Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10]2[C:11](=[O:26])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:13]=[C:14]([Cl:16])[N:15]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N(CC)CC)C.[CH3:34][Si:35]([C:38]#[CH:39])([CH3:37])[CH3:36]>C1COCC1.[Cu](I)I.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:16][C:14]1[N:15]=[C:10]([NH:9][C:3]2[C:2]([C:39]#[C:38][Si:35]([CH3:37])([CH3:36])[CH3:34])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=2)[C:11](=[O:26])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:13]=1
Reactant: COc1ccc(Cn2cc(Cl)nc(Nc3ncc(C)cc3Br)c2=O)cc1
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2cc(Cl)nc(Nc3ncc(C)cc3C#C[Si](C)(C)C)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.4 %

Procedure:
In a 1 L round bottom combined 3-(3-bromo-5-methylpyridin-2-ylamino)-5-chloro-1-(4-methoxybenzyl)pyrazin-2(1H)-one (51.90 g, 119.12 mmol), triphenylphosphine (1.56 g, 5.96 mmol), (Ph3P)PdCl2 (4.18 g, 5.96 mmol) and suspended in anhydrous THF (450 mL). Triethylamine (18.08 g, 178.68 mmol) and trimethylsilyl acetylene (35.10 g, 357.36 mmol) were added next and mixture was stirred at ambient temperature, under N2 for 10 minutes. Copper iodide (catalytic) was added last and reaction was stirred at ambient temperature. Reaction was monitored by analytical LCMS at one hour intervals and CuI was added until reaction is complete. The completed reaction was concentrated in vacuo, taken up with ethyl acetate (700 mL) and brine (300 mL) and filtered off undissolved solids before taking on to extraction. The organic layer was washed with additional brine (4×300 mL), dried with MgSO4, filtered and concentrated in vacuo. Chromatography on silica gel plug with ethyl acetate/hexanes (1/9), two attempts, afforded the desired product (43.36 g. 81% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.11 (s, 9 H) 2.26 (s, 3 H) 3.73 (s, 3 H) 5.00 (s, 2 H) 6.91 (d, J=8.59 Hz, 2 H) 7.38 (d, J=8.59 Hz, 2 H) 7.45 (s, 1 H) 7.74 (d, J=2.27 Hz, 1 H) 8.25 (d, J=2.27 Hz, 1 H) 9.51 (s, 1 H). ESI-MS: m/z 453.3 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][C@@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22]>>[C:21]([C@@H:20]([NH:19][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])[CH2:24][CH:25]([CH3:27])[CH3:26])(=[O:22])[NH2:23]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Product: CC(C)C[C@H](NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and (S)-2-Amino-4-methyl-pentanoic acid amide (CAN 687-51-4) as starting materials and isolated (13.5 mg, 24%) as a white solid; MS (ESI, m/z): 374.0 (M+H+).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C@H:15]3[CH2:20][CH2:19][CH:18]([C:21]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[O:22])[CH2:17][C@@H:16]3[C:28](OC)=[O:29])=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([P+]([O:42][N:43]1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.Cl.C1(C2CCNCC=2)C=CC=CC=1.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[OH:42][NH:43][C:28]([C@H:16]1[CH2:17][CH:18]([C:21]([N:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)=[O:22])[CH2:19][CH2:20][C@@H:15]1[C:13]([N:10]1[CH2:11][CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1)=[O:14])=[O:29]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: COC(=O)[C@H]1CC(C(=O)N2CCCC2)CC[C@@H]1C(=O)N1CCC(c2ccccc2)CC1
Agent: C1=C(c2ccccc2)CCNC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NO)[C@H]1CC(C(=O)N2CCCC2)CC[C@@H]1C(=O)N1CC=C(c2ccccc2)CC1
Reaction time: 0.17 h
Yield: 79.7 %

Procedure:
Part 8. methyl (1S,2S)-2-[(4-phenylpiperidin-1-yl)carbonyl]-5-(pyrrolidin-1-ylcarbonyl)cyclohexanecarboxylate: The product from Part 7 (0.112 g, 0.395 mmol) was dissolved in DMF (4.0 mL) and treated with BOP reagent (0.210 g, 0.474 mmol). After stirring for 10 min, the HCl salt of 4-phenyl-1,2,3,6-tetrahydropyridine (81 mg, 0.415 mmol) was added followed by N,N-diisopropylethylamine (206 μL, 1.18 mmol). The reaction mixture was stirred at rt overnight. It was poured into a saturated aq. NaHCO3 solution and extracted with EtOAc. The organic phase was washed with water (2×) and brine, dried over MgSO4, filtered and concentrated. The residue was flash chromatographed (silica, hexanes:EtOAc, 5:1 to 4:1 to 3:1) to provide the desired product (0.126 g, 79.7% yield). LCMS: m/z 425.2 (M+H)+.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]1([CH3:22])[NH:20][C:19](=O)[CH2:18][CH2:17]1.P(Cl)(Cl)(Cl)=O>>[CH3:15][C:16]1([CH3:22])[N:20]=[C:19]([N:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:6][C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:18][CH2:17]1
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Reactant: CC1(C)CCC(=O)N1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)CCC(N2c3ccccc3Oc3ccccc32)=N1

Procedure:
Reaction of phenoxazine, 5,5-dimethyl-2-pyrrolidinone and phosphorus oxychloride according to the procedure 25 of Example 1 provides the free base 10-(5,5-DIMETHYL-1-PYRROLIN-2-YL)PHENOXAZINE, m.p. 148-150° C. Conversion of the free base to the hydrochloride salt affords 10-(5,5-DIMETHYL-1-PYRROLIN-2-YL)PHENOXAZINE HYDROCHLORIDE, m.p. 239-242.5° C. (corr.), in a 48% overall yield.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:12]([NH:14][CH2:15][CH3:16])=O)[CH2:11][CH2:10]CC=1.[CH3:17][CH2:18]OCC>>[CH:16]1([CH2:15][NH:14][CH2:12][CH:7]2[CH2:11][CH2:10]2)[CH2:18][CH2:17]1
Reactant: CCNC(=O)C1=CCCC1
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C1CC1CNCC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a suspension of lithium aluminum hydride (1.3 g, 9.35 mmol) in 10 mL dry ether, a solution of N-cyclopentenoyl-ethylamine (1.7 g, 13.3 mmol) in dry ether (10 mL) was added under a nitrogen atmosphere. This reaction was stirred at RT for 8 h and the reaction mixture was then quenched with saturated sodium sulfate solution, filtered, and the precipitate was washed with diethyl ether. The filtrate was concentrated to afford the title amine (0.8 g, yield: 69%).
Reaction SMILES: [CH2:1](Cl)[C:2](=[CH2:4])[CH3:3].C(Cl)C=C.[Li]C.[O:12]1[CH:14]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13]1>C1COCC1>[CH3:3][C:2]([CH2:1][CH2:13][CH:14]([OH:12])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH2:4]
Reactant: C=C(C)CCl
Reactant: CCCCC1CO1
Agent: [Li]C
Solvent: C1CCOC1
Solvent: C=CCCl
Product: C=C(C)CCC(O)CCCC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 67.3 %

Procedure:
Methallylchloride (3.16 mmol) was weighed into an 8 ml vial, sealed with a septum and placed under argon. THF (2 to 4 ml) was added to the vial and the allyl chloride solution was cooled to -78° C. The allyl chloride was added rapidly via a cannula to a suspension of the zerovalentcopper species prepared according to the procedure of Example 1 (7.96 mmol)at -100° C. and stirred for 10 min. MeLi (6.30 mmol) was added to the newly formed organocopper solution at -90° C. and stirred for 15 min. 1,2-Epoxyhexane (1.01 mmol) was added from a vial to the new organocopper solution at -90° C., warmed to 0° C. over 3 hours, and held at 0° C. for 12 hours. The reaction was quenched with NH4Cl (sat'd), extracted with Et2O (2×50 ml), washed with brine (2×50 ml), and dried over MgSO4. Flash silicagel chromatography, using gradient mixtures of hexane and ethyl acetate, afforded 2-methyl-1-nonen-5-ol (0.68 mmol, Entry 10 in Table III). Rf =0.23 in 9:1 (v/v) hexane and ethyl acetate, respectively (67% yield): IR (neat) 3317, 3070, 3016, 2954, 2931, 2869, 2854, 1647, 1452, 1375, 1126, 1084, 1053, 1036, 1003, 885 cm-1. 1H NMR (360 MHz) 4.72 (bs, 2H), 3.63-3.58 (m, 1H), 2.20-2.05 (m, 2H), 1.74 (s, 3H), 1.68-1.30 (m, 8H), 0.91 (t, J=7.0 Hz, 3H). 13C NMR (50 MHz) 145.9, 110.0, 71.7, 37.2, 35.2, 34.0, 27.8, 22.7, 22.4, 14.0.
Reaction SMILES: [Si](O[CH2:19][C@H:20]1[O:27][C@@H:24]([O:25][CH3:26])[C@H:23]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:22]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:21]1[O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.[S:67]([O:74]S(C(F)(F)F)(=O)=O)([C:70]([F:73])([F:72])[F:71])(=[O:69])=[O:68].C([O-])(O)=O.[Na+]>ClCCl>[CH2:29]([O:28][C@@H:23]1[C@@H:22]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@H:21]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:20]([CH2:19][O:74][S:67]([C:70]([F:73])([F:72])[F:71])(=[O:69])=[O:68])[O:27][C@H:24]1[O:25][CH3:26])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CO[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CO[C@@H]1O[C@H](COS(=O)(=O)C(F)(F)F)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of methyl 6-O-tert-butyldiphenylsilyl-2,3,4-tri-O-benzyl-β-D-glucopyranoside (800 mg, 1.71 mmol) in 8.55 mL of dry dichloromethane at -78° C. was added 2,6-di-tert-butyl-4-methyl pyridine (632 mg, 3.08 mmol) followed by triflic anhydride (345 μl, 2.05 mmol). After stirring 15 minutes at -78° C., the mixture was warmed to room temperature over 20 minutes, and then poured into a solution of saturated aqueous NaHCO3 (20 mL) and extracted with ethyl acetate (50 mL) . The organic layer was washed with saturated NaHCO3 (3×20 mL), saturated aqueous NaCl (1×20 mL), and dried over magnesium sulfate. Concentration provided crude target compound, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br[CH:11]([C:13]1[CH:14]=[C:15]([C:30]([O:32][CH3:33])=[O:31])[CH:16]=[C:17]2[C:22]=1[O:21][C:20]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[CH:19][C:18]2=[O:29])[CH3:12]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:9])=[C:4]([NH:5][CH:11]([C:13]2[CH:14]=[C:15]([C:30]([O:32][CH3:33])=[O:31])[CH:16]=[C:17]3[C:22]=2[O:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:19][C:18]3=[O:29])[CH3:12])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1F
Reactant: COC(=O)c1cc(C(C)Br)c2oc(N3CCOCC3)cc(=O)c2c1
Solvent: ClCCl
Product: COC(=O)c1cc(C(C)Nc2cccc(Cl)c2F)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
3-chloro-2-fluoroaniline (0.239 mL, 2.17 mmol) was added to a stirred suspension of methyl 8-(1-bromoethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (215 mg, 0.54 mmol) dissolved in DCM (3 mL) at room temperature. The resulting suspension was stirred for 16 hrs then the temperature was increased to 50° C. for 16 hrs. The crude product was purified by flash chromatography on silica gel eluting with 5% methanol in DCM. The solvent was evaporated to dryness to afford methyl 8-(1-(3-chloro-2-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (206 mg, 82%) as a white solid. Mass Spectrum: M+H+ 461.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH2:12].[CH2:14]([CH2:16][NH2:17])[OH:15]>C(#N)C>[OH:15][CH2:14][CH2:16][NH:17][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH2:12]
Reactant: COC(=O)c1cc(Cl)cc(C)c1N
Reactant: NCCO
Solvent: CC#N
Product: Cc1cc(Cl)cc(C(=O)NCCO)c1N
Temperature: 70 °C
Yield: 88.3 %

Procedure:
To a 100 mL round-bottom flask, 0.1 mol of 2-amino-3-methyl-5-chlorobenzoic acid methyl ester having the structural formula of VIII-3, 100 mL of acetonitrile, 0.4 mol of ethanolamine were added, heated to 70° C. and reacted for 3 hours, after treatment 20.2 grams of N-hydroxyethyl-2-amino-3-methyl-5-chlorobenzamide having a structural formula of III-3 was obtained, and the yield was 88.4%; To a 50 mL round-bottom flask, 3.0 mmol of N-hydroxyethyl-2-amino-3-methyl-5-chlorobenzamide having the structural formula of III-3, 3.0 mmol of 1-(3,5-dichloropyridine-2-yl)-3-bromo-1H-pyrazole-5-carboxylic acid having a structural formula of II-3, 10 mL of acetonitrile were added, and 9.0 mmol of potassium carbonate and 0.2 gram of potassium iodide were added under stirring, cooled to −7° C. and a 3 mL acetonitrile solution of 12 mmol methanesulfonyl chloride was dripped, after dripping was completed reacted at 0° C. for 1.0 hour, reacted at 20° C. for 1.0 hour, 10 mL of water was added and stirred for 0.5 hour, filtered and dried to obtain 1.52 grams of 1-(3,5-dichloropyridine-2-yl)-3-bromo-N-(2-methyl-4-chloro-6-hydroxyethylaminocarbonyl)phenyl-1H-pyrazole-5-formamide having a structural formula of I-29 as a pale yellow solid, and the yield was 92.7%.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])([CH3:10])[CH3:9])[CH:7]=1.[B:16]1(B2OC(C)(C)C(C)(C)O2)[O:20]C(C)(C)C(C)(C)[O:17]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])(=O)C.[K+]>O1CCOCC1.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]>[CH2:14]([S:11]([C:8]([C:6]1[CH:7]=[C:2]([B:16]([OH:20])[OH:17])[CH:3]=[N:4][CH:5]=1)([CH3:10])[CH3:9])(=[O:13])=[O:12])[CH3:15]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CCS(=O)(=O)C(C)(C)c1cncc(Br)c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CCS(=O)(=O)C(C)(C)c1cncc(B(O)O)c1
Temperature: 80 °C

Procedure:
A vial containing the title compound from Example 62 Step D (0.030 g, 0.103 mmol), bis(pinacolato)diboron (0.052 g, 0.205 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.019 g, 0.021 mmol), tricyclohexylphosphine (0.012 g, 0.041 mmol) and potassium acetate (0.030 g, 0.308 mmol) in 1,4-dioxane (0.510 mL) was flushed with nitrogen, sealed tightly and heated to 80° C. overnight. The reaction was then passed through a syringe filter and concentrated under reduced pressure to provide the title compound: LCMS m/z 258.29 [M+H]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:11]=[C:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:14][CH:15]=1.O>CN(C=O)C.CC(C)=O>[NH2:9][C:10]1[N:11]=[C:12]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:13]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:14][C:15]=1[Br:1]
Reactant: CC(C)n1nc(-c2ncc(N)nc2-c2ccccc2)ccc1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 52.5 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
N-bromosuccinimide (875 mg) was added to a solution of 6-(5-amino-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (1.51 g) in DMF (15 ml). The mixture was stirred at 50-55° C. for one hour and poured into water (150 ml). The precipitate was collected by filtration, dissolved in CHCl3, dried over MgSO4 and concentrated under reduced pressure to give a solid. The solid was suspended in acetone and collected by filtration to give 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone as a solid (1.26 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH:10]([CH2:16][OH:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:20]([C:24]1[N:25]=[N:26][C:27](Cl)=[CH:28][C:29]=1[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:32][CH:31]=1)[CH2:21][CH2:22][CH3:23]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:14])([F:15])[CH:10]([CH2:16][O:17][C:27]2[N:26]=[N:25][C:24]([CH2:20][CH2:21][CH2:22][CH3:23])=[C:29]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]4)=[CH:34][CH:35]=3)[CH:28]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(F)C(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1nnc(OCC2CN(C(=O)OC(C)(C)C)CCC2(F)F)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
To a solution of 4,4-difluoro-3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.8 mmol, 0.2 g) in 5 mL of THF was added 60% NaH (4.0 mmol, 96 mg). The mixture was stirred at room temperature for 10 min, then a solution of 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (Example 14, 0.4 mmol, 0.14 g) was added. The mixture was refluxed for 1 h, quenched with water, extracted with EtOAc. The organic layer was washed with saturated sodium bicarbonate, brine, dried, evaporated, the resulting residue was chromatographed with 20:1 DCM/MeOH to afford 3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4,4-difluoro-piperidine-1-carboxylic acid tert-butyl ester (150 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][OH:20])[C:13]1=[O:21].C(N(CC)CC)C.[C:29]([Si:33](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:32])([CH3:31])[CH3:30].O>CN(C)C=O.CN(C)C1C=CN=CC=1>[Si:33]([O:20][CH2:19][CH2:18][C:14]1[C:13](=[O:21])[N:12]([C:3]2[C:2]([CH3:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][C:4]=2[CH3:11])[CH:17]=[CH:16][CH:15]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(CCO)c1=O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
760 mg (2.64 mmol) of the compound from Example 53A and 0.55 ml (3.9 mmol) of triethylamine are dissolved in 7 ml of anhydrous N,N-dimethylformamide. 16 mg (0.13 mmol) of 4-dimethylaminopyridine and 1.09 g (3.95 mmol) of tert-butyl(chloro)diphenylsilane are added, and the mixture is stirred at RT for 2 h. The mixture is then added to water and, after phase separation, extracted three times with ethyl acetate. The combined organic phases are washed twice with water, dried over sodium sulphate, filtered, and evaporated under reduced pressure. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 5:1). This gives 971 mg (58% of theory) of the desired product.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][CH2:5][N:6]([CH3:20])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[C:16]([F:19])([F:18])[F:17]>CO.[Ni]>[CH3:21][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]([CH3:20])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:16]([F:17])([F:19])[F:18]
Reactant: CN(C)CCCN(C)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Ni]
Solvent: CO
Product: CN(C)CCCN(C)c1ccc(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A suspension of N,N,N′-trimethyl-N′-(4-nitro-2-trifluoromethyl-phenyl)-propane-1,3-diamine (1 g, 3.28 mmol) and Raney Ni (˜0.300 g) in MeOH (20 mL) is stirred for 2 h 40 min at rt, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of Celite and concentrated to afford the title compound as a brown oil: ES-MS: 276.2 [M+H]+; single peak at tR=1.30 min (System 1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=3)[O:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+:30]>C1COCC1.CCO>[Na+:30].[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]#[C:13][C:14]3[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=3)[O:17][CH2:18][CH2:19][CH2:20][C:21]([O-:23])=[O:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCOc1cccc(C=Cc2ccc3ccc(Br)cc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C([O-])CCCOc1cccc(C#Cc2ccc3ccc(Br)cc3n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the ethyl ester from Step 4 (380 mg) in THF (4 mL) and EtOH (2 mL) was added 2N NaOH (0.65 mL) and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness and passed through a neutral XAD-8 resin, eluting with H2O and then with EtOH, to afford the title compound as a white solid: m.p. 250° C. (d).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[C:18]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:20])[CH3:19]
Reactant: O=C(O)c1cc(-c2ccc(F)cc2)ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2ccc(F)cc2)cc1C(=O)O

Procedure:
A solution of 3.0 grams of 2-hydroxy-5-(4'-fluorophenyl)-benzoic acid in 12 ml. of pyridine and 8 ml. of acetic anhydride is heated on a steam bath for 20 minutes. The mixture is then poured onto ice and the product extracted with methylene chloride. The methylene chloride solution is dried and then evaporated. The residue is recrystallized from benzene to yield 2-acetoxy 5-(4'-fluorophenyl)-benzoic acid (m.p. 134° - 137° C.).
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][CH:17]=[C:16]([CH3:20])[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:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: ON=C(Cl)c1cncc(Cl)c1
Reactant: C#Cc1cccc(C)c1
Agent: N
Product: Cc1cccc(-c2cc(-c3cncc(Cl)c3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 1-ethynyl-3-methylbenzene (Aldrich, 35 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ 2.42 (s, 3H), 7.38 (d, J=7.5 Hz, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.66-7.75 (m, 2H), 7.75 (s, 1H), 8.44 (t, J=2.1 Hz, 1 H), 8.80 (d, J=2.4 Hz, 1H), 9.09 (d, J=2.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 271 (M+H)+, 273 (M+H)+.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:8][CH2:7][CH2:6][NH:5]2)[CH2:3][O:2]1.C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:28][C:27]([C:29]([N:31]3[CH2:34][CH:33]([O:35][C:36]4[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=4)[CH2:32]3)=[O:30])=[N:26][N:25]=2)=[CH:20][CH:19]=1.[Na].C([O-])(O)=O.[Na+]>ClCCl>[CH2:3]1[C:4]2([CH2:8][CH2:7][CH2:6][N:5]2[CH2:40][C:39]2[CH:38]=[CH:37][C:36]([O:35][CH:33]3[CH2:34][N:31]([C:29]([C:27]4[O:28][C:24]([C:21]5[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=5)=[N:25][N:26]=4)=[O:30])[CH2:32]3)=[CH:43][CH:42]=2)[CH2:1][O:2]1
Reactant: C1CNC2(C1)COC2
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4)C3)o2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CCCC56COC6)cc4)C3)o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
2-Oxa-5-azaspiro[3.4]octane (0.03 g, 0.26 mmol) was dissolved in dichloromethane (2 ml). Triethylamine (0.04 ml, 0.29 mmol) was added, followed by 4-(1-(5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)benzaldehyde (0.1 g, 0.26 mmol) and finally sodium triacetoxyhydroborate (0.112 g, 0.53 mmol). The mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with dichloromethane (10 ml) and subsequently shaken with NaHCO3 (sat. 3 ml). The two phases were separated by the use of a phase separator. Evaporation of the organic phase afforded a residue, which was purified by preparative reverse-phase. HPLC at pH 10 to give 0.075 g (60%) of the desired product as a solid. 1H NMR (600 MHz, DMSO) δ 1.62 (dt, 2H), 2.1-2.15 (m, 2H), 2.49 (t, 2H), 3.88 (s, 3H), 3.91 (s, 2H), 4.09 (ddd, 1H), 4.43 (d, 2H), 4.54 (ddd, 1H), 4.63 (ddd, 1H), 4.80 (d, 2H), 5.09 (ddd, 1H), 5.16 (ddd, 1H), 6.86 (d, 2H), 7.17-7.21 (m, 2H), 7.30 (d, 2H), 8-8.04 (m, 2H). MS (APCI+) m/z 477.2 [M+H]+, LC purity: 95%