction mixture was stirred at −78° C. for 10 min. The −78° C. bath was removed and the mixture was allowed to stir at ambient temperature for 1 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution and extracted with three portions of ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, and concentrated to give 2.24 g of crude material. Purification by flash chromatography (silica gel, 7 to 10% ethyl acetate/hexane) gave the title compound as a mixture of 4 diastereomers. LC/MS 363 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[N:27]1([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:39][CH2:38][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:41][CH:40]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccc(CN2CCCCC2)cc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(CN4CCCCC4)cc3)c2CC1)C(F)(F)F
Yield: 72.5 %

Procedure:
Use a method similar to the General Procedure)-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethansulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (300 mg, 0.69 mmol) and 4-(piperidin-1-ylmethyl)-benzylamine (174 mg, 0.84 mmol). Purify by chromatography on silica gel (150 g) eluting with a gradient of DCM to 4:1 DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) to obtain 7-chloro-6-[4-(piperidin-1-ylmethyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (240 mg, 71%). MS (ES+) m/z: 480 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[N:7][OH:8])[CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[CH3:26][C:27]([O:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=1[C:36]([OH:38])=[O:37])=[O:28]>>[C:27]([O:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=1[C:36]([O:38][C:4]1([N:7]=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:37])(=[O:28])[CH3:26]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: ON=C1CCOCC1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: CC(=O)Oc1ccccc1C(=O)OC1(N=O)CCOCC1

Procedure:
4-Nitrosotetrahydro-2H-pyran-4-yl 2-(acetyloxy)benzoate was prepared from tetrahydro-pyran-4-one oxime, lead tetraacetate and Aspirin using conditions of General Method 3. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.15 (1H, dd, 7.8, 1.5 Hz), 7.65 (1H, td, 7.8, 1.5 Hz), 7.40 (1H, t, 7.6 Hz), 7.17 (1H, d, 8.1 Hz), 4.08 (2H, dt, 11.6, 4.1 Hz), 3.79 (2H, td, 11.5, 2.4 Hz), 2.21-2.29 (5H, m), 1.96-1.99 (2H, m).
Reaction SMILES: [OH-].[Na+].[C:3]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:8]=[CH:7][C:6](/[C:9](/[CH3:29])=[CH:10]/[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([O:26][CH2:27][CH3:28])[C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1>C(O)C>[C:3]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:4]=[CH:5][C:6](/[C:9](/[CH3:29])=[CH:10]/[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([O:26][CH2:27][CH3:28])[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccccc3)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
Sodium hydroxide (1M, 0.45 ml, 0.45 mmol) was added to a solution of (E)-(S)-ethyl 3-[4-(3-biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-ethoxy-propionate (example 1) (0.100 g, 0.225 mmol) in ethanol (20 ml) and the mixture stirred at 70° C. for 2.5 h. After cooling to room temperature the resulting mixture was partitioned between water (50 ml) and ethyl acetate and the aqueous phase collected. The aqueous phase was acidified with 1N hydrochloric acid (5 ml) and extracted with ethyl acetate (100 ml), and the organic phase collected, washed with brine, dried (Na2SO4) and evaporated to give (E)-(S)-3-[4-(3-biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-ethoxy-propionic acid as a white solid; 0.014 g (15%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[Br:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6](=[O:16])[CH:7]([NH:8][C:21]1[CH:22]=[CH:23][C:18]([Br:17])=[CH:19][CH:20]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(Cc1ccccc1)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of L-phenylalanine tert-butyl ester (1.47 g, 6.64 mmol), 4-bromophenylboronic acid (2.67 g, 13.28 mmol), triethylamine (1.9 mL, 13.28 mmol) and copper (II) acetate (1.21 g, 6.64 mmol) in dichloromethane (50 mL) was stirred at room temperature for 24 h. The solids were removed by filtration through a pad of silica gel and the desired product was obtained by chromatography eluting with 5% ethyl acetate in hexanes. 1H NMR (CDCl3)7.2 (m, 8 H), 6.48 (d, 2 H), 4.18 (t, 2 H, H-2 and NH), 3.08 (d, 2 H), 1.35 (s, 9 H)
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19]>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:13][C:12]=1[C:18]([F:19])([F:20])[F:21]
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Product: O=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 4-fluorobenzaldehyde and 4-chloro-3-(trifluoromethyl)phenol.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[C:7]([C:9]2[N:13](C3CCCCO3)[CH:12]=[N:11][N:10]=2)[CH:6]=[CH:5][C:4]=1[C:20]1[N:25]=[C:24]2[NH:26][C:27](=[O:30])[CH2:28][NH:29][C:23]2=[N:22][CH:21]=1>C(O)C>[ClH:1].[CH3:2][C:3]1[CH:8]=[C:7]([C:9]2[NH:13][CH:12]=[N:11][N:10]=2)[CH:6]=[CH:5][C:4]=1[C:20]1[N:25]=[C:24]2[NH:26][C:27](=[O:30])[CH2:28][NH:29][C:23]2=[N:22][CH:21]=1
Reactant: Cc1cc(-c2nncn2C2CCCCO2)ccc1-c1cnc2c(n1)NC(=O)CN2
Agent: Cl
Solvent: CCO
Product: Cc1cc(-c2nnc[nH]2)ccc1-c1cnc2c(n1)NC(=O)CN2
Temperature: 80 °C
Yield: 94.4 %

Procedure:
Hydrochloric acid (6 N in water 0.149 mL, 0.894 mmol) was added to a stirred mixture of 7-(2-methyl-4-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.070 g, 0.179 mmol) in ethanol (3 mL) at 80° C. The system was purged with nitrogen. The resulting mixture was sealed and heated at 80° C. The resulting mixture was heated at 80° C. for 25 min and then cooled to room temperature. Solids were collected by filtration, washed with methanol and dried under high vacuum at 40° C. to give the desired product (0.058 g, 0.169 mmol, 94% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ (ppm) 11.32 (s, 1H), 8.66 (s, 1H), 7.97 (s, 1H), 7.92 (dd, J=1.37, 7.97 Hz, 1H), 7.74 (s, 1H), 7.50 (d, J=7.97 Hz, 1H), 4.14 (s, 2H), 2.44 (s, 3H); MS (ESI) m/z 308.3 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]4[O:22][CH:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].C(O)C.C(O)(=O)C.[H][H]>[Pd].O>[CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]4[O:22][C@H:6]5[C@@H:7]([OH:8])[CH2:9][CH2:10][C@:11]2([OH:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1
Reactant: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: COc1ccc2c3c1O[C@H]1[C@@H](O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Yield: 84 %

Procedure:
14-Hydroxycodeinone (4.5 g) was warmed with ethanol (2.17 g/g 14-hydroxycodeinone) to 60-65° C. and acetic acid was added in portions until all solid dissolved. Following the addition of 10% Pd/C (dry, 0.01 g/g 14-hydroxycodeinone) and water (0.01 g/g 14-hydroxycodeinone) to compensate for the water in the dry Pd/C catalyst, the hydrogenation was performed with hydrogen being introduced at 80° C. The reaction was sampled after 22 h and was determined to be complete. This reaction resulted in low levels of 6α-oxycodol. After isolation (84% yield by LOD), the level of 6α-oxycodol was also determined to be low by analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O:17]CC)=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[OH-].[Na+:31]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O-:17])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[Na+:31]
Reactant: CCOC(=O)c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C([O-])c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Temperature: 60 °C

Procedure:
Ethyl 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)methyl]-2-pyridinecarboxylate (108 mg, 0.25 mmol) was dissolved in 3 ml of ethanol and 1 ml of water. Sodium hydroxide (4 equivalents) was added. The mixture was stirred at 60° C. until TLC showed no more SM (starting material) (˜2 hours). The reaction mixture was cooled down and extracted with ethyl acetate (3×). Dried over MgSO4. Sodium 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}-phenyl)methyl]-2-pyridinecarboxylate was obtained as a white solid (94 mg).