Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.Cl[C:25]1[CH:26]=[C:27]([F:32])[C:28]([F:31])=[N:29][CH:30]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[F:31][C:28]1[C:27]([F:32])=[CH:26][C:25]([C:13]2[CH:12]=[N:11][N:10]([CH2:9][CH2:8][O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH:14]=2)=[CH:30][N:29]=1
Reactant: Fc1cc(Cl)cnc1F
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Fc1cc(-c2cnn(CCOC3CCCCO3)c2)cnc1F
Temperature: 100 °C
Yield: 60.5 %

Procedure:
A 48 mL tube was charged with 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.4 g, 19.9 mmol), 5-chloro-2,3-difluoropyridine (1.7 mL, 16.6 mmol), X-Phos (1.6 g, 3.3 mmol), Potassium phosphate (3.5 g, 16.6 mmol), PdOAc2 (0.4 g, 1.7 mmol), 1,4-dioxane (50 mL), and water (5.0 mL), flushed with argon, sealed, then heated at 100° C. for 3 hours. The mixture was concentrated and purified by MPLC, eluting with 2.5% MeOH/DCM over 40 minutes to afford 2,3-difluoro-5-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)pyridine as a clear oil which solidified upon standing at room temperature (3.1 g, 60.5% yield). LC/MS shows the product as the free alcohol. However, the structure of the product is as drawn above. MS m/z=226.2 [M+1]+. Calc'd for C15H17F2N3O2: 309.3
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][C:38]([NH2:41])=[N:39][CH:40]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[NH2:41][C:38]1[N:39]=[CH:40][C:35]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])=[O:15])[C:5]3[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=3[N:7]=2)=[CH:36][N:37]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnc(N)nc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Yield: 17.3 %

Procedure:
To a 5-mL microwave vial was added DMSO (2 mL) and it was degassed with nitrogen for 5 min. Next added 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.187 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyrimidinamine (49.7 mg, 0.225 mmol), sodium carbonate (59.5 mg, 0.562 mmol) and bis(triphenylphosphine)palladium(II) chloride (9.20 mg, 0.013 mmol). The mixture was degassed for additional 5 min, sealed, and irradiated (microwave) at 135° C. for 15 h. The mixture was filtered and the residue was washed with DMSO. The DMSO solution of the crude product was purified using reverse-phase HPLC. The TFA salt of the product was neutralized with saturated NaHCO3 solution, filtered, washed with water, and dried under high vacuum to give 14 mg (17%) of product. LCMS E-S (M+H)=433.2 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52 (d, J=6.4 Hz, 6 H), 2.13 (s, 3 H), 2.22 (s, 3 H), 4.40 (d, J=4.6 Hz, 2 H) 5.22-5.41 (m, 1 H), 5.90 (s, 1 H), 7.18 (m, 2 H), 8.08 (s, 1 H), 8.34 (s, 1 H), 8.86 (m, 1 H), 9.11 (s, 2 H), 11.58 (br. s., 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2].[Br:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][Br:23])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2]
Reactant: BrCCOCCOCCOCCBr
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOCCOCCBr
Yield: 59 %

Procedure:
A mixture of 3.08 g of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoic acid ethyl ester, 16.0 of 1,11-dibromo-3,6,9-trioxaundecane and 2.8 g of anhydrous potassium carbonate in 75 ml of anhydrous acetone was stirred at reflux for 5 days. During this period, 1.0 g portions of potassium carbonate were added after 18 hours and after 25 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil (20 g) which was chromatographed on 200 g of silica gel using 10% ethyl acetatetoluene to give 3.24 g (59% yield) of 4-[4-acetyl-3-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester as an oil.
Reaction SMILES: [OH:1][C:2]1([C:16]([O:18]C)=[O:17])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C@@:20]12([OH:29])[N:27]([CH3:28])[C@@H:24]([CH2:25][CH2:26]1)[CH2:23][CH:22]=[CH:21]2.[Na].O>C(#N)C>[C@@:20]12([OH:29])[N:27]([CH3:28])[C@@H:24]([CH2:25][CH2:26]1)[CH2:23][CH:22]=[CH:21]2.[OH:1][C:2]1([C:16]([O-:18])=[O:17])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[O:9][C:10]2[C:15]1=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: COC(=O)C1(O)c2ccccc2Oc2ccccc21
Agent: CN1[C@@H]2CC=C[C@@]1(O)CC2
Agent: [Na]
Solvent: CC#N
Solvent: O
Product: O=C([O-])C1(O)c2ccccc2Oc2ccccc21

Procedure:
13.65 g (0.053 mol) of methylester 3a, 8.35 g (0.06 mol) of tropenol and 0.2 g of sodium are heated as a melt at 75 mbar for 4 hours over a bath of boiling water with occasional agitation. After cooling, the sodium residues are dissolved with acetonitrile, the solution is evaporated to dryness, and the residue is extracted with dichloromethane/water. Then the organic phase is washed with water, dried over magnesium sulfate, and the solvent is distilled off. The product is purified by recrystallization from diethyl ether/petroleum ether. Yield: 5.28 g of white crystals (27% of theoretical yield); melting point: 117° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[CH:6][C:5]=1[C:15]1[C:16]([S:21]([NH:24][C:25]2[O:29][N:28]=[C:27]([CH3:30])[C:26]=2[CH3:31])(=[O:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=1.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36].C(N(CC)CC)C>C(Cl)Cl>[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([N:2]([CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[CH:6][C:5]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH:24][C:25]1[O:29][N:28]=[C:27]([CH3:30])[C:26]=1[CH3:31])(=[O:22])=[O:23])[CH3:1])=[O:36]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)c2ccccc2Cl)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 25.7 %

Procedure:
To a solution of 0.12 g (0.29 mmol) of 2'-[(methylamino)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (prepared as described in Step (A) of Example 28) in 5 mL of CH2Cl2, 0.061 g (0.348 mmol) of 2-chlorobenzoyl chloride and 0.065 g (0.638 mmol) of triethylamine were added. The mixture was then stirred at room temperature for 12 hr and evaporated. The residue was purified by reverse phase preparative HPLC on a 30×500 mm ODS S10 column using 72% solvent B (90% MeOH, 10% H2O, 0.1% TFA) and 28% solvent A (10% MeOH, 90% H2O, 0.1% TFA). The appropriate fractions were collected and neutralized with aqueous sodium bicarbonate to pH 7 and concentrated to 10 mL. The solution was then acidified to pH 4 using aqueous sodium bisulfate and the white solid was filtered and dried to provide 0.043 g (26%) of the title compound of this Example as a white solid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[OH2:23]>C(OC(=O)C)(=O)C>[F:1][C:2]([F:21])([F:22])[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:6](=[O:23])[CH:5]=[C:4]([CH3:20])[O:18][C:16]=3[CH3:17])=[CH:11][CH:10]=2)=[CH:19][CH:20]=1
Reactant: CC(=O)Cc1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Reactant: O
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(=O)c(-c2ccc(Oc3ccc(OC(F)(F)F)cc3)cc2)c(C)o1
Reaction time: 0.5 h

Procedure:
To a vigorously stirred mixture of polyphosphoric acid (60 g) and acetic anhydride (26 ml) at 90° was added over 15 min a solution of 4-(4-trifluoromethoxyphenoxy) phenylpropan-2-one (9.3 g) in acetic anhydride (30 ml). The mixture was stirred for a further 30 min at 90° then poured into water (1 liter) and extracted with toluene (2×500 ml). The combined extracts were washed with water then satd. aq. sodium bicarbonate and dried over magnesium sulphate. Concentration in vacuo gave an orange oil which was chromatographed on silica gel, eluting with dichloromethane then 1:19 methanol/dichloromethane, to give the title compound as an oil (4.1 g), NMR δH (CDCl3) 6.9-7.4 (8H, m), 6.16 (1H, s), 2.24 (3H, s), 2.16 (3H, s).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[CH:10]=[CH:11][CH:12]=1)=O.[NH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[NH2:25]>C(O)C.CCOC(C)=O>[F:20][C:19]([F:21])([F:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[CH:4]=[CH:3][N:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[N:25]=2)[CH:8]=1
Reactant: CN(C)C=CC(=O)c1cccc(-c2ccccc2C(F)(F)F)c1
Reactant: NNc1ccccn1
Solvent: CCO
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccccc1-c1cccc(-c2ccn(-c3ccccn3)n2)c1
Yield: 12.9 %

Procedure:
To a solution of the product from Step 1 (0.224 g, 0.7 mmol) in ethanol (3.5 mL) was added 2-hydrazinopyridine (0.076 g, 0.7 mmol) and the solution was refluxed for 16 hours. The reaction was cooled, diluted with EtOAc, washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. The organic phase was filtered, concentrated, and the crude product was purified by reverse phase HPLC (acetonitrile/water system) (gradient: 30% to 100% acetonitrile over 12 minutes) to give product A (0.033 g, 29% yield, retention time 5.28 minutes) and the regioisomeric product B (0.021 g, 18% yield, retention time 7.25 minutes).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:16][CH2:17][CH2:18][N:12]([CH3:11])[CH2:13][CH2:14]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CN1CCCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
The mixture of 1 -fluoro-4-nitrobenzene (880 mg, 6.2 mmol), 1-methylhomopiperazine (2.3 mL, 18.6 mmol), Cs2CO3 (6.1 g, 18.6 mmol) in 20 mL DMF was stirred at 100° C. for 1.5 hr. It was diluted with DCM, filtered to remove the inorganic salts, washed with water, dried, evaporated in vacuuo to afford 1-(4-nitrophenyl)-4-methylhomopiperazine in quantitative yield. ES-MS: (M+H)+236.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:32]1[C:33]([CH3:39])=[CH:34][C:35]([Cl:38])=[N:36][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:32]1[CH:37]=[N:36][C:35]([Cl:38])=[CH:34][C:33]=1[CH3:39]
Reactant: CC1(C)OB(c2cc(S(=O)(=O)N3CCCCc4ccccc43)ccc2Cl)OC1(C)C
Reactant: Cc1cc(Cl)ncc1Br
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: [K+]
Solvent: C1COCCO1
Product: Cc1cc(Cl)ncc1-c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Temperature: 100 °C
Yield: 23.6 %

Procedure:
A mixture of 1-[4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzenesulfonyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (67 mg, 0.18 mmol), 5-bromo-2-chloro-4-picoline (45 mg, 0.22 mmol), Pd(PPh3)4 (11 mg, 0.01 mmol), K2CO3 (130 mg, 0.93 mmol) in 1,4-Dioxane (1 mL), was heated at 100° C. for 12 hrs. This mixture was cooled to rt and the solvent evaporated. The residue was purified by silica gel column chromatography eluted with (Hexanes/Ethyl acetate, 9/1) to yield 1-[4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzenesulfonyl]-2,3,4,5-tetrahydro-1H-1-benzazepine 4-1 (0.019 g, 23% yield). MS: 447 (M+H)+; tR=9.94 min (method 2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:6]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[N:14][CH:15]=2)[CH:7]=1.[Cl:32][C:33]1[N:38]=[C:37](Cl)[C:36]([CH3:40])=[CH:35][N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:28]([O:27][C:25]([NH:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:35]2[C:36]([CH3:40])=[CH:37][N:38]=[C:33]([Cl:32])[N:34]=2)=[CH:7][C:6]=1[CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[N:14][CH:15]=1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)Nc1cncc(CCc2cc(N)ccc2NC(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cnc(Cl)nc1Nc1ccc(NC(=O)OC(C)(C)C)c(CCc2cncc(NC(=O)OC(C)(C)C)c2)c1
Yield: 8.6 %

Procedure:
To a solution of tert-butyl [5-(2-{5-amino-2-[(tert-butoxycarbonyl)amino]phenyl}ethyl)pyridin-3-yl]carbamate (0.27 g, 0.63 mmol) (prepared in Example C49, step D) and 2,4-dichloro-5-methylpyrimidine (0.103 g, 0.63 mmol) in N,N-dimethylformamide (4 mL) was added potassium carbonate (0.446 g, 3.23 mmol). The resultant mixture was stirred overnight at rt overnight. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude was purified by silica gel column chromatography to give the desired product (30 mg, 9%). LCMS for C28H34ClN6O4 (M+H)+: m/z=555.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]([CH3:26])([CH3:25])[CH2:9][C:10]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[CH:7]=1.[OH-:29].[K+].OO.Cl>CCO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]([CH3:26])([CH3:25])[CH2:9][C:10]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]([NH2:16])=[O:29])[CH:7]=1
Reactant: [OH-]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cccc(C#N)c1)C(F)(F)F
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cccc(C(N)=O)c1)C(F)(F)F
Reaction time: 24 h
Yield: 67.4 %

Procedure:
To a solution of 24 mg (0.061 mmol) of 3-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]benzonitrile in EtOH was added 15 mg (0.23 mmol) of potassium hydroxide followed by 0.2 mL of 30% aqueous hydrogen peroxide. The mixture was stirred for 24 hours and then diluted with water, made acidic with 1 N aqueous HCl, and extracted with three 5 mL portions of EtOAc. The combined organic layers were washed with two 5 mL portions of saturated aqueous sodium bicarbonate, two 5 mL portion of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford crude product which was purified on silica gel using dichloromethane-hexanes (1:1) to load the sample and then eluting with EtOAc-hexanes (1:99, then 3:97, then 6:93, then 1:9, then 2:8, then 3:7, then 4:6, then 1:1) to afford 17 mg (67%) of the title compound as a clear resin, m.p. 70° C.-75° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:16][C@@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][N:18]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH2:4][N:21]1[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:17]([CH3:16])[CH2:22]1
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(N2CCOCC2)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: C[C@@H]1CN(Cc2ccc(N3CCOCC3)cc2F)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
A 100 mL round-bottom flask was charged with 2-fluoro-4-(morpholin-4-yl)benzaldehyde (0.800 g, 3.82 mmol, 1.00 equiv), tert-butyl (2R)-2-methylpiperazine-1-carboxylate (0.840 g, 4.20 mmol, 1.10 equiv), 1,2-dichloroethane (20 mL). The mixture was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (2.40 g, 11.3 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with H2O (10 mL), extracted with dichloromethane (3×10 mL). The organic layers were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80) to provide 1.40 g (93% yield) of tert-butyl (2R)-4-[[2-fluoro-4-(morpholin-4-yl)phenyl]methyl]-2-methylpiperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 394 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][C@H:6]([CH2:14][OH:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].O.[C:17]1(C)[CH:22]=CC(S(O)(=O)=O)=C[CH:18]=1.COC(C)=C>C(Cl)Cl>[Br:1][CH2:2][C:3]([N:5]1[C@@H:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][O:15][C:17]1([CH3:22])[CH3:18])=[O:4]
Reactant: O=C(CBr)N[C@H](CO)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=C(C)OC
Solvent: O
Solvent: ClCCl
Product: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)CBr
Reaction time: 0.25 h
Yield: 889.5 %

Procedure:
To a mixture of 2-bromo-N-(1(S)-hydroxymethyl-2-phenylethyl)acetamide (1.55 g, 5.45 mmol) and p-toluenesulfonic acid monohydrate (100 mg) in CH2Cl2 (50 mL) was added 2-methoxypropene (1.50 mL, 15.7 mmol) dropwise via syringe. After 15 minutes at ambient temperature, the resultant mixture was washed with 1M pH 7 phosphate buffer (25 mL) and brine (25 mL), dried over Na2SO4, and concentrated to give a dark solid, which was triturated with MTBE/hex to provide 1.46 g (86%) of 3-(2-bromoacetyl)-2,2-dimethyl-4(S)-phenylmethyl-oxazolidine as a pale yellow solid. 1H NMR (DMSO-d6): δ 7.33-7.17 (m, 5H), 4.21-4.15 (m, 1H), 4.04, 3.86 (AB quartet, 2H, J=12.1 Hz), 3.79 (dd, 1H, J=4.8, 9.2 Hz), 3.71 (d, 1H, J=9.2 Hz), 2.99 (dd, 1H, J=5.0, 13.4 Hz), 2.70 (dd, 1H, J=9.2, 13.2 Hz), 1.55 (s, 3H), 1.38 (s, 3H). Anal. Calculated for C14H18NO2Br: C, 53.86; H, 5.81; N, 4.49; Br, 25.59. Found: C, 53.91; H, 5.82; N, 4.47; Br, 25.58.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[N:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[C:4]([CH3:18])[CH:3]=1.CCN(C(C)C)C(C)C.Cl.[CH2:29]([O:31][NH2:32])[CH3:30]>CN(C=O)C>[CH2:29]([O:31][NH:32][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][N:16]=[CH:17][C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=1[CH3:18])[CH3:30]
Reactant: Cc1cc(I)ccc1Nc1cnccc1C(=O)O
Reactant: CCON
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCONC(=O)c1ccncc1Nc1ccc(I)cc1C
Reaction time: 4 h
Yield: 53 %

Procedure:
3-[(4-iodo-2-methylphenyl)amino]isonicotinic acid 2c (60 mg, 0.17 mmol) was dissolved in 6 ml dry DMF followed by the addition of DIPEA (0.20 mmol, 37 μl), ByBOP (0.20 mmol, 107 mg) and O-ethylhydroxylamine hydrochloride (0.34 mmol, 34 mg). The mixture was stirred for 4 h and the volatiles were removed in vacuo. The crude material was purified by preparative reversed phase HPLC to give 36 mg (91 μmol; 53% yield) of pure desired product.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][CH2:38][O:39][C:40]1[N:41]=[C:42]2[C:47](=[CH:48][CH:49]=1)[N:46]=[C:45]([CH2:50][CH3:51])[CH:44]=[C:43]2[O:52][CH2:53][C:54]1[CH:59]=[CH:58][C:57]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:66]2[N:67]=[N:68][N:69]([C:71]([C:84]3[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=3)([C:78]3[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=3)[C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=3)[N:70]=2)=[CH:56][CH:55]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[CH2:50]([C:45]1[CH:44]=[C:43]([O:52][CH2:53][C:54]2[CH:55]=[CH:56][C:57]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=3[C:66]3[N:67]=[N:68][N:69]([C:71]([C:84]4[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=4)([C:78]4[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=4)[C:72]4[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=4)[N:70]=3)=[CH:58][CH:59]=2)[C:42]2[C:47](=[CH:48][CH:49]=[C:40]([O:39][CH2:38][CH2:37][OH:36])[N:41]=2)[N:46]=1)[CH3:51]
Reactant: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2nc(OCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2nc(OCCO)ccc2n1
Reaction time: 1 h
Yield: 89.9 %

Procedure:
A 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (THF) (67.8 ml) was added to a solution of compound E (32.1 g) in dry THF (400 ml), and the solution was left to stand for 1 hour. The solution was then diluted with ethyl acetate (400 ml), washed with water (400 ml) and dried (MgSO4). Volatile material was removed by evaporation, and the residue triturated with ether to give 2-ethyl-6-(2-hydroxyethoxy)-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-1,5-naphthyridine (A) (21.6 g), as a white solid, m.p. 170°-173° C.; NMR (d6 -DMSO): 1.3(t,3H), 2.85(q,2H), 3.75(q,2H), 4.45(t,2H), 4.85(t,1H), 5.35(s,2H), 6.8-6.9(m,7H), 7.1-7.7 (complex m,17H), 7.8(dd,1H), 8.15(d,1H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[N:8]=[C:9]=[S:10].[CH3:11][C:12]1[S:13][C:14]([C:17]([NH:19][NH2:20])=[O:18])=[CH:15][N:16]=1>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:20][NH:19][C:17]([C:14]1[S:13][C:12]([CH3:11])=[N:16][CH:15]=1)=[O:18]
Reactant: S=C=NC1CC2C=CC1C2
Reactant: Cc1ncc(C(=O)NN)s1
Product: Cc1ncc(C(=O)NNC(=S)NC2CC3C=CC2C3)s1

Procedure:
The title compound was prepared from a mixture of bicyclo[2.2.1]hept-5-en-2-ylisothiocyanate (50 mg, 0.33 mmol) and 2-methylthiazole-5-carboxylic acid hydrazide (58 mg, 0.36 mmol) similar to Example 80 and isolated as a white solid (10 mg, 9%). 1H NMR (DMSO-d6): 10.11 (s, 1H), 9.34 (s, 1H), 8.22 (s, 1H), 7.73 (s, 1H), 6.07 (ddd, J=8.1, 5.1, 2.7 Hz, 2H), 3.99 (s, 1H), 2.82 (brs, J=8.8 Hz, 2H), 2.72 (s, 3H), 1.52-1.35 (m, 4H).