Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH:14]=[C:15]2[CH2:20][CH2:21][C:22]([OH:24])=[O:23].Cl>O>[OH:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH:14]=[C:15]2[CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: COc1cccc2c1CCC=C2CCC(=O)O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)CCC1=CCCc2c(O)cccc21
Temperature: 180 °C
Reaction time: 3 h

Procedure:
To pyridine hydrochloride (200 g), 3-(5-methoxy-3,4-dihydronaphthalen-1-yl)propanoic acid (25.1 g; known compound (see J. Chem. Soc. Perkin Trans. I., 1739–1742(1987)) was added, followed by stirring at 180° C. for 3 hours. The reaction mixture was cooled to room temperature, and diluted with water. The aqueous layer was acidified with a concentrated hydrochloric acid. The aqueous layer was extracted with an ethyl acetate. The extract was extracted with a saturated aqueous sodium hydrogen carbonate solution. The combined aqueous layer was acidified with a concentrated hydrochloric acid, followed by extracting with an ethyl acetate. The combined organic layer was washed with a saturated saline, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to thereby obtain the title compound (11.8 g) having the following physical data.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:4]=[C:5]([C:8](O)=[O:9])[S:6][CH:7]=1.C1N=C[N:15](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-]>C1COCC1>[F:1][C:2]([F:12])([F:11])[C:3]1[N:4]=[C:5]([C:8]([NH2:15])=[O:9])[S:6][CH:7]=1
Reactant: O=C(O)c1nc(C(F)(F)F)cs1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1nc(C(F)(F)F)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
To a solution of 4-trifluoromethyl-thiazole-2-carboxylic acid (50 g, 1 eq.) in anhydrous THF (480 mL) was added carbodiimidazole (45.2 g, 1.1 eq.) portionwise under nitrogen in an ice/water bath (about 5° C.). The reaction mixture was stirred at room temperature for 16 hrs. NH4OH (25% in H2O; 1.930 mL) was added. The solution was stirred for 4 hrs, and then partitioned in DCM (500 mL) and H2O (500 mL). Aqueous layer was further extracted with DCM (500 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to yield compound 285a as an orange solid in 72% yield. MS (ESI, EI+) m/z=197 (MH+).
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][CH2:12][NH2:13])(=O)=O)=CC=1.N1C=CC=CC=1.Cl[P:22]1(=[O:27])[O:26][CH2:25][CH2:24][O:23]1>C(#N)C>[NH2:13][CH2:12][CH2:11][O:10][P:22]1(=[O:27])[O:26][CH2:25][CH2:24][O:23]1
Reactant: Cc1ccc(S(=O)(=O)OCCN)cc1
Reactant: O=P1(Cl)OCCO1
Solvent: CC#N
Solvent: c1ccncc1
Product: NCCOP1(=O)OCCO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethanolamine p-toluenesulphonate (10.0 g, 39.8 mmol was dissolved in dry acetonitrile (500 ml) at 60° C. The solution was cooled to 30° C. when pyridine (3.15 g, 39.8 mmol) was added. A solution of 2-chloro-2-oxo-1,3,2-dioxaphospholane (5.68 g, 39.8 mmol) in dry acetonitrile (5 ml) was then added over 10 minutes. The mixture was stirred at ambient temperature for 4 hours and then the acetonitrile evaporated in vacuo to give 2-(2-aminoethoxy)-2-oxo-1,3,2-dioxaphospholane as a viscous oil.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:16]=[CH:15][C:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C:8]=2[CH:7]=1)(=[O:5])[CH3:4].O>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[CH:16]=[CH:15][C:9]2[O:10][C:11]([CH3:13])([CH3:14])[O:12][C:8]=2[CH:7]=1)=[O:5]
Reactant: CC(=O)c1ccc2c(c1)OC(C)(C)O2
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC1(C)Oc2ccc(C(=O)CBr)cc2O1
Reaction time: 15 h

Procedure:
Bromine (1.5 cc) is added in the course of 5 minutes at a temperature in the region of 20° C. to a stirred solution of 5-acetyl-2,2-dimethyl-1,3-benzodioxole (5.8 g) in carbon tetrachloride (100 cc), and the mixture is left with stirring for 15 hours at the same temperature. The reaction mixture is taken up with water (150 cc). The organic phase is separated off after settling has taken place, dried over anhydrous magnesium sulphate, filtered and evaporated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). 5-(2-Bromoacetyl)-2,2-dimethyl-1,3-benzodioxole (7.1 g) is obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:15])[NH:8][C:9]=1[CH:10]=[CH:11][N:12](C)C)(=O)[CH3:2].C(O)(=O)C.C(N)=N>CN(C)C=O>[CH3:2][C:1]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=[O:15])[NH:8]2
Reactant: CC(=O)c1ccc(=O)[nH]c1C=CN(C)C
Agent: N=CN
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1nccc2[nH]c(=O)ccc12
Yield: 83.8 %

Procedure:
A mixture containing 10.3 g of 5-acetyl-6-(2-dimethylaminoethenyl)-2(1H)-pyridinone, 10.4 g of formamidine acetate and 75 ml of dimethylformamide was heated on a steam bath for 5 hours and then concentrated to dryness on a rotary evaporator. The residue was treated with 50 ml of water and again stripped to dryness. The white residue was recrystallized from isopropyl alcohol to yield 6.7 g of 5-methyl-1,6naphthyridin-2(1H)-one, m.p. 238°-240° C. This compound was the same as the compound of Example E-7a, e.g., a mixed melting point showed no depression and the infrared and nuclear magnetic resonance spectral data for the compounds were respectively the same.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH:10]=O)=[CH:4][CH:3]=1.[CH:13]1[C:18]([NH:19][NH2:20])=[CH:17][CH:16]=[C:15]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:14]=1.Cl.N1C=CC=N1>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:19]([C:18]3[CH:13]=[CH:14][C:15]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:16][CH:17]=3)[N:20]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=CCC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: c1cn[nH]c1
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-n2nccc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Yield: 25.2 %

Procedure:
3-[4-(Chloro)phenyl]-propane-1,3-dione from Step 1 (18.3 g, 0.1 mol) and 4-sulfonamidophenylhydrazine hydrochloride (22.4 g, 0.1 mol) were dissolved in 150 mL of absolute ethanol and heated to reflux for 16 hours. The solution was cooled to room temperature, diluted with 100 mL of water and let stand, whereupon crystals of pyrazole formed that were isolated by filtration to provide 8.4 g (25%) of a white solid: mp 185°-187° C.; 1H NMR (CDCl3 /300 MHz) 7.89 (d, J=8.7Hz, 2H), 7.76 (d, J=1.8Hz, 1H), 7.43 (d,J=8.7Hz, 2H), 7.34 (d, J=8.7Hz, 2H), 7.17 (d, J=8.7Hz, 2H), 6.53 (d, J=1.8Hz, 1H), 4.93 (brs 2H). Anal. Calc'd for C15H12N3SO2Cl: C, 53.97; H, 3.62; N, 12.59. Found: C, 54.08; H, 3.57; N, 12.64.
Reaction SMILES: [OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([O:12][CH3:13])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[CH2:14]([Li])CCC.IC>C1COCC1>[CH3:14][O:1][C:2]12[CH2:3][CH2:4][C:5]([C:10]([O:12][CH3:13])=[O:11])([CH2:8][CH2:9]1)[CH2:6][CH2:7]2
Reactant: [Li]CCCC
Reactant: COC(=O)C12CCC(O)(CC1)CC2
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C12CCC(OC)(CC1)CC2
Temperature: 60 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
To a solution of methyl 4-hydroxybicyclo[2.2.2]octane-1-carboxylate (8.9 g, 48 mmol) in anhydrous THF (150 mL) at −78° C. was added n-butyl lithium (23 mL, 57.5 mmol, 2.5 M solution in hexane) over 30 min, followed by the slow addition of iodomethane (14 g, 98 mmol). The mixture was stirred at 60° C. for 3 h and quenched by addition of saturated aqueous ammonium chloride solution (50 mL). The resulting solution was concentrated and the residue was extracted with ethyl acetate (150 mL×2). The organic layers were combined and washed with brine, dried over magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to give the title product (6.5 g, 67%). 1H NMR (400 MHz, CDCl3) δ ppm 3.64 (s, 3H), 3.18 (s, 3H), 1.95-1.89 (m, 6H), 1.70-1.65 (m. 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:12]=[CH:11][NH:10][N:9]=1.[Cl:13]Cl>C(O)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([Cl:13])=[CH:11][NH:10][N:9]=1
Reactant: Clc1ccccc1-c1cc[nH]n1
Reactant: ClCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: Clc1ccccc1-c1n[nH]cc1Cl
Temperature: 25 °C
Yield: 44.5 %

Procedure:
6.8 g (0.038 mol ) of 3-(2'-chlorophenyl)-1H-pyrazole, prepared as in Example 9, are dissolved, at temperature and with stirring, in 30 ml of acetic acid. 2.9 g (0.0409 mol) of chlorine are then introduced into the reaction mixture. Stirring is maintained for 1 hour at room temperature and then the acetic acid is driven off under reduced pressure. The residue is taken up in methylene chloride and this organic solution is washed with an aqueous bicarbonate solution, then with water and then dried over Na2SO4 before being concentrated to dryness. The residue is chromatographed on a silica column (eluent: heptane/ethyl acetate 60/40). 3.6 g of 3-(2'-chlorophenyl)-4-chloro-1H-pyrazole (compound 96) are obtained, which is of honey-like consistency (yield 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17]C)=[O:16])=[CH:11][C:10]=2[CH3:19])=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[CH2:30][N:31]1[C@@H:35]([CH3:36])[C@@H:34]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[CH:38]=2)[O:33][C:32]1=[O:44].[Li+].[OH-].Cl>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][C:10]=2[CH3:19])=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][C:21]=1[CH2:30][N:31]1[C@@H:35]([CH3:36])[C@@H:34]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[CH:38]=2)[O:33][C:32]1=[O:44]
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4ccnc(C)c4)[C@@H]3C)c2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2ccnc(C)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 4′-methoxy-2-methyl-2″-{[(4S,5R)-4-methyl-5-(2-methylpyridin-4-yl)-2-oxo-1,3-oxazolidin-3-yl]methyl}-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (30.1 mg, 0.050 mmol) in 1,4-dioxane (1.5 mL) and water (1.5 mL) was added 1M aqueous LiOH (0.498 mL, 0.498 mmol). The mixture was stirred at room temperature for 4 h. The mixture was acidified with 1N HCl. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The crude material was purified by preparative HPLC reverse phase (C-18), eluting with MeCN/water. The fractions were collected and lyophilized to give 4′-methoxy-2-methyl-2″-{[(4S,5R)-4-methyl-5-(2-methylpyridin-4-yl)-2-oxo-1,3-oxazolidin-3-yl]methyl}-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid. LCMS calc.=591.2; found=591.1 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 8.83 (s, 1H); 8.02 (s, 1H); 7.94 (t, J=10.0 Hz, 1H); 7.72 (s, 0.5H); 7.69 (t, J=6.0 Hz, 1H); 7.64 (s, 0.5H); 7.49-7.43 (m, 3H); 7.40 (d, J=5.2 Hz, 0.5H); 7.35 (d, J=5.4 Hz, 0.5H); 7.31 (m, 1H); 7.16 (dd, J=2.1, 6.0 Hz, 1H); 7.12 (t, J=8.8 Hz, 1H); 5.56 (d, J=8.1 Hz, 0.5H); 5.26 (d, J=8.2 Hz, 0.5H); 4.94 (dd, J=8.7, 15.7 Hz, 1H); 4.77 (br s, 1H); 4.20 (d, J=15.8 Hz, 0.5H); 4.00 (d, J=15.7 Hz, 0.5H); 3.90 (s, 1.5H); 3.89 (s, 1.5H); 3.89-3.81 (m, 1H); 2.82 (s, 1.5H); 2.81 (s, 1.5H); 2.41 (s, 1.5H); 2.36 (s, 1.5H); 0.62 (d, J=6.5 Hz, 1.5H); 0.49 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH3:15])[CH2:10][CH2:9]2)[N:5]=[CH:4][N:3]=1.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[OH:33])[CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[N:5]=[CH:4][N:3]=[C:2]([O:33][C:31]4[CH:30]=[CH:29][CH:28]=[C:27]5[C:32]=4[CH:23]=[N:24][CH:25]=[CH:26]5)[CH:7]=3)[CH2:9][CH2:10]2)[CH3:15])=[CH:17][CH:18]=1
Reactant: CC(c1ccc(F)cc1)N1CCN(c2cc(F)ncn2)CC1
Reactant: Oc1cccc2ccncc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(c1ccc(F)cc1)N1CCN(c2cc(Oc3cccc4ccncc34)ncn2)CC1
Temperature: 115 °C

Procedure:
A mixture of 4-fluoro-6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidine, Example 33(a), (0.05 g, 0.17 mmol), isoquinolin-8-ol (0.037 g, 0.25 mmol, Monomer Chem, Inc.) cesium carbonate (0.081 g, 0.25 mmol), and DMSO (1 mL) was heated in a microwave synthesizer at 115° C. for 0.5 h. The reaction mixture was allowed to cool to room temperature, diluted with H2O (30 mL) and extracted with DCM (2×50 mL). The combined organic extracts were washed with H2O (2×30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient: 0-8% MeOH/DCM) to give the title compound as a white solid. Mp: 114° C. MS (ESI, pos. ion) m/z: 430 (M+1).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[S:30]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31]1>ClCCCl>[F:22][C:2]([F:1])([F:21])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:35]([C:32]3[CH:33]=[CH:34][S:30][CH:31]=3)(=[O:37])=[O:36])[CH2:17][CH2:16]2)=[CH:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: O=S(=O)(Cl)c1ccsc1
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccsc1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reaction time: 18 h

Procedure:
To a solution of 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol (50 mg, 0.152 mmol, published PCT patent application no. WO 2006/094842) and triethylamine (63.6 μL, 0.457 mmol) in 1,2-dichloroethane (1.5 mL) was added 3-thiophenesulfonyl chloride (1M in dichloroethane, 168 μL, 0.168 mmol, ASDI, Newark, Del.). The reaction was shaken on an orbital shaker for 18 h. The reaction solvent was removed under reduced pressure and the crude product was purified by reverse-phase preparative HPLC using a Sunfire Prep C18 OBD (100×19 mm, 5 μm) column, 0.1% TFA in MeOH/H2O, gradient (65% to 95% over 4.5 min) to provide 1,1,1,3,3,3-hexafluoro-2-(4-(4-(3-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1H NMR (400 MHz, DMSO-d6) δ 8.35-8.27 (m, 1H), 7.85 (dd, J=5.1, 2.9 Hz, 1H), 7.47 (d, J=8.8 Hz, 2H), 7.37 (d, J=5.1 Hz, 1H), 7.02 (d, J=9.0 Hz, 2H), 3.33-3.28 (m, 4H), 3.07-3.01 (m, 4H). m/z (ESI, +ve ion) 475.1 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.597 μM; GK-GKRP EC50 (LC MS/MS)=0.964 μM.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:30][C:31]1[CH:36]=[C:35]([Cl:37])[C:34]([Cl:38])=[CH:33][C:32]=1OC(ON=C(C#N)C(OCC)=O)=O>C(OCC)(=O)C>[Cl:30][C:31]1[CH:36]=[C:35]([Cl:37])[C:34]([Cl:38])=[CH:33][C:32]=1[O:21][C:20](=[O:22])[C@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CCOC(=O)C(C#N)=NOC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1cc(Cl)c(Cl)cc1Cl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.2 %

Procedure:
To a solution of N-benzyloxycarbonyl-L-phenylalanine (1.5 g) and triethylamine (0.7 ml) in ethyl acetate (20 ml), ethyl 2-(2,4,5-trichlorophenyl)oxycarbonyloxyimino-2-cyanoacetate (1.9 g) is added, and the resulting mixture is stirred at room temperature for 4 hours. The reaction mixture is treated as in Example 16 to give N-benzyloxycarbonyl-L-phenylalanine 2,4,5-trichlorophenyl ester (1.9 g). M.P. 139° - 140°C.
Reaction SMILES: [O:1]1[C:3]2([CH2:19][O:20][C:21](=[O:35])[N:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:4][CH2:5][C:6]3[C:11]([CH:2]12)=[CH:10][CH:9]=[CH:8][C:7]=3[O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C1C=CN=CC=1.[FH:42]>C(Cl)Cl>[F:42][CH:2]1[C:11]2[C:6](=[C:7]([O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1([OH:1])[CH2:19][O:20][C:21](=[O:35])[N:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)COc1cccc2c1CCC1(COC(=O)N(c3ccccc3)c3ccccc3)OC21
Reactant: F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)COc1cccc2c1CCC(O)(COC(=O)N(c1ccccc1)c1ccccc1)C2F
Reaction time: 2 h

Procedure:
To a solution of 1,2-epoxy-2-(N,N-diphenylcarbamoyloxymethyl)-5-ethoxycarbonylmethyloxy-1,2,3,4-tetrahydronaphthalene (0.2 g) in CH2Cl2 (30 ml) was added HF-pyridine (0.5 ml) at 0° C. After being stirred for 2 hours, the solvent was removed in vacuo. The residue was extracted with ethyl acetate. The mixture was washed with 1N-HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 1-fluoro-2-hydroxy-2-(N,N-diphenylcarbamoyloxymethyl)-5-ethoxycarbonylmethyloxy-1,2,3,4-tetrahydronaphthalene (70 mg)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@@H:21]([NH2:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[C:32]([CH3:33])=[C:31](I)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@@H:21]([NH:23][C:31]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:24])[C:32]=1[CH3:33])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(I)ccc(C#N)c1Cl
Reactant: C[C@H](N)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: Cc1c(N[C@@H](C)[C@@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCN2C(=O)OC(C)(C)C)ccc(C#N)c1Cl
Temperature: 110 °C
Yield: 99 %

Procedure:
To a solution of 61F (325 mg, 0.94 mmol) in degassed toluene:DMSO (2:1, 7 mL) at rt was added 61G (260 mg, 0.94 mmol), Cs2CO3 (614 mg, 1.89 mmol) and a solution of Pd2(dba)3 and (S)—N,N-dimethyl-1-[(R)-2-(diphenyphosphino)ferrocenyl]ethylamine (1:6 ratio, 0.06 mol %) in nitrogen degassed toluene (3 mL). The reaction was degassed with nitrogen for 30 min, sealed and heated at 110° C. for 48 h. Cool to rt and extract with EtOAc (50 mL) and wash with water followed by sat'd aqueous NaHCO3. Dry over MgSO4, filter and concentrate. Purification by flash chromatography (40 g ISCO silica gel cartridge, 0-10% EtOAc in hexane gradient) gave the title compound (460 mg): MS (ES) m/z 494.29 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)=O)=[CH:4][CH:3]=1.[C:20]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)(=[O:22])[CH3:21].[OH-].[K+].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCOCC1
Reactant: COc1ccc(C(=O)c2ccc(Cl)cc2)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccc(Cl)cc2)cc1OC
Reaction time: 0.5 h
Yield: 8.3 %

Procedure:
6.92 g (25 mmol) 4-chloro-3',4'-dimethoxybenzophenone, 12.9 g (100 mmol) N-acetylmorpholine and 11.2 g (170 mmol) powdered potassium hydroxide (85%) were mixed well and allowed to stand at room temperature for 30 minutes, with occasional stirring. The viscous mass so obtained was then added to a vigorously stirred mixture of 100 ml water and 50 ml toluene. The toluene phase was dried and separated over a column containing 50 g silica gel using 150 ml each of 95:5, 90:10 and 80:20 toluene-acetone mixture as eluant. The fractions with an Rf value of 0.37 (Toluene/Acetone 7:3) were evaporated in a rotary evaporator, after which 0.8 g of the title compound were obtained by trituration with a little diisopropyl ether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])=[C:10]([N:23]([CH3:25])[CH3:24])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:44])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[CH:43]=[CH:42][N:41]=[N:40]2)[CH:34]=1)C>>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[C:13]([NH:14][C:30](=[O:29])[CH2:31][C:32](=[O:44])[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([N:39]3[CH:43]=[CH:42][N:41]=[N:40]3)[CH:34]=2)=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])=[C:10]([N:23]([CH3:24])[CH3:25])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1-c1cccc(F)c1F
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1-c1cccc(F)c1F

Procedure:
The title compound was prepared from (5-amino-2-dimethylamino-2′,3′-difluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example J3) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example K1) according to the general procedure M. Obtained as a yellow solid (253 mg).
Reaction SMILES: [CH:1]([C@@H:4]1[N:8]([C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[N:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:25]=5)=[CH:20][CH:19]=4)=[C:11]3[N:10]=2)[C:7](=[O:37])[NH:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:41][CH2:42][O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]>>[Si:44]([O:43][CH2:42][CH2:41][N:6]1[CH2:5][C@H:4]([CH:1]([CH3:3])[CH3:2])[N:8]([C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[N:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:35])[CH3:36])[N:25]=5)=[CH:20][CH:19]=4)=[C:11]3[N:10]=2)[C:7]1=[O:37])([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)[C@H]1CNC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Agent: [H-]
Agent: [Na+]
Product: CC(C)[C@H]1CN(CCO[Si](C)(C)C(C)(C)C)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a solution of (S)-5-isopropyl-1-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (0.23 g, 0.443 mmol) at 0° C. was added sodium hydride (0.0355 g, 0.887 mmol) and the reaction stirred 10 minutes. (2-Bromoethoxy)(tert-butyl)dimethylsilane (0.212 g, 0.887 mmol) was added and the reaction stirred for 2 hours while warming to ambient temperature. The reaction was poured onto water and extracted into EtOAc. The combined organic layers were washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The crude material was chromatographed using 20% EtOAc/dichloromethane as eluent to yield (S)-1-(2-(tert-butyldimethylsilyloxy)ethyl)-4-isopropyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (0.18 g, 60%).