Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]=2[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:3][CH:2]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:21][C:18]([F:20])([F:19])[C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:4]2[C:5]3[CH2:10][N:9]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:8][CH2:7][C:6]=3[N:1]=[CH:2][N:3]=2)=[CH:17][CH:16]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CNCC3)cc1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CN(c2ccccc2)CC3)cc1
Reaction time: 6 h
Yield: 6.4 %

Procedure:
The (5,6,7,8-Tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-(4-trifluoromethylphenyl)amine (100 mg, 0.34 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added phenylboronic acid (83 mg, 0.68 mmol), Cu(OAc)2 (124 mg, 0.68 mmol) and triethylamine (0.68 g, 0.095 mL). The mixture was agitated for 6 h and the solvent was removed under the vacuum. The residue was purified using a gradient of ethyl acetate:hexane (0-400%) to give the desired compound as reddish powder (8.0 mg, 6.0%).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]1([S:19]([CH2:22][CH2:23][S:24][C:25]2[N:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=O)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:34]([NH:41][CH3:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH2:34]([N:41]([CH3:42])[C:27](=[O:29])[C:26]1[CH:30]=[CH:31][CH:32]=[N:33][C:25]=1[S:24][CH2:23][CH2:22][S:19]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:20])=[O:21])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CNCc1ccccc1
Reactant: O=C(O)c1cccnc1SCCS(=O)(=O)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)c1cccnc1SCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
132 mg (0.81 mmol) of CDI were added to a solution of 250 mg (0.77 mmol) of 2-(2-(phenylsulfonyl)ethylthio)nicotinic acid in DCM (6 ml), and the mixture was stirred for 1 hour at RT. A solution of 93 mg (0.77 mmol) of N-benzyl-N-methylamine in DCM (6 ml) was then added, and stirring was continued for a further 16 h at RT. The reaction solution was then washed in each case three times with sat. aq. ammonium chloride solution and saturated aqueous NaHCO3 solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. CC with the residue (DCM→DCM/MeOH 99.5:0.5) yielded 152 mg (0.36 mmol, 46%) of N-benzyl-N-methyl-2-(2-(phenylsulfonyl)ethylthio)nicotinamide.
Reaction SMILES: [OH:1][CH:2]1[C:8]([CH3:10])([CH3:9])[CH2:7][C:6](=[O:11])[C:5]([CH3:12])=[CH:4][CH:3]1[O:13][CH3:14].[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28])[C:21](O)=[O:22])([O-:17])=[O:16]>>[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28])[C:21]([O:1][CH:2]1[C:8]([CH3:9])([CH3:10])[CH2:7][C:6](=[O:11])[C:5]([CH3:12])=[CH:4][CH:3]1[O:13][CH3:14])=[O:22])([O-:17])=[O:16]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: COC1C=C(C)C(=O)CC(C)(C)C1O
Product: COC1C=C(C)C(=O)CC(C)(C)C1OC(=O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Yield: 85 %

Procedure:
5-Hydroxy-4-methoxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU154) obtained in Example 4 (25.0 g, 126 mM) was treated with 3,4-dinitrobenzoic acid according to the procedures described in Example 20, and crystallized from methanol to obtain 42.1 g (85%) of 5-(3,4-dinitrobenzoyloxy)-4-methoxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU409) as light yellow needles. Melting point: 103° to 104° C.
Reaction SMILES: CO[C:3](=[O:10])[CH2:4][C:5]([CH:7]1[CH2:9][CH2:8]1)=O.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(=O)C>[CH:7]1([C:5]2[CH2:4][C:3](=[O:10])[N:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:18]=2)[CH2:8][CH2:9]1
Reactant: COC(=O)CC(=O)C1CC1
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Product: O=C1CC(C2CC2)=NN1c1ccccc1
Temperature: 120 °C
Yield: 86.9 %

Procedure:
To a solution of methyl-3-cyclopropyl-3-oxopropionate (17 g) in acetic acid (40 mL) in a round bottom flask under argon was added phenylhydrazine (12.93 g). The mixture was immersed into an oil bath and heated to 120° C. overnight. The reaction vessel was then cooled and the acetic acid was evaporated in vacuo and the remaining solid was dissolved in EtOAc and water. The phases were separated and the aqueous phase was extracted with further EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo and azeotroped with toluene (2×). The crude residue was then purified via trituration with a 1:1 mixture of ether/pentane to afford the desired 5-cyclopropyl-2-phenyl-2,4-dihydro-pyrazol-3-one (20.8 g) as a light brown solid. MS (ESI+): 201.3 ([M+H]+).
Reaction SMILES: Cl[C:2]1=[N:3][C:4]2[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=2[O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=3)=[CH:9][C:8]1=2.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[O:31]1[CH2:32][CH2:33][N:28]([C:2]2=[N:3][C:4]3[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=3[O:6][C:7]3[CH:12]=[CH:11][C:10]([C:13]4[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=4)=[CH:9][C:8]2=3)[CH2:29][CH2:30]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1ccc(-c2ccc3c(c2)C(Cl)=Nc2ccccc2O3)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccc3c(c2)C(N2CCOCC2)=Nc2ccccc2O3)cc1
Temperature: 130 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
To a stirring solution of title compound 69 (285 mg, 0.754 mmol) in toluene (5.0 mL) was added morpholine (1.00 g, 11.48 mmol) and the reaction mixture was stirred at 130° C. for 4 h. It was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by flash chromatography with 10%-30% ethyl acetate in hexanes to afford title compound 70 (223 mg, 69%) as a white solid. LRMS (ESI): (calc) 428.17 (found) 429.5 (MH)+. 1H NMR (400 MHz, CD3OD) δ (ppm): 8.09 (d, J=8.6 Hz, 2H), 7.84 (dd, J=8.4, 2.3 Hz, 1H), 7.71-7.69 (m, 3H), 7.40 (d, J=8.4 Hz, 1H), 7.17-7.01 (m, 4H), 4.38 (q, J=7.1 Hz, 2H), 3.90-3.75 (m, 4H), 3.60-3.48 (m, 4H), 1.40 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5](I)=[CH:4][N:3]=1.[N:11]1([C:17](=[O:33])[CH2:18][N:19]2[CH:23]=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:21]=[N:20]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.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>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([C:22]2[CH:21]=[N:20][N:19]([CH2:18][C:17](=[O:33])[N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH:23]=2)=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cnn(CC(=O)N3CCCCC3)c2)OC1(C)C
Reactant: Nc1ncc(I)cc1C=O
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: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncc(-c2cnn(CC(=O)N3CCCCC3)c2)cc1C=O
Temperature: 25 °C

Procedure:
5.1 200 mg (0.806 mmol) of 2-amino-5-iodopyridine-3-carbaldehyde and 501 mg (1.570 mmol) of 1-piperidin-1-yl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]ethanone are dissolved in 4 ml of N,N-dimethylformamide in an argon-filled microwave vessel, and 2.5 ml (5 mmol) of 2M sodium carbonate solution and 93.2 mg (0.081 mmol) of tetrakis(triphenylphosphine)palladium(0) are added. The reaction solution is irradiated with microwaves for 30 min at 120° C. in the Biotage SmithSynthesizer. The reaction mixture is cooled to room temperature, water is added, and the mixture is filtered. The filtrate is extracted three times with ethyl acetate, and the combined organic phases are washed 2× with water, dried using sodium sulfate, and evaporated to dryness. The oily residue is purified by means of RP-HPLC, giving 2-amino-5-[1-(2-oxo-2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]pyridine-3-carbaldehyde as yellowish powder; ESI-MS [M+H]+ 314.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:16][N+:17]([CH3:19])=[CH2:18].[I-]>CN(C=O)C>[CH3:16][N:17]([CH2:19][C:14]1[N:10]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=2[C:7]#[N:8])[CH:11]=[N:12][C:13]=1[CH3:15])[CH3:18]
Reactant: C=[N+](C)C
Reactant: Cc1cn(-c2ccc(F)cc2C#N)cn1
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc(F)cc2C#N)c1CN(C)C
Yield: 34 %

Procedure:
In analogy to example 5b, 5-fluoro-2-(4-methyl-imidazol-1-yl)-benzonitrile was reacted with Eschenmoser's salt in DMF for 24 h at 90° C. Evaporation of the solvent, aqueous workup and crystallization from Ethyl acetate/diisopropylether afforded the title compound as a white solid (yield: 34%). MS: m/e=259.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=3Br)[S:9][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(B(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C=O)C.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=3)[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(-c3cccc(OC)c3Br)sc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCB(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(-c2nc3ccc(OC)cc3s2)c1
Temperature: 50 °C
Yield: 38.3 %

Procedure:
To a solution of 6-methoxy-2-(2-bromo-3-methoxy-phenyl)-benzothiazole (0.182, 0.52 mmol) in dry DMF (3 mL) was added cesium carbonate (0.51 g, 1.57 mmol), triethylborane (0.58 mL, 1M in THF, 0.58 mmol) and 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane (18 mg, 0.022 mmol). The mixture was heated to 50° C. for 24 h, then cooled to room temperature. Saturated sodium bicarbonate was added and the mixture was extracted with ethylacetate. Combined ethylacetate were washed with brine, concentrated. After chromatographic purification gave 6-methoxy-2-(3-methoxy-phenyl)-benzothiazole (54 mg, 38% yield) as a white solid. Mass spec: MH+=272.
Reaction SMILES: [N+:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([CH3:11])[N:5]=1)([O-])=O.C>CO>[NH2:1][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([CH3:11])[N:5]=1
Reactant: Cc1ccc(O)c([N+](=O)[O-])n1
Solvent: CO
Product: Cc1ccc(O)c(N)n1

Procedure:
3.5 g of 2-nitro-3-hydroxy-6-methylpyridine are placed under a hydrogen pressure in 50 ml of methanol in the presence of 1 gram of palladinized charcoal. The mixture is stirred and filtered. The methanol is evaporated off.
Reaction SMILES: C[OH:2].[CH2:3]([O:10][CH:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=C)[CH:13]([F:27])[CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:3]([O:10][CH:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:2])[CH:13]([F:27])[CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CO
Reactant: C=C(COC1CCC(OCc2ccccc2)CC1F)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(COC1CCC(OCc2ccccc2)CC1F)c1ccccc1
Temperature: 25 °C
Yield: 83 %

Procedure:
A methanol (300 mL) solution of [1-({[4-(Benzyloxy)-2-fluorocyclohexyl]oxy}methyl)vinyl]benzene (2.02 g, 5.95 mmol) was cooled to −70° C. Ozone gas was bubbled through the solution until a blue color appeared. The solution was purged with nitrogen then a solution of triphenylphosphine (2.34 g, 8.92 mmol) in methylene chloride (100 mL) was added. Contents of the reaction flask were warmed to room temperature and the solvent was removed under reduced pressure. The remaining residue was subjected to flash column chromatography (hexane:ethyl acetate, 90:10) to give 2-{[4-(Benzyloxy)-2-fluorocyclohexyl]oxy}-1-phenylethanone as a colorless oil (1.68 g, 83% yield).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH:15](O)[CH3:16])=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]1[CH2:22][CH2:21][NH:20][C:19]1=[O:23]>>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH:15]([N:20]3[CH2:21][CH2:22][O:18][C:19]3=[O:23])[CH3:16])=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(O)c1ccc(C#Cc2ccccc2)cn1
Reactant: O=C1NCCO1
Product: CC(c1ccc(C#Cc2ccccc2)cn1)N1CCOC1=O

Procedure:
The title compound, white solid, MS: m/e=293.1 (M+H+), can be prepared in accordance with the general method of example 31, step 2 from rac-1-(5-phenylethynyl-pyridin-2-yl)-ethanol (example 42, step 1) and oxazolidin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][CH2:11][CH:12]2OCCO2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:18]([NH:21][CH2:22][CH2:23][NH2:24])(=[O:20])[CH3:19]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:24]([CH2:23][CH2:22][NH:21][C:18](=[O:20])[CH3:19])[CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)NCCN
Reactant: O=C(CCC1OCCO1)c1ccc(Cl)c(Cl)c1
Solvent: CC(=O)O
Product: CC(=O)NCCn1cccc1-c1ccc(Cl)c(Cl)c1
Yield: 84.2 %

Procedure:
3',4'-Dichloro-3-(1,3-dioxolan-2-yl)propiophenone (10.0 g) was dissolved in 20 ml of acetic acid and added under argon and while stirring to a solution of 7.4 g of N-acetylethylenediamine in 80 ml of acetic acid. The reaction mixture was heated to reflux overnight, the acetic acid was subsequently removed in a vacuum. The residue was taken up in 200 ml of methylene chloride and washed with a mixture of 100 ml of saturated sodium hydrogen carbonate solution and 100 ml of 2N sodium hydroxide solution. The aqueous phase was back-extracted twice with 100 ml of methylene chloride each time, the organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 12.5 g of dark brown oil were chromatographed on 500 g of silica gel with ethyl acetate as the eluent. 9.1 g (84%) of N-[2-[2-(3,4-dichlorophenyl)-pyrrol-1-yl]ethyl]acetamide were isolated as a yellow-brown oil. MS: m/e=296, 298, 300 (9:6:1, M+).
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH2:29][CH2:30][CH2:31][C:32]1[N:40]=[C:39]2[C:35]([N:36]=[CH:37][N:38]2[C@H:41]2[C@H:45]([O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])[C@H:44]([O:54][Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56])[C@@H:43]([CH2:62][O:63][CH3:64])[O:42]2)=[C:34]([NH:65][CH2:66][CH:67]([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)[C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[N:33]=1>C(#N)C>[CH:10]([N:8]1[CH2:9][CH:6]([NH:29][CH2:30][CH2:31][C:32]2[N:40]=[C:39]3[C:35]([N:36]=[CH:37][N:38]3[C@H:41]3[C@H:45]([O:46][Si:47]([C:50]([CH3:51])([CH3:52])[CH3:53])([CH3:49])[CH3:48])[C@H:44]([O:54][Si:55]([C:58]([CH3:59])([CH3:60])[CH3:61])([CH3:57])[CH3:56])[C@@H:43]([CH2:62][O:63][CH3:64])[O:42]3)=[C:34]([NH:65][CH2:66][CH:67]([C:68]3[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=3)[C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=3)[N:33]=2)[CH2:7]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCN)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCNC4CN(C(c5ccccc5)c5ccccc5)C4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 24 h
Yield: 51.8 %

Procedure:
1-Benzhydryl-3-azetidinyl methanesulfonate (90 mg, 0.28 mmol) and potassium carbonate (50 mg, 0.36 mmol) were added to a stirred solution of N-{2-(2-aminoethyl)-9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-9H-purin-6-yl}-N-(2,2-diphenylethyl)amine (200 mg) (preparation 18) in acetonitrile (3 ml). The reaction mixture was heated at reflux for 5 hr and then allowed to stand at room temperature for a further 24 hr. The resulting mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and the aqueous layer extracted with more ethyl acetate. The combined organic solutions were washed with brine and dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (98:2:0.2) to give the title compound (135 mg) as a foam. MS: 955 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1>CO.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>[OH:25][CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:11]([O:12][CH3:13])=[O:26])=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Product: COC(=O)c1ccc([C@H](C)N2CC[C@](CCCO)(c3ccccc3)OC2=O)cc1
Yield: 158.9 %

Procedure:
A mixture of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (80 mg, 0.19 mmol), Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) and TEA (38 mg, 0.38 mmol) in methanol (10 mL) was stirred in a sealed tube under 50 Psi carbon monoxide atmosphere at 80° C. overnight. The mixture was filtered, and the filtrate was concentrated to give the crude product, which was purified by preparative TLC to give methyl 4-((S)-1-((R)-6-(3-hydroxypropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)benzoate (60 mg, crude).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH:9]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOCC>[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:13])([CH3:14])[CH:9]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: BrCCCCBr
Reactant: CC1(C)Oc2c(O)cccc2C1N1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Product: CC1(C)Oc2c(OCCCCBr)cccc2C1N1CCCCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Crushed potassium hydroxide (19.6 g) and tetrabutyl ammonium chloride (1.7 g) are added to a solution of 7-hydroxy-3-piperidino-2,2-dimethylbenzofuran (14.4 g) in 1,4-dibromobutane (69.4 ml) and the mixture stirred at RT under nitrogen for 5 hours. The reaction mixture is diluted with ether, washed with water, extracted with 5% aq. HCl and the acidic phase washed with ether. The acidic phase is made basic thereby forming an oil which is taken up in ether, washed with sat'd aq. NaCl, dried, filtered and evaporated in vacuo affording the desired product as a liquid.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@H:22]3[C@@H:18]([CH2:19][N:20]([C:25]4[CH2:29][CH2:28][C:27](=[O:30])[CH:26]=4)[CH2:21]3)[C@@H:17]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1C[O:53]CC1>>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@H:22]3[C@@H:18]([CH2:19][N:20]([C:25]4[CH2:29][CH:28]([OH:53])[C:27](=[O:30])[CH:26]=4)[CH2:21]3)[C@@H:17]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CC[C@@H]2CN(C3=CC(=O)CC3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: C[C@@H](O[C@H]1CC[C@@H]2CN(C3=CC(=O)C(O)C3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 20 mg (0.07 mmol) of 3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-one (Example 7) and 170 mg (0.39 mmol) MoOPH in ˜2 mL dry THF under nitrogen atmosphere at −78° C. was added ×0.076 mL (0.15 mmol) of 2.0 M solution of KHMDS. The resulting mixture was stirred at −78° C. for 2 hr then quenched by the addition of sat. aq. NH4Cl. The mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over drying agent and filtered. The residue was purified by prep TLC eluting with CHCl3/2N NH3 in MeOH (9/1) to afford the title compound as a mixture of diastereomers. 1H-NMR (CDCl3): δ: 7.71 (1 H, s), 7.23 (2 H, s), 7.00 (2 H, m), 6.93 (2 H, t, J=8.2 Hz), 4.85, 4.71 (1 H, s), 4.47 (1 H, m), 4.20 (1 H, m), 3.80-3.65 (1 H, m), 3.37 (1 H, m), 3.25-3.08 (1 H, m), 3.10-2.80 (3 H, m), 2.58 (1 H, m), 2.50-2.30 (1 H, m), 2.15 (1 H, m), 1.95 (2 H, m), 1.35 (3 H, d, J=6.0 Hz). MS: (MH)+ 572.5. The diastereomers were separated by HPLC on CHIRACEL AS column eluting with hexanes/EtOH (85/15) to afford the individual diastereomers.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[NH:28][C:29](=[O:35])[C:30]([O:32][CH2:33][CH3:34])=O.[C:36]([O:44][CH3:45])(=[O:43])[C:37]#[C:38][C:39]([O:41][CH3:42])=[O:40]>C(Cl)CCl>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[N:28]1[C:29](=[O:35])[C:30]([O:32][CH2:33][CH3:34])=[C:38]([C:39]([O:41][CH3:42])=[O:40])[CH:37]1[C:36]([O:44][CH3:45])=[O:43]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CCOC(=O)C(=O)Nc1ccc(F)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: CCOC1=C(C(=O)OC)C(C(=O)OC)N(c2ccc(F)cc2F)C1=O
Temperature: 80 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
To a stirred solution of triphenylphosphine (629 mg, 2.40 mmol) and Intermediate 11A (458 mg, 2.00 mmol) in ClCH2CH2Cl (1 mL) was added dimethyl but-2-ynedioate (0.26 mL, 2.1 mmol) drop wise at rt. The reaction mixture was stirred at 80° C. in a capped vial for 18 h. The reaction mixture was allowed to cool to rt, loaded on to a 40 g silica gel column and purified with 0-100% EtOAc/Hex to give Intermediate 11B (560 mg, 1.58 mmol, 79.0% yield) as a slightly tan viscous oil. HPLC/MS (Method L) RT=1.77 min, [M+H]+ 356.0.
Reaction SMILES: [C:1]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[O:19]1CCC[CH2:20]1.C([Li])CCC.CN(C)C=O>C(Cl)Cl>[F:18][C:13]1[C:12]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:17][CH:16]=[CH:15][C:14]=1[CH:20]=[O:19]
Reactant: CCCCCCCCCC#Cc1ccccc1F
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCC#Cc1cccc(C=O)c1F
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 45.2 %

Procedure:
To a solution of 2-(1-undecynyl)fluorobenzene (7.00 g) and tetrahydrofuran (70 ml) was added slowly n-butyllithium (1.6M, 17.8 ml) at -78° C. The reaction mixture was stirred at -78° C. for 1.5 hrs. Dimethylformamide (2.28 ml) was added slowly, and the solution was allowed to warm to room temperature over 1 hr, with stirring. Methylene chloride (300 ml) was added, and the solution was washed with 50% hydrochloric acid. The aqueous phase was extracted with methylene chloride. The extracts were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was chromatographed on silica (250 g), eluting with hexane followed by ethyl acetate/hexane (1:4). The appropriate fractions were collected and evaporated to provide 3.53 g (45.2%) of product as an oil.