Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[Br:25][C:26]([CH2:28]Br)=[CH2:27]>C1COCC1>[C:1]1([C:7]2([CH2:28][C:26]([Br:25])=[CH2:27])[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2c3ccccc3-c3ccccc32)cc1
Reactant: C=C(Br)CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(Br)CC1(c2ccccc2)c2ccccc2-c2ccccc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 9-phenylfluorene in anhydrous THF is cooled to -78° C. under a nitrogen atmosphere. A solution of nBuLi in hexanes (1 eq) is added dropwise via syringe. After stirring at -78° C. for 10 min a solution of 2,3-dibromopropene (1.2eq) in THF is added dropwise via syringe. The solution is stirred at -78° C. for 1 h and then allowed to warm to room temperature. The reaction mixture is quenched by the addition of sat. aq NH4Cl. The resulting mixture is extracted with ether. The organic layer is washed with H2O and then brine, dried (Na2SO4), and concentrated in vacuo. The concentrate is purified by flash chromatography on silica gel eluting with hexanes-ethyl acetate to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C@@:15]4([CH2:21][CH2:20][O:19][CH2:18][C:17]([NH2:22])=[N:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:23]1[C:24]([F:29])=[N:25][CH:26]=[CH:27][CH:28]=1)=[CH:11][CH:10]=3.Cl.[F:31][C:32]1([F:37])[CH2:36][CH2:35][NH:34][CH2:33]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC(OC)(C)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].[Cl-].[NH4+]>[F:31][C:32]1([F:37])[CH2:36][CH2:35][N:34]([C:2]2[N:7]=[CH:6][C:5]3[O:8][C:9]4[C:14]([C@@:15]5([CH2:21][CH2:20][O:19][CH2:18][C:17]([NH2:22])=[N:16]5)[C:4]=3[CH:3]=2)=[CH:13][C:12]([C:23]2[C:24]([F:29])=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:11][CH:10]=4)[CH2:33]1
Reactant: FC1(F)CCNC1
Reactant: NC1=N[C@@]2(CCOC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Agent: Cl[Pd+]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: COC(C)(C)C
Product: NC1=N[C@@]2(CCOC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(N3CCC(F)(F)C3)cc12
Reaction time: 0.17 h

Procedure:
A vial was charged with (S)-3-chloro-7-(2-fluoropyridin-3-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amine (50.0 mg, 0.122 mmol), 3,3-difluoropyrrolidine hydrochloride (36.0 mg, 0.243 mmol), and RuPhos precatalyst (8.87 mg, 0.012 mmol). The vial was flushed with N2 gas, then lithium bis(trimethylsilyl)amide (1M in THF) (608 μl, 0.608 mmol) was added slowly to the mixture. After about 10 mins, the mixture was diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was purified on a 12 g Redi-Sep Gold silica-gel column eluting with a 90:10:1 mixture of DCM/MeOH/NH4OH in EtOAc to provide (S)-3-(3,3-difluoropyrrolidin-1-yl)-7-(2-fluoropyridin-3-yl)-6′,7′-dihydro-2′H-spiro[chromeno [2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amine as off white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.06 (br. s., 1 H) 2.14 (br. s., 1 H) 2.51-2.61 (m, 2 H) 3.33-3.41 (m, 2 H) 3.58 (t, J=7.59 Hz, 2 H) 3.81 (t, J=13.04 Hz, 2 H) 4.34-4.46 (m, 2 H) 6.00 (br. s., 2 H) 6.57 (s, 1 H) 7.28 (d, J=8.33 Hz, 1 H) 7.48 (t, J=5.34 Hz, 1 H) 7.53 (d, J=8.76 Hz, 1 H) 7.62 (s, 1 H) 8.00-8.07 (m, 1 H) 8.10 (s, 1 H) 8.22 (d, J=4.06 Hz, 1 H).
Reaction SMILES: [CH2:1]([CH:4]1[O:21][C:20]2[C:15](=[C:16]([O:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[C:14]2[C:5]1=[C:6]1[C:11](=[CH:12][CH:13]=2)[NH:10][C:9]([CH3:25])([CH3:24])[C:8](=[O:26])[NH:7]1)[CH:2]=[CH2:3].[C:27](=O)([O-])[O-].[Cs+].[Cs+].CI>CC#N.O>[CH2:1]([CH:4]1[O:21][C:20]2[C:15](=[C:16]([O:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[C:14]2[C:5]1=[C:6]1[C:11](=[CH:12][CH:13]=2)[NH:10][C:9]([CH3:25])([CH3:24])[C:8](=[O:26])[N:7]1[CH3:27])[CH:2]=[CH2:3]
Reactant: C=CCC1Oc2cccc(OC)c2-c2ccc3c(c21)NC(=O)C(C)(C)N3
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Solvent: CI
Product: C=CCC1Oc2cccc(OC)c2-c2ccc3c(c21)N(C)C(=O)C(C)(C)N3
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.7 %

Procedure:
To a solution of xiii (10 mg, 0.029 mmol) in CH3CN (1 mL) was added cesium carbonate (14 mg, 0.043 mmol) and methyl iodide (3.5 mL, 0.57 mmol) and the mixture was stirred at room temperature for 12 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The organic extracts were combined, washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by preparative thin layer chromatography to provide compounds xv (6.2 mg, 60%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][NH:11]2)=O)(C)(C)C.[F:15][C:16]1[CH:17]=C(Br)[CH:19]=[CH:20][CH:21]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[F:15][C:16]1[CH:17]=[C:6]([N:8]2[CH2:13][CH:12]3[CH2:14][CH:9]2[CH2:10][NH:11]3)[CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Reactant: Fc1cccc(Br)c1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Fc1cccc(N2CC3CC2CN3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
To a mixture containing 2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (100 mg, 0.5 mmol), 3-fluoro-phenylbromide (103.8 mg, 0.6 mmol), Pd(AcO) (8 mg, 0.03 mmol), 2-(di-t-butylphosphino)biphenyl (20 mg, 0.07 mmol) and sodium t-butoxide (100 mg, 1 mmol) in toluene (3 mL) was degassed with Ar. The reaction mixture was heated at 50 C for overnight. At the end of reaction, ethyl acetate was added and the mixture was filter through celite. After removal of solvent, TFA was added to the residue. The reaction mixture was stirred at ambient temperature for 1 hour. The excess TFA was removed under vacuum and the residue was purified using prep-HPLC to give desired product (60 mg, 41% yield for two steps) as TFA salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]([CH2:16][CH3:17])[N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:35]=[C:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[CH3:37]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:35]=[C:36]([C:38]1[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=1)[CH3:37])[C:6]1[CH:11]([CH2:16][CH3:17])[N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1
Reactant: COc1ccc(C(C)=CBr)cc1
Reactant: CCC1c2[nH]c3ccc(Cl)cc3c2CCN1C
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CCC1c2c(c3cc(Cl)ccc3n2C=C(C)c2ccc(OC)cc2)CCN1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 8.4 %

Procedure:
6-chloro-1-ethyl-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (91 mg, 0.36 mmol) was dissolved in DMF (5 mL). To this solution was added CuI (7 mg, 0.036 mmol), L-proline (8 mg, 0.073 mmol), K3PO4 (156 mg, 0.734 mmol). The reaction mixture was stirred for 10 min at room temperature followed by addition of 1-(1-bromoprop-1-en-2-yl)-4-methoxybenzene (100 mg, 0.44 mmol). The reaction mixture was heated at 80° C. for 18 h. Solvent was evaporated under reduced pressure, the residue was diluted with brine and extracted with ethyl acetate. Organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain 12 mg of 6-chloro-1-ethyl-9-(2-(4-methoxyphenyl)prop-1-enyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. 1H NMR (DMSO) OXALATE SALT 7.60 (m, 3H), 7.18 (s, 2H), 7.05 (s, 1H), 7.0 (d, 2H), 3.80 (s, 3H), 3.70 (m, 1H), 2.90 (m, 4H), 2.70 (m, 3H), 1.80 (m, 5H), 0.95 (t, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:35]([O:36][CH3:37])=[CH:34][C:24]2[CH2:25][CH2:26][N:27]([CH2:30][C@@H:31]([OH:33])[CH3:32])[CH2:28][CH2:29][C:23]=2[CH:22]=1>>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])=[N:7][C:2]([NH:20][C:21]2[C:35]([O:36][CH3:37])=[CH:34][C:24]3[CH2:25][CH2:26][N:27]([CH2:30][C@@H:31]([OH:33])[CH3:32])[CH2:28][CH2:29][C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc2c(cc1N)CCN(C[C@H](C)O)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)CCN(C[C@H](C)O)CC2
Yield: 70 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and (S)-1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol. The product was isolated as an off-white foam (72 mg, 70%). MS: 513 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.22 (s, 1H), 7.91 (s, 1H), 7.42 (s, 1H), 6.66 (s, 1H), 6.57 (s, 1H), 6.51 (s, 1H), 6.33 (s, 2H), 5.60 (s, 1H), 5.35 (s, 1H), 5.32 (s, 1H), 4.47 (t, J=8 Hz, 1H), 3.88 (s, 4H), 3.08 (s, 1H), 2.88 (m, 8H), 2.62 (br s, 2H), 2.53 (m, 2H), 2.27 (m, 2H), 1.66 (d, J=8.5 Hz, 1H), 1.16 (d, J=6 Hz, 3H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][N:9]([S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23])[CH2:10][CH2:11][N:12]1[CH:17]=[CH:16][C:15]2[CH:18]=[CH:19][O:20][C:14]=2[C:13]1=[O:21])(=O)=O.[I-:34].[Na+].CC(C)=O>O>[I:34][CH2:6][CH2:7][CH2:8][N:9]([CH2:10][CH2:11][N:12]1[CH:17]=[CH:16][C:15]2[CH:18]=[CH:19][O:20][C:14]=2[C:13]1=[O:21])[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23]
Reactant: [I-]
Reactant: CS(=O)(=O)OCCCN(CCn1ccc2ccoc2c1=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=c1c2occc2ccn1CCN(CCCI)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 92.9 %

Procedure:
3-{(2-Nitrobenzenesulfonyl)-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]amino}propyl methanesulfonate (480 mg, 0.96 mmol) and sodium iodide (720 mg, 4.8 mmol) were added to acetone (20 ml), and heated under reflux for 5 hours. The reaction mixture was cooled to room temperature, water was added, and extraction with dichloromethane was performed. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure to thereby obtain 474 mg (yield: 93%) of N-(3-iodopropyl)-2-nitro-N-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]benzenesulfonamide as a yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:21]1[CH2:30][C@H:29]([O:31][CH2:32][CH2:33][CH2:34][OH:35])[CH2:28][C@H:22]1[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20].[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[C:40]([O:48][C:49]([F:52])([F:51])[F:50])[CH:39]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:44]([C:41]1[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[CH:39][C:40]=1[O:48][C:49]([F:50])([F:51])[F:52])(=[O:46])=[O:45])[C:6](=[O:11])[C:5]2([N:21]1[CH2:30][C@H:29]([O:31][CH2:32][CH2:33][CH2:34][OH:35])[CH2:28][C@H:22]1[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccc(C)cc1C1(N2C[C@H](OCCCO)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3C[C@H](OCCCO)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 29.8 %

Procedure:
With 870 mg of the compound obtained in Step 139-4 and 603 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 390 mg of the title compound (amorphous) was obtained by a similar procedure to Example 2.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13]Br)[CH2:2][CH2:3][CH3:4].[C:16]1([C:22]2[N:23]=[C:24]([SH:33])[NH:25][C:26]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH2:1]([O:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][S:33][C:24]1[NH:25][C:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:23]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CCCCOCCNC(=O)CCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCOCCNC(=O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Yield: 138.4 %

Procedure:
N-(2-butoxyethyl)-5-bromopentanamide (3.89 g, 13.9 mmol), 4,5-diphenyl-1H-imidazole-2-thiol (3.57 g, 14.2 mmol), potassium carbonate (2.38 g, 17.2 mmol) and tetra-n-butylammonium iodide (1.50 g, 4.06 mmol) were mixed in 100 mL anhydrous tetrahydrofuran, and heated to reflux for 18 hours. After cooling, the mixture was poured into water (400 mL). This mixture was extracted with ethyl acetate (2×400 mL), and the extracts were combined, dried over anhydrous magnesium sulfate and evaporated. The residue was eluted through a short plug of silica gel (ethyl acetate), and evaporation afforded sufficiently pure N-(2-butoxyethyl)-5-(4,5-diphenyl-1H-imidazol-2-ylthio)-pentanamide (8.69 g).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:12]1[CH:60]=[CH:59][C:15]2[NH:16][C:17]([CH2:19][CH2:20][CH:21]3[CH2:24][CH:23]([N:25]([CH2:27][C@@H:28]4[C@H:32]5[O:33]C(C)(C)[O:35][C@H:31]5[C@H:30]([N:38]5[C:42]6[N:43]=[CH:44][N:45]=[C:46]([NH:47]CC7C=CC(OC)=CC=7OC)[C:41]=6[CH:40]=[CH:39]5)[CH2:29]4)[CH3:26])[CH2:22]3)=[N:18][C:14]=2[CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C([SiH](CC)CC)C>O>[NH2:47][C:46]1[C:41]2[CH:40]=[CH:39][N:38]([C@@H:30]3[CH2:29][C@H:28]([CH2:27][N:25]([CH:23]4[CH2:22][CH:21]([CH2:20][CH2:19][C:17]5[NH:16][C:15]6[CH:59]=[CH:60][C:12]([C:8]([CH3:9])([CH3:10])[CH3:11])=[CH:13][C:14]=6[N:18]=5)[CH2:24]4)[CH3:26])[C@@H:32]([OH:33])[C@H:31]3[OH:35])[C:42]=2[N:43]=[CH:44][N:45]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCc4nc5cc(C(C)(C)C)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(C(C)(C)C)ccc3[nH]2)C1
Reaction time: 8 h
Yield: 40.3 %

Procedure:
Trifluoroacetic Acid (5 ml) added to a mix lure of Water (0.5 ml) and 7-((3aS,4R,6R,6aR)-6-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.20 g, 0.28 mmol) at RT. The reaction was allowed to proceed overnight upon which it was quenched with Triethylsilane (0.088 ml, 0.55 mmol). The volatiles were removed in vacuo and resulting residue was partitioned between saturated NaHCO3 and DCM/MeOH (10:1). Aqueous extracted 3× more with DCM/MeOH (10:1) and combined organics were dried over MgSO4, filtered, concentrated and purified by flash chromatography (DCM/7N NH3 in MeOH 87:13) to give the desired product as an off-white foam (0.060 g). MS (ESI+) for C30H41N7O2 m/z 532.3 [M+H]+; MS (ESI−) for C30H41N7O2 m/z 530.4 [M−H]−; HPLC purity >94% (ret. time, 2.723 min.) 1H NMR (400 MHz, d4-MeOH) δH 8.079 (s, 1H), 7.500 (s, 1H), 7.418-7.398 (m, 1H), 7.310-7.307 (m, 1H), 7.230-7.216 (m, 1H), 6.619-6.610 (m, 1H), 4.355-4.316 (m, 1H), 3.926-3.887 (m, 1H), 3.088-3.017 (m, 0.5H (methine of trans isomer)), 2.879-2.809 (m, 2H), 2.745-2.685 (m, 0.5H (methine of cis isomer), 2.532-2.512 (m, 1H), 2.446-2.373 (m, 2H), 2.294-2.276 (m, 2H), 2.202-2.012 (m, 5H), 1.685-1.603 (m, 1H), 1.545-1.504 (m, 1H), 1.383 (s, 1H). Retention time: 2.723 mins HPLC Conditions: Agilent Zorbax Exlipse XDB-C18 column, 4.6×50 mm (1.8 um packing), Solvent A—Water (0.1% TFA), Solvent B—Acetonitrile (0.07% TFA) 6 min gradient from 5 to 95% B; 1 min hold; then recycle.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([NH2:23])=[O:22])[CH2:16]1>CO>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([NH2:23])=[O:22])[CH2:16]1
Reactant: COCOc1ccc(C2CCCC(C(N)=O)C2)c(OCOC)c1
Solvent: CO
Product: NC(=O)C1CCCC(c2ccc(O)cc2O)C1
Yield: 31.2 %

Procedure:
(±)-3-[2,4-Bis(methoxymethoxy)phenyl]cyclohexanecarboxamide (22 mg), methanol (2 ml) and acidic ion exchange resin (300 mg) were heated to reflux for 5 hr. The reaction mixture was filtered and the resin was washed with methanol. The combined filtrate and washings were evaporated in vacuo and the crude residue was purified by preparative HPLC to give the title compound as a white solid (5 mg, 31%). δH(CD3OD) 1.45-1.82 (6H, m), 2.07-2.19 (2H, m), 2.62-2.69 (1H, m), 3.00-3.09 (1H, m), 6.20-6.28 (2H, m), 6.89 (1H, d); m/z (ES+) 236 (M+H)+.
Reaction SMILES: [C:1]([O-:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Na+].[CH3:12][C:13]([CH3:43])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:14][Sn:15](Cl)([CH2:26][C:27]([CH3:35])([CH3:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:16][C:17]([CH3:25])([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(C)C>[C:1]([O-:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:24][C:17]([CH3:25])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:16][Sn+:15]([CH2:26][C:27]([CH3:34])([CH3:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:14][C:13]([CH3:12])([CH3:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C[Sn](Cl)(CC(C)(C)c1ccccc1)CC(C)(C)c1ccccc1)c1ccccc1
Agent: CCCCCCCC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C[Sn+](CC(C)(C)c1ccccc1)CC(C)(C)c1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 94.8 %

Procedure:
Sodium caprylate 6.6 g was added to 200 ml of isopropanol, and with stirring, the mixture was heated to 50° C. To the resulting solution was added 22.2 g of tris(β,β-dimethylphenethyl)tin chloride over 30 minutes. The mixture was further stirred for 30 minutes. The insoluble material precipitated was separated by filtration, and the filtrate was concentrated to give 25.1% (yield 94.8%) of tris(β,β-dimethylphenethyl)tin caprylate as a slightly pale yellow viscous syrup.
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.C(O)(=O)CCCCCCC/C=C\CCCCCC.[CH:44]1([N:50]=[C:51]=[N:52][CH:53]2[CH2:58][CH2:57][CH2:56]CC2)CCCCC1>C(Cl)Cl>[CH3:1][N:50]([C:51]1[CH:56]=[CH:57][CH:58]=[CH:53][N:52]=1)[CH3:44]
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCCCC/C=C\CCCCCCCC(=O)O
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: ClCCl
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 365 mg of radicicol, 636 mg of palmitoleic acid, 20 ml of dry methylene chloride, 716 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 654 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:16])[C:13]([OH:15])=O)=[CH:11][C:5]=2[CH2:4][O:3]1.Br.[NH2:19][C@H:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][C:24]([OH:30])=[CH:25][CH:26]=2)[CH2:21]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[CH3:17][C:2]1([CH3:1])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:16])[C:13]([NH:19][C@H:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][C:24]([OH:30])=[CH:25][CH:26]=4)[CH2:21]3)=[O:15])=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: N[C@H]1CCc2ccc(O)cc2C1
Reactant: CC1(C)OCc2cc([C@@H](O)C(=O)O)ccc2O1
Agent: Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)OCc2cc([C@@H](O)C(=O)N[C@H]3CCc4ccc(O)cc4C3)ccc2O1
Yield: 88.9 %

Procedure:
(-)-(R)-2-(2,2-Dimethylbenzo[1,2-d]-1,3-dioxan-6-yl)2-hydroxyacetic acid (130 mg), 148 mg of (S)-2-amino-7-hydroxytetralin hydrobromide and 243 mg of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate were dissolved in 1.4 ml of N,N-dimethylformamide, 0.15 ml of triethylamine was added to the solution with stirring under ice-cooling, and the mixture was subjected to 15 hours of reaction. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by aminopropylated silica gel medium pressure liquid column chromatography (eluent: ethyl acetate/acetone=4/1) and then recrystallized from ethyl acetate to give 186 mg of (-)-(2R)-2-(2,2-dimethylbenzo[1,2-d]-1,3-dioxan-6-yl)-2-hydroxy-N-((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide having a melting point of 169 to 170° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N+:19]=1[O-])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH3:26][N:27](C)C(Cl)=O.C[Si](C#N)(C)C>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:26]#[N:27])[N:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CC(c1cccc[n+]1[O-])C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CN(C)C(=O)Cl
Agent: C[Si](C)(C)C#N
Solvent: ClCCl
Product: CC(c1cccc(C#N)n1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A mixture of the product of part (i) (0.90 g), N,N-dimethylcarbamoyl chloride (0.80 g) and trimethylsilyl cyanide (0.80 g) in dichloromethane (10 ml) was stirred at room temperature for 7 days and the resulting solution was evaporated. The residue was treated with 5N hydrochloric acid (10 ml) and the mixture was agitated in an ultrasonic bath for 0.05 hour to give a clear solution. A solid formed on standing which was filtered off, washed with acetone followed by ether, and dried to give the title compound as the hydrochloride salt, (0.28 g), m.p. 219° (with decomposition).
Reaction SMILES: [N+:1]([C:4]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].Br[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>[Cu]I.O>[CH3:11][C:10]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH:6][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1
Reactant: Cc1cccc(N)c1[N+](=O)[O-]
Reactant: OCCc1ccc(Br)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cccc(Nc2ccc(CCO)cc2)c1[N+](=O)[O-]
Temperature: 200 °C
Yield: 20.7 %

Procedure:
A mixture of 2-nitro-3-methylaniline (Newman, M. S.; Kannan R. J. Org. Chem., 1976, 41, 3356., 1.9 g, 12.4 mmol), 4-bromophenylethyl alcohol (2.5 g, 12.4 mmol), K2CO3 (1.7 g, 12.4 mmol and CuI (230 mg, 1.24 mmol) was placed in a sealed tube and heated at 200° C. for 2 h. After cooling, the mixture was poured into water (100 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with 2N aqueous NaOH (100 mL) and brine (100 mL), then dried (Na2SO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 700 mg (21%) of the title compound as an orange oil: