Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:15][CH2:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:7]=1[CH3:8].CN(C)C=O.[H-].[Na+].[CH:33]1([CH2:36]Br)[CH2:35][CH2:34]1>C(Cl)(Cl)Cl>[CH:33]1([CH2:36][N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:18])[CH2:16][O:15][C:3]2[C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=[C:5]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:4]=2)[CH2:35][CH2:34]1
Reactant: BrCC1CC1
Reactant: Cc1nc(-c2ccccc2)nc(OCC(=O)Nc2ccccc2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2)nc(OCC(=O)N(CC2CC2)c2ccccc2)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a mixture of 2-(5,6-dimethyl-2-phenyl-4-pyrimidinyloxy)-N-phenylacetamide (1.5 g) obtained in Example 189 and dimethylformamide (30 ml) is added sodium hydride (about 60% oily, 0.2 g) at 0-5° C., and the mixture is stirred at 0° C. for one hour. To the mixture is added cyclopropylmethyl bromide (0.67 g) at the same temperature, and the mixture is stirred at room temperature for two hours. To the reaction solution are added chloroform and ice-water, and the chloroform layer is collected, washed with water, and dried over anhydrous sodium sulfate. The chloroform layer is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from isopropanol to give the desired compound (1.56 g), m.p. 119-121° C.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@@H:9]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:8]2)[O:4][NH:3]1.C(O)(=O)C>Br>[F:27][C:24]([F:25])([F:26])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][C@H:9]1[CH2:8][C@H:7]([C:5]2[O:4][NH:3][C:2](=[O:1])[CH:6]=2)[CH2:12][CH2:11][NH:10]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccccc1C(F)(F)F
Agent: Br
Solvent: CC(=O)O
Product: O=c1cc([C@@H]2CCN[C@@H](Cc3ccccc3C(F)(F)F)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
Trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(2-(trifluoromethyl)benzyl)piperidine-1-carboxylate (157 mg, 0.41 mmol) was dissolved in hydrogen bromide (33% in acetic acid (3 mL, 17.13 mmol) and the mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx III, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(2-(trifluoromethyl)benzyl)piperidin-4-yl)isoxazol-3(2H)-one (53 mg, 40%). 1H NMR (600 MHz, cd3od) δ 1.95 (ddd, 1H), 2.08-2.19 (m, 2H), 2.19-2.28 (m, 1H), 3.07-3.18 (m, 2H), 3.18-3.25 (m, 1H), 3.33-3.43 (m, 2H), 3.51-3.62 (m, 1H), 5.75 (d, 1H), 7.43-7.51 (m, 2H), 7.63 (t, 1H), 7.73 (d, 1H). HRMS Calculated for [C16H17F3N2O2+H]+: 327.1320. Found: 327.1297
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[C:25]([C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH3:37])[CH3:36])[CH:30]=5)=[CH:26][CH:27]=[CH:28][N:23]4[N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH3:36][N:35]([CH3:37])[C:31]1[CH:30]=[C:29]([C:25]2[C:24]3[N:23]([N:22]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[CH:15][CH:16]=4)[N:38]=3)[CH:28]=[CH:27][CH:26]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: CN(C)c1cccc(-c2cccn3nc(Nc4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc23)c1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cccc(-c2cccn3nc(Nc4ccc(C5CCNCC5)cc4)nc23)c1

Procedure:
[8-(3-Dimethylamino-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(4-piperidin-4-yl-phenyl)-amine was prepared from 4-{4-[8-(3-dimethylamino-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester (0.288 g, 0.563 mmol) and trifluoroacetic acid (1 mL) in a manner analogous to Example 312 to give product (0.218 g, 94%). MP=104-108° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.56 (s, 1H), 8.74 (d, 1H), 7.82 (d, 1H), 7.62 (d, 2H), 7.50 (s, 1H), 7.32 (m, 2H), 7.15 (m, 3H), 6.80 (d, 1H), 3.65 (br m, 1H), 3.15 (m, 2H), 3.00 (s, 6H), 2.60 (br m, 3H), 1.65 (m, 2H), 1.45 (m, 2H). MS=413 (MH)+.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].FC(F)(F)C(O)=O.[N:17]1([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:30]=[C:31]([O:38][C@@H:39]([C@H:41]4[CH2:45][NH:44][C:43](=[O:46])[CH2:42]4)[CH3:40])[C:32]4[N:33]([N:35]=[CH:36][CH:37]=4)[CH:34]=3)=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([N:20]1[CH2:19][CH2:18][N:17]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:30]=[C:31]([O:38][C@@H:39]([C@H:41]4[CH2:45][NH:44][C:43](=[O:46])[CH2:42]4)[CH3:40])[C:32]4[N:33]([N:35]=[CH:36][CH:37]=4)[CH:34]=3)=[CH:25][CH:24]=2)[CH2:22][CH2:21]1)(=[O:5])=[O:3]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cn2nccc12)[C@H]1CNC(=O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Oc1nc(-c2ccc(N3CCN(S(C)(=O)=O)CC3)cc2)cn2nccc12)[C@H]1CNC(=O)C1
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Methanesulfonic anhydride (9.3 mg, 0.05 mmol) was added to a solution of (R)-4-((R)-1-(6-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrazin-4-yloxy)ethyl)pyrrolidin-2-one 2,2,2-trifluoroacetate 5.44 (22.38 mg, 0.04 mmol) and triethylamine (0.05 mL, 0.36 mmol) in dichloromethane (1.8 mL). After two hours, reaction mixture was loaded directly onto silica gel and purified (0-8% methanol/dichloromethane) to yield (R)-4-((R)-1-((6-(4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)pyrrolidin-2-one 5.46 (19.2 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.Br[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:24])[CH2:15][CH2:16]2)[N:3]=1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Reactant: Cc1ccncc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: Cc1cccc(C#CC=C2CCN(c3cnccc3C)CC2)n1
Temperature: 150 °C
Yield: 6.6 %

Procedure:
A mixture of the compound of Example 3 (0.102 g, 0.48 mmol), 3-bromo-4-methylpyridine (0.046 g, 0.40 mmol), cesium carbonate (0.658 g, 2 mmol), 2-(dicyclohexylphosphino)biphenyl (8.8 mg, 0.024 mmol), palladium(II)acetate (0.0027 mg, 0.012 mmol), in anhydrous and degassed toluene (3 mL) was heated in a microwave oven at at 150° C. for 15 min in a sealed vessel. The reaction mixture was cooled, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (CHCl3-1.4 N MeOH NH3 100:0.25) affording the title product (0.008 g).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([Br:21])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>CO.O>[Br:21][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:22])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A solution of 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (10.02 g, 25.75 mol) in methanol (100 mL) and water (100 mL) was treated with lithium hydroxide (15.4 g, 515 mmol). The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was then concentrated in vacuo to remove methanol. The resulting aqueous residue was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (1×400 mL). The organic layer was washed with water (1×300 mL) and a saturated aqueous sodium chloride solution (1×300 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (9.58 g, 99%) as a white solid which was used without further purification: mp 149–150° C.; FAB-HRMS m/e calcd for C15H19BrO4S (M+H)+ 375.0266, found 375.0274.
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][C:23]([O-:25])=O)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+].N1C=CC=CC=1.C(Cl)(=O)C([Cl:36])=O>C1(C)C=CC=CC=1>[C:1]([O:20][CH2:21][CH2:22][C:23]([Cl:36])=[O:25])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C([O-])CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(Cl)CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3.30 g of potassium 3-trityloxypropionate in 75 ml of toluene, cooled to 0° C., was added 0.5 ml of pyridine, and subsequently 15 ml of oxalyl chloride were added within 10 minutes. The mixture was stirred for 30 minutes at room temperature and then evaporated in vacuo. The oily residue was taken up in 30 ml of toluene, and the solvent was evaporated in vacuo. The residue was taken up in 50 ml of methylene chloride and 50 ml of hexane, and the solution was stirred at 0° C. Unsoluble material was filtered off, and the filtrate was evaporated in vacuo to yield 2.81 g of 3-trityloxypropionyl chloride as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[C:32]([C:35]1[S:39][C:38](B(O)O)=[CH:37][CH:36]=1)(=[O:34])[CH3:33]>>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([C:38]2[S:39][C:35]([C:32](=[O:34])[CH3:33])=[CH:36][CH:37]=2)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cc(Br)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: CC(=O)c1ccc(B(O)O)s1
Product: COC(=O)c1cc(-c2ccc(C(C)=O)s2)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 95.3 %

Procedure:
In the same manner as described in Example 241, 505.4 mg (1.0 mmol) of the product of Example 89 and 374 mg (2.2 mmol) of 5-acetylthiophene-2-boronic acid provided 525 mg (95%) of the desired product as a cream colored solid. Electrospray Mass Spec 551 (M+H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[NH:18][CH:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.[H-].[Na+].[Br:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][N:29]=1>CN(C=O)C>[Br:27][C:28]1[N:29]=[CH:30][C:31]([CH2:34][N:18]2[CH:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:8]4[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=4[CH3:12])[C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)=[O:24])[CH:14]=3)[C:19]2=[O:23])=[CH:32][CH:33]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)[nH]ccc2c1
Reactant: BrCc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(Br)nc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product of Example 11 (400 mg) in DMF (5 mL) was added sodium hydride (60 mg) and the reaction stirred at room temperature for 10 minutes before the addition of a solution of 2-bromo-5-(bromomethyl)pyridine (760 mg) in DMF (5 mL). The reaction mixture was stirred at room temperature for 30 min.
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:19][CH:20]1[CH2:25][N:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=2[O:21]1.O>CN(C)C=O>[C:1]1([N:7]2[C:11]3([CH2:12][CH2:13][N:14]([C:20]4([CH3:19])[CH2:25][N:24]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:23]5[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=5[O:21]4)[CH2:15][CH2:16]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: ClCC1CN(c2ccccc2)c2ccccc2O1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(N2CCC3(CC2)C(=O)NCN3c2ccccc2)CN(c2ccccc2)c2ccccc2O1
Temperature: 90 °C
Yield: 38.5 %

Procedure:
1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one (2.03 g; 8.8 mmol) is added to a stirred solution of 2-chloromethyl-4-phenyl-2,3-dihydro-4H-1,4-benzoxazine (1.29 g; 4 mmol) in dimethylformamide (20 ml). The reacting mixture is heated at 90° C. for 8 hours. After cooling, water (100 ml) is added and the product is extracted twice with ethyl acetate (80 ml). The organic layer is washed twice with water (30 ml) and dried over anhydrous sodium sulphate. The solid residue, obtained after evaporation of the solvent under reduced pressure, is purified by flash column chromatography on silica gel by using hexane/acetone=9/1 as eluant, thus obtaining 0.7 g of pure 2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl-4-phenyl-2,3-dihydro-4H-1,4-benzoxazine, yield 37%; m.p. 191°-193° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[Li+].CCC[CH2-].C[O:17]B(OC)OC.Cl.OO>CCCCCC>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[OH:17]
Reactant: COc1ccc(F)c(F)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: OO
Agent: [CH2-]CCC
Solvent: CCCCCC
Product: COc1ccc(F)c(F)c1O

Procedure:
Using the procedure of Example 39, 125 g of 3,4-difluoro-anisole (commercial) and 500 ml of a 1.6M solution of N-butyllithium in hexane were reacted at -72° C., and then 92.4 ml of trimethylborate, 500 ml of hydrochloric acid and 120 g of intermediate compound were reacted and the product was reacted with 440 ml of 30% hydrogen peroxide to obtain 82.4 g of the expected product melting at 46.6° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[Br:17][C:18]1[C:23]2[CH:24]=[C:25]([CH2:27]Br)[O:26][C:22]=2[C:21]([O:29][CH3:30])=[CH:20][CH:19]=1>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][CH2:27][C:25]2[O:26][C:22]3[C:21]([O:29][CH3:30])=[CH:20][CH:19]=[C:18]([Br:17])[C:23]=3[CH:24]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COc1ccc(Br)c2cc(CBr)oc12
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Br)c2cc(COC3CCN(C(=O)OC(C)(C)C)CC3)oc12
Reaction time: 8 h
Yield: 37.2 %

Procedure:
Sodium hydride (72 mg of a 60% dispersion in oil) was added to a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (363 mg) in N,N-dimethylformamide (10 ml) under an inert atmosphere at ambient temperature. After stirring for 30 minutes 4-bromo-2-bromomethyl-7-methoxybenzofuran (526 mg) was added and the reaction stirred overnight. The reaction mixture was preadsorbed onto silica and purified by column chromatography eluting with 25% ethyl acetate in hexane to afford the desired product as a yellow oily solid (269 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:14]1[CH2:19][CH2:18][C:17]([O:23][CH3:24])([C:20]([OH:22])=O)[CH2:16][CH2:15]1)[CH2:10]2)=[O:5])[CH3:2].Cl.[CH3:26][C:27]1([NH2:31])[CH2:30][CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:24][O:23][C:17]1([C:20](=[O:22])[NH:31][C:27]2([CH3:26])[CH2:30][CH2:29][CH2:28]2)[CH2:16][CH2:15][N:14]([CH:9]2[CH2:8][CH:7]3[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[CH2:19][CH2:18]1
Reactant: CC1(N)CCC1
Reactant: CCOC(=O)N1C2CCC1CC(N1CCC(OC)(C(=O)O)CC1)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1C2CCC1CC(N1CCC(OC)(C(=O)NC3(C)CCC3)CC1)C2
Temperature: 25 °C
Reaction time: 60 h
Yield: 25.4 %

Procedure:
1-[8-(Ethoxycarbonyl)-8-azabicyclo[3.2.1]oct-3-yl]-4-methoxypiperidine-4-carboxylic acid (0.093 g, assumed 0.27 mmol) was dissolved in DMF (5 mL) and (1-methylcyclobutyl)amine hydrochloride (0.05 g, 0.411 mmol), HATU (0.156 g, 0.41 mmol) and DIPEA (0.177 g, 0.24 mL, 1.37 mmol) were added. The reaction mixture was stirred at rt for 60 h and the solvents were removed in vacuo. The residue was partitioned between DCM and sat. NaHCO3 sol., the organic layer was washed with sat. NaCl sol. and dried (MgSO4). The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 μm, 60 A, 25 mL per min, gradient 0% to 10% MeOH in DCM]) to give ethyl 3-{4-methoxy-4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate isomer 1 (0.028 g, 25%) as a pale yellow gum.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[N:10][CH:9]=2)=[C:4](F)[CH:3]=1.[CH3:15][O-:16].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[N:10][CH:9]=2)=[C:4]([O:16][CH3:15])[CH:3]=1
Reactant: C[O-]
Reactant: Cc1ncc(-c2ccc(Br)cc2F)o1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Br)ccc1-c1cnc(C)o1
Temperature: 80 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a mixture of 5-(4-bromo-2-fluorophenyl)-2-methyl-1,3-oxazole (10 g) in DMF (80 mL) was added sodium methoxide (28% methanol solution, 11.3 g) at 0° C., and the mixture was stirred at 80° C. for 2 hr under a nitrogen atmosphere. The reaction mixture was cooled to 0° C., and diluted with water, and the resultant solid was collected by filtration to give the title compound (10.4 g).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=3[OH:19])[CH:14]=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([O-])([O-])=O.[K+].[K+].Br[CH:27]([CH3:29])[CH3:28]>CN(C=O)C.CCOC(C)=O>[C:1]12([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=3[O:19][CH:27]([CH3:29])[CH3:28])[CH:14]=[O:15])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=Cc1ccc(O)c(C23CC4CC(CC(C4)C2)C3)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C=O)cc1C12CC3CC(CC(C3)C1)C2
Yield: 86 %

Procedure:
To a stirred suspension of 3-(1-admantyl)-4-hydroxybenzaldehyde (0.5 g, 1.95 mmol) and K2CO3 (0.276 g, 2 mmol) in anhydrous DMF (5 ml) was added 2-bromopropane (1 ml) and the mixture was reflux for 2 h. The reaction mixture was brought to room temperature and diluted to 50 ml with EtOAc and washed with H2O. The organic layer was separated, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was crystallized from MeOH to give the title compound (0.25 g, 86%), as a colourless solid. 1H-NMR (CDCl3) 1.42 (d, 6H, J=6 Hz); 1.76 (broad s, 6H); 2.07 (broad s, 3H); 2.12 (s, 6H); 4.69-4.78 (m, 1H); 6.91 (d, 1H, J=8.44 Hz); 7.66 (dd, 1H, J=2.13, 8.45 Hz); 7.76 (d, 1H, J=2.11 Hz); 9.84 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(C(C)C)CC)(C)C.[C:20]12([CH2:30][NH2:31])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:20]12([CH2:30][NH:31][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[N:10][C:2]=3[CH3:1])[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]3)[CH2:21]1)[CH2:29]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: Cc1ncccc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ncccc1C(=O)NCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a mixture of 2-methylnicotinic acid (2.06 g, 15 mmol) in 40 mL of DMF is added sequentially diisopropylethylamine (5.2 mL, 30 mmol), 1-adamantan-1-ylmethanamine (2.5 g, 15 mmol), and benzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 8 g, 18 mmol). The resulting mixture is stirred at rt for 17 h. The mixture is then poured into ice water (150 mL), and the precipitated solid is collected by vacuum filtration and dried in vacuo to afford the title compound as an off-white solid. Mass spec. (285.19, M+H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:18]([O-])([OH:20])=[O:19]>>[N+:18]([C:10]1[CH:9]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:13]=[CH:12][C:11]=1[NH:14][C:15](=[O:17])[CH3:16])([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(Oc2ccccc2)cc1
Product: CC(=O)Nc1ccc(Oc2ccccc2)cc1[N+](=O)[O-]
Temperature: -15 °C
Reaction time: 2 h

Procedure:
N-(4-phenoxy-phenyl)-acetamide (1.00 g, 4.03 mmol) prepared in Step A was dissolved in fuming nitric acid (2 mL), and the mixture was stirred for 2 h at −15° C. After completion of the reaction, the reaction mixture was poured into 100 mL of ice water, which was then extracted with ethyl acetate. The extracted organic solution was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (0.67 g, 2.33 mmol).
Reaction SMILES: CC([CH:5]([O:9][CH2:10][C:11]#[C:12][CH2:13][CH:14]([C:22]1[O:23][CH:24]=[CH:25][CH:26]=1)OC1CCCCO1)[C:6]([O-:8])=[O:7])(C)C.C1(=[O:32])CCC=C1.C(=O)([O-])[O-].[Na+].[Na+].C1(C=CC(O)=CC=1)O.Cl>>[OH:32][CH:25]1[CH2:26][C:22](=[O:23])[C:14]([CH2:13][C:12]#[C:11][CH2:10][O:9][CH2:5][C:6]([OH:8])=[O:7])=[CH:24]1
Reactant: O=C1C=CCC1
Reactant: CC(C)(C)C(OCC#CCC(OC1CCCCO1)c1ccco1)C(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: Oc1ccc(O)cc1
Product: O=C(O)COCC#CCC1=CC(O)CC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound is prepared by the method of Example 2 using 1 g of the title compound of Example 15, with the exception that the intermediate cyclopentenone is rearranged using aqueous sodium carbonate solution (pH 10-11) containing 1% hydroquinone. After stirring for 24 hours at room temperature, the reaction mixture is acidified to pH 2-3 with dilute hydrochloric acid and extracted with ether. The combined extracts are washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness. The residue is chromatographed on Biosil A (using ethyl acetate/hexane is eluent) to afford the title compound. ##STR21##