Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:10][C:5]=2[O:4][C:3]=1[C:26]([OH:28])=[O:27].[CH3:29]N1C=CCN(C2C=CC(C)=CC=2)N1>CCOCC>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:10][C:5]=2[O:4][C:3]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: Cc1ccc(N2CC=CN(C)N2)cc1
Reactant: CCCCCCCCCCCCCCOc1ccc2c(C)c(C(=O)O)oc2c1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCOc1ccc2c(C)c(C(=O)OC)oc2c1
Reaction time: 1 h

Procedure:
0.4 g (1.03 mmoles) of 3-methyl-6-tetradecyloxy-benzofuran-2-carboxylic acid and 0.3 g (2.00 mmoles) of 1-methyl-3-p-tolyltriazine are stirred in ether and refluxed for 15 minutes. The mixture is then allowed to stand at room temperature for 1 hour. It is then refluxed for 15 minutes. The reaction mixture is worked-up by extraction with diethyl ether and HCl. The ether is distilled off and is replaced by dioxane. The resultant mixture is heated on a steam bath for 1 hour. It is then extracted with diethyl ether/HCl, H2O and NaHCO3 (aq.). The extract is evaporated and the ether replaced with methanol. The methyl ester of 3-methyl-6-tetradecyloxy-benzofuran-2-carboxylic acid is allowed to crystallize from the mixture.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:9][C@@H:8]([CH3:10])[CH2:7][C:6]=1OS(C(F)(F)F)(=O)=O)=[O:4].[CH3:19][O:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][O:31][CH3:32])=[CH:25][C:24]=1B(O)O.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH2:9][C@@H:8]([CH3:10])[CH2:7][C:6]=1[C:25]1[CH:24]=[C:23]([O:22][CH2:21][O:20][CH3:19])[CH:28]=[CH:27][C:26]=1[O:29][CH2:30][O:31][CH3:32])=[O:4]
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)C[C@H](C)C1
Reactant: COCOc1ccc(OCOC)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Product: COCOc1ccc(OCOC)c(C2=C(C(=O)OC)C[C@@H](C)C2)c1
Reaction time: 2 h
Yield: 81.6 %

Procedure:
Prepare a mixture of 4-Methyl-2-trifluoromethanesulfonyloxy-cyclopent-1-enecarboxylic acid methyl ester 3a (2.5 g, 8.7 mmol), 2,5-Bis-methoxymethoxy phenylboronic acid 7 (2.31 g, 9.5 mmol), tetrakis(triphenylphosphine)palladium (485 mg, 0.435 mmol), and LiCl (1.1 g, 26.1 mmol) in DME (80 mL). Add 2.0 M solution of Na2CO3 (10 mL, 21.7 mmol) and heat the reaction to reflux and stir for 2 hours. Cool the reaction to room temperature and partitioned between CH2Cl2 and saturated aqueous NaHCO3. Separate and extract the aqueous solution with CH2Cl2 (2×). Combine the organic extracts, dry (Na2SO4), filter and concentrate in vacuo. Purify by flash chromatography (125 g SiO2, 0-30% EtOAc/hexane and 30% EtOAc/hexane) to afford 2-(2,5-Bis-methoxymethoxy-phenyl)-4-methyl-cyclopent-1-enecarboxylic acid methyl ester 8a (2.4 g, 7.1 mmol, 83%) as a yellow oil. 1H NMR (δ, 400 MHz, CDCl3): 7.02 (d, 1H, J=9.2 Hz), 6.90 (dd, 1H, J=9.2, 3.1 Hz), 6.80 (d, 1H, J=3.1 Hz), 5.10 (s, 2H), 5.03 (s, 2H), 3.56 (s, 3H), 3.48 (s, 3H), 3.44 (s, 3H), 3.01-2.91 (m, 2H), 2.53-2.37 (m, 3H), 1.14 (d, 3H, J=6.6 Hz). HRMS calcd. 337.1651; found (electrospray, M+1) 337.1647.
Reaction SMILES: Br[C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:22])=[CH:4][N:3]=1.[NH:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[N:24]1.CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.[Cu](I)I.O.C(OCC)(=O)C>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:7]2[C:2]([N:23]3[C:31]4[C:26](=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[N:24]3)=[N:3][CH:4]=[C:5]([Cl:22])[CH:6]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: c1cnc2cn[nH]c2c1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2Br)cc1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2-n2ncc3ncccc32)cc1

Procedure:
A solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-benzene sulfonamide (226 mg, 0.559 mmol), 1H-pyrazolo[4,3-b]pyridine (100 mg, 0.839 mmol), trans-N,N′-dimethyl-cyclohexane-1,2-diamine (18 μL, 0.112 mmol), copper iodide (22 mg, 0.112 mmol), and cesium carbonate (383 mg, 1.17 mmol) in 2 mL of N,N-dimethylacetamide was heated at 130° C. for 2 hours. Ethyl acetate and water were added and the layers were separated. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude reside was subsequently purified by flash column chromatography (0-100% ethyl acetate in hexanes) to afford 4-tert-butyl-N-(5-chloro-2-pyrazolo[4,3-b]pyridin-1-yl-pyridin-3-yl)-benzenesulfonamide: MS (ES) M+H expected 442.1, found 442.0.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[CH:9]=[C:10]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=3[O:22][C:23](F)(F)F)[CH:17]=[O:18])[C:11]([CH3:13])=[CH:12][C:7]=2[O:6][C:5]([CH3:28])([CH3:27])[C:4]1=[O:29])[CH3:2].BrC1C(C)=CC2OC(C)(C)C(=O)N(CC)C=2C=1.COC1C=CC(C=O)=CC=1B(O)O>>[CH2:1]([N:3]1[C:8]2[CH:9]=[C:10]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=3[O:22][CH3:23])[CH:17]=[O:18])[C:11]([CH3:13])=[CH:12][C:7]=2[O:6][C:5]([CH3:28])([CH3:27])[C:4]1=[O:29])[CH3:2]
Reactant: CCN1C(=O)C(C)(C)Oc2cc(C)c(-c3cc(C=O)ccc3OC(F)(F)F)cc21
Agent: CCN1C(=O)C(C)(C)Oc2cc(C)c(Br)cc21
Agent: COc1ccc(C=O)cc1B(O)O
Product: CCN1C(=O)C(C)(C)Oc2cc(C)c(-c3cc(C=O)ccc3OC)cc21

Procedure:
This was prepared using a procedure similar to that described to make Compound 1D, except using Compound 1C and 2-methoxy-5-formylphenylboronic acid in Step D. MS (electrospray): mass calculated for C21H23NO4, 353.16; m/z found 354.1 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][C:16]([CH3:24])([CH3:23])[C:15]=3[CH:14]=[C:13]([CH:25]=[O:26])[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:27]([Mg]Br)#[CH:28]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:20]3[C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][C:16]([CH3:24])([CH3:23])[C:15]=3[CH:14]=[C:13]([CH:25]([OH:26])[C:27]#[CH:28])[CH:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2cc(C=O)cc3c2C(C)(C)CCC3(C)C)cc1
Reactant: C#C[Mg]Br
Product: C#CC(O)c1cc(-c2ccc(C(C)(C)C)cc2)c2c(c1)C(C)(C)CCC2(C)C
Yield: 80 %

Procedure:
In a manner similar to that of Example 1f, by reacting 350 mg (1 mmol) of 4-(4-tert-butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenecarbaldehyde with 2.6 mL (1.3 mmol) of 0.5 N ethynylmagnesium bromide solution. White crystals are obtained (m=300 mg; yield=80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[CH:16][C:17]3[CH:18]=[C:19]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:28]=1>CCOC(C)=O.[Pt]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([CH2:16][C:17]3[CH:18]=[C:19]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:28]=1
Reactant: CS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3ccc(Cl)cc32)c1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cccc(CC2c3ccccc3CCc3ccc(Cl)cc32)c1
Reaction time: 18 h
Yield: 13.9 %

Procedure:
Dissolve N-[3-(3-chloro-10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenyl]-methanesulfonamide (200 mg, 0.49 mmol) in EtOAc (30 mL) and add 5% Pt/C (150 mg). Stir for 18 h under an atmosphere of hydrogen. Add 5% Pt/C (200 mg). Stir for 24 h under an atmosphere of hydrogen. Filter and concentrate to give 140 mg crude product. Purify using reverse-phase UV guided HPLC to give 28 mg viscous tan oil, MS (ES) 410 (M−1). HPLC shows 99% purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:9]([NH2:11])[CH3:10].C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:9]([NH:11][C:41]([C:37]1[CH:36]=[C:35]2[C:40](=[CH:39][CH:38]=1)[N:32]([CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:20]3[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:30][CH:29]=1)[C:33]([CH3:45])=[C:34]2[CH3:44])=[O:42])[CH3:10]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: COc1ccccc1[C@H](C)N
Product: COc1ccccc1[C@H](C)NC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(2-methoxyphenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 533 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH:7]=[CH2:8])[C:3]([OH:5])=[O:4].C([O-])(O)=O.[Na+].Cl[C:15]([O:17][CH3:18])=[O:16].Cl>O.CCOCC>[CH3:18][O:17][C:15]([NH:1][C@@H:2]([CH2:6][CH:7]=[CH2:8])[C:3]([OH:5])=[O:4])=[O:16]
Reactant: COC(=O)Cl
Reactant: C=CC[C@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: C=CC[C@H](NC(=O)OC)C(=O)O
Temperature: 0 °C
Reaction time: 20 h
Yield: 83.1 %

Procedure:
A mixture of (S)-2-aminopent-4-enoic acid (1.0 g, 8.69 mmol) and NaHCO3 (2.26 mg, 26.9 mmol) in H2O (40 mL) was cooled to 0° C. A mixture of methyl chloroformate (740 μL, 9.55 mmol) dissolved in Et2O (4 mL) was slowly added to the aqueous mixture and stirred for 20 hours coming to ambient temperature. Mixture was adjusted to pH 3.0 with HCl (conc). The mixture was extracted with EtOAc and then dried (MgSO4), filtered and concentrated to afford 1.25 g (83%) of the title compound. MS (ESI) m/z 174 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]([O:11][CH2:12][CH2:13][CH2:14][OH:15])(=[O:10])[C:7]([CH3:9])=[CH2:8]>N1C=CC=CC=1>[C:6]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:3](=[O:4])[CH2:2][Cl:1])(=[O:10])[C:7]([CH3:9])=[CH2:8]
Reactant: O=C(Cl)CCl
Reactant: C=C(C)C(=O)OCCCO
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCCOC(=O)CCl

Procedure:
Chloroacetoxypropyl methacrylate (CAPM) was prepared by condensation of chloroacetyl chloride with hydroxypropyl methacrylate in pyridine (cf Chem. Abs. 68, 105913 g) b.p. 92°-4° C./0.2mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12.[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+]>Cl.CN1C(=O)CCC1.O>[ClH:1].[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]3[CH2:15][CH2:16][CH2:17][C:3]3=[C:2]([NH:23][C:22]3[CH:24]=[CH:25][C:19]([F:18])=[CH:20][CH:21]=3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(F)cc1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Fc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 120 °C
Yield: 63.2 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.072 g, 0.27 mmol), 4-fluoroaniline (0.052 mL, 0.54 mmol) and cone. HCl (1 drop) in NMP (2 mL). The resulting mixture was heated at 120° C. under microwave irradiation for 3 h. After this time, the reaction mixture was cooled, diluted with water (25 mL) then treated with saturated sodium bicarbonate until pH˜8 and extracted with ethyl acetate. The combined extract was washed with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 1:1) as the eluent to afford the free base of the title compound (0.064 g, 70%) as an oil. MW=338.81. 1H NMR (DMSO-d6, 500 MHz) δ 8.14 (s, 1H), 7.93-7.90 (m, 1H), 7.76 (dt, J=7.0, 2.0 Hz, 1H), 7.45-7.39 (m, 2H), 7.31-7.26 (m, 2H), 7.24-7.18 (m, 2H), 7.13 (s, 1H), 2.91 (t, J=7.5 Hz, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.09 (quin, J=7.5 Hz, 2H). Treatment with 1.25M HCl in methanol (0.15 mL, 0.19 mmol, 1.0 eq.) afforded the title compound (0.064 g, 91%) as a white solid. MW=375.27. M.p. 103-106° C. 1H NMR (DMSO-d6, 500 MHz) δ 13.99 (br s, 1H), 9.05 (br s, 1H), 7.92-7.89 (m, 1H), 7.75-7.70 (m, 1H), 7.57-7.49 (m, 2H), (m, 2H), 7.31-7.25 (m, 2H), 7.04 (s, 1H), 3.04 (t, J=7.5 Hz, 2H), 2.87 (t, J=7.5 Hz, 2H), 2.17 (quin, J=7.5 Hz, 2H); ESI MS m/z 339 [m+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:3]1.[CH:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CCCCCCC.C(Cl)Cl>[C:22]([C:4]1[CH:5]=[C:6]([C:7]([F:8])([F:9])[F:10])[N:2]([CH3:1])[N:3]=1)#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: C#CCCCCC
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(C(F)(F)F)n(C)n2)cc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: CCCCCC#Cc1cc(C(F)(F)F)n(C)n1

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 7:3; yield (100 mg, 82%); 1H NMR δ (CDCl3): 6.63 (s, 1H), 3.95 (s, 3H), 2.38 (t, J=7.34 Hz, 2H), 1.64-1.56 (m, 2H), 1.46-1.28 (m, 4H), 0.90 (t, J=7.36 Hz, 3H); LCMS m/z: 244.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:9]2[O:14][C:13]3[C:15]([C:18]([O:20]C)=[O:19])=[CH:16][S:17][C:12]=3[C:11](=[O:22])[CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>CO.O1CCOCC1.O>[CH:3]1([C:9]2([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:14][C:13]3[C:15]([C:18]([OH:20])=[O:19])=[CH:16][S:17][C:12]=3[C:11](=[O:22])[CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1csc2c(=O)cc(C3CCCCC3)oc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)c1csc2c1OC(c1ccccc1)(C1CCCCC1)CC2=O
Temperature: 50 °C
Yield: 114.8 %

Procedure:
0.3 mL of 1N sodium hydroxide and 1.0 mL of water were added to a solution of 0.040 g of Compound 3D in 1.8 mL of MeOH and 0.9 mL of 1,4-dioxane at 20-25° C., while stirring. The mixture was heated at 50° C. for 3.5 hours. After cooling to 20-25° C., the mixture was diluted with water and acidified to pH 1 with 3N hydrochloric acid. The precipitated solid was collected by filtration and washed with water to afford 0.028 g (73.5%) of the title compound, melting at 269-275° C.
Reaction SMILES: [CH3:1][C:2]12[O:8][CH:5]([CH:6]=[CH:7]1)[C:4]([C:9]([F:12])([F:11])[F:10])=[C:3]2[C:13]([F:16])([F:15])[F:14].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[C:13]([F:14])([F:15])[F:16]
Reactant: CC12C=CC(O1)C(C(F)(F)F)=C2C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(O)c(C(F)(F)F)c1C(F)(F)F
Yield: 85.2 %

Procedure:
A mixture of Example 359A (12.0 g, 0.05 mol) and boron trifluoride-diethyl ether complex (150 mL) was stirred at room temperature overnight, then neutralized carefully with 20% aqueous potassium carbonate, then the mixture was extracted with ether. The ether layer was dried over MgSO4 and evaporated under reduced pressure to afford 10.4 g (85%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)#[CH:13].N>>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: ON=C(Cl)c1cncc(Cl)c1
Reactant: C#Cc1ccc(F)cc1
Agent: N
Product: Fc1ccc(-c2cc(-c3cncc(Cl)c3)no2)cc1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 1-ethynyl-4-fluorobenzene (Aldrich, 36 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.41-7.57 (m, 2H), 7.76 (s, 1H), 7.90-8.05 (m, 2H), 8.43 (t, J=2.2 Hz, 1H), 8.80 (d, J=2.4 Hz, 1H), 9.08 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 275 (M+H)+, 277 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH2:21]([N:11]1[CH2:12][CH2:13][C:9]([C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)([OH:14])[CH2:10]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCBr
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: CCCCN1CCC(O)(c2cc(F)cc(F)c2)C1
Temperature: 120 °C
Yield: 55.3 %

Procedure:
In a sealed tube a mixture of enantiomer E1 of 3-(3,5-difluorophenyl)pyrrolidin-3-ol (0.18 g, 0.92 mmol), acetonitrile (5 mL), potassium carbonate (0.25 g, 1.84 mmol) and n-butylbromide (0.1 mL, 1.01 mmol) was heated under microwave irradiation at 120° C. for 45 min. Aqueous sodium carbonate (10%, 5 mL) was added and the aqueous phase was extracted with ethyl acetate (2×50 mL), the combined organic phase was dried (Na2SO4) and evaporated. Purification on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) and by flash chromatography on silica gel (ethyl acetate/methanol, 7:1) gave the title compound (0.13 g). [α]D=+21.9° (methanol). The amine was converted to the oxalic acid salt and recrystallized from methanol/diisopropyl ether: M.p. 146-147° C.; MS m/z (relative intensity, 70 eV) 255 (M+, 5), 212 (bp), 98 (66), 57 (51), 182 (39), 127 (18).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:27]([OH:29])=[O:28])[CH2:10][O:11][C:12]1[C:17]([N+:18]([O-])=O)=[CH:16][CH:15]=[CH:14][C:13]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CCO>[NH2:18][C:17]1[C:12]([O:11][CH2:10][C@@H:9]([C:27]([OH:29])=[O:28])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[C:13]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1c(-c2ccccc2)cccc1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](COc1c(N)cccc1-c1ccccc1)C(=O)O
Reaction time: 10 h
Yield: 61.4 %

Procedure:
In an autoclave containing 500 mg of 35 (1.243 mmol), 54 mg of Pd/C (10%) and 33 mL of EtOH, hydrogenation is performed at 2 bar for 10 h at 20° C. After filtration of the catalyst on celite, the solvent is evaporated and 284 mg of expected product 36 are obtained, which product is used directly for the next step.
Reaction SMILES: O=O.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]=1O)([CH3:6])([CH3:5])[CH3:4].[OH-:18].[K+].[OH-:20].[Na+]>>[C:3]([C:7]1[CH:12]=[C:11]([OH:20])[CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]=1[C:8]1[C:7]([C:3]([CH3:5])([CH3:4])[CH3:6])=[CH:12][C:11]([OH:18])=[CH:10][C:9]=1[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: [OH-]
Agent: O=O
Agent: [K+]
Agent: [Na+]
Product: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1-c1c(C(C)(C)C)cc(O)cc1C(C)(C)C

Procedure:
oxidizing the resulting reaction liquid using oxygen without isolating said 2,6-di-t-butyl phenol from the liquid in the presence of KOH or NaOH as an alkaline catalyst to produce 3,3',5,5'-tetra-t-butyl-4,4'-biphenol,
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:42][CH2:41][C:32]2([O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]2)[CH2:31][CH2:30]1.C([Sn](=O)CCCC)CCC.[N:53]([Si](C)(C)C)=[N+:54]=[N-:55].C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH2:23]([C:6]1[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]([CH:29]2[CH2:42][CH2:41][C:32]3([O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]3)[CH2:31][CH2:30]2)[C:2](=[O:1])[C:7]=1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[NH:55][N:54]=[N:53][N:22]=2)=[CH:13][CH:14]=1)[CH2:24][CH3:25]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OC(C)(C)C(C)(C)O3)c2ncnn12
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n(C2CCC3(CC2)OC(C)(C)C(C)(C)O3)c2ncnn12
Temperature: 110 °C
Reaction time: 48 h
Yield: 27.9 %

Procedure:
A mixture of 4′-{[5-oxo-7-propyl-4-(2,2,3,3-tetramethyl-1,4-dioxaspiro[4.5]dec-8-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.2 g), dibutyltin oxide (0.026 g), azidotrimethylsilane (1.2 g) and toluene (15 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.06 g, 28%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[N:13]=1.[F:21][C:22]([F:36])([F:35])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([Sn](C)(C)C)=[CH:27][N:26]=1.[Cl-].[Li+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:28]3[CH:29]=[CH:30][C:25]([O:24][CH2:23][C:22]([F:36])([F:21])[F:35])=[N:26][CH:27]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: C[Sn](C)(C)c1ccc(OCC(F)(F)F)nc1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(Br)cc2)CO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: Fc1cccc(F)c1C1=NC(c2ccc(-c3ccc(OCC(F)(F)F)nc3)cc2)CO1

Procedure:
2-(2,6-Difluorophenyl)-4-(4-bromophenyl)oxazoline (VP4) (2.0 g, 5.9 mmol) was mixed with 2-trifluoroethoxy-5-trimethylstannylpyridine (2.61 g, 7.7 mmol), tetrakis(triphenylphosphine)palladium (0.22 g, 0.18 mmol) and lithium chloride (0.38 g, 8.9 mmol) in dioxane (30 ml) and refluxed for 9 hours. After extractive work-up and column chromatography, 2-(2,6-difluorophenyl)-4-[4-(2-trifluoroethoxypyridin-5-yl)phenyl]oxazoline was obtained, 1.37 g, colorless crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[CH:12]([OH:22])[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40](B4OC(C)(C)C(C)(C)O4)=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:32]=[CH:33][C:34]([C:37]3[CH:38]=[CH:39][C:40]([C:2]4[N:3]=[CH:4][C:5]5[C:10]([C:11]=4[CH:12]([OH:22])[CH2:13][CH2:14][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:9][CH:8]=[CH:7][CH:6]=5)=[CH:41][CH:42]=3)=[CH:35][CH:36]=2)[CH2:30][CH2:29]1)=[O:27])[CH3:24]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Reactant: OC(CCCc1ccccc1)c1c(Cl)ncc2ccccc12
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4ncc5ccccc5c4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: 1-(3-chloro-isoquinolin-4-yl)-4-phenyl-butan-1-ol and 1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester.