Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:12]([O:13][CH2:14][C:15]([CH2:17][CH3:18])=[O:16])=[C:11]([Br:19])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>C1COCC1.O>[Br:1][C:2]1[C:12]([O:13][CH2:14][C:15]([CH2:17][CH3:18])=[O:16])=[C:11]([Br:19])[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(Br)c(OCC(=O)CC)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)COc1c(Br)ccc(C(=O)O)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.280 g (3.20 mmol) of ethyl 2,4-dibromo-3-(ethylcarbonylmethoxy)benzoate were dissolved in 15 ml of THF and 15 ml of water, and 0.143 g (3.6 mmol) of NaOH was added. The mixture was stirred at RT for 12 h and then evaporated to dryness. The residue was taken up in water, and 6 N HCl was added. The resulting precipitate was filtered off with suction and dried. This gave 2,4-dibromo-3-(ethylcarbonylmethoxy)benzoic acid in the form of a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]#[N:12])[CH:8]=2)[NH:3]1.Cl.[H][H]>CO>[NH2:12][CH2:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[CH2:10]2
Reactant: [H][H]
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Agent: Cl
Solvent: CO
Product: NCc1ccc2c(c1)CC(=O)N2

Procedure:
A solution of the compound obtained in Step B (35 mmoles) in MeOH (500 ml) is added to 6 ml of concentrated HCl. The reaction mixture is stirred for 3 days under 10 bars of hydrogen. After filtration over Celite, the filtrate is evaporated to dryness to yield the title product in the form of a white powder, which is used directly in the next reaction.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1.CS(O[CH:16]1[CH2:19][N:18]([C:20]([C:22]2[O:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:25][N:26]=2)=[O:21])[CH2:17]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[CH3:10][C:4]1[CH:3]=[C:2]([O:1][CH:16]2[CH2:17][N:18]([C:20]([C:22]3[O:23][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:25][N:26]=3)=[O:21])[CH2:19]2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: Cc1cc(O)ccc1C=O
Reactant: CS(=O)(=O)OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)ccc1C=O
Temperature: 90 °C
Reaction time: 20 h
Yield: 71.9 %

Procedure:
To a solution of 4-hydroxy-2-methylbenzaldehyde (0.11 g, 0.79 mmol) and 1-(5-phenyl-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yl methanesulfonate (0.20 g, 0.62 mmol, Intermediate IB above) in DMF (10 mL) under nitrogen was added Cs2CO3 (0.24 g, 0.74 mmol). The mixture was stirred at 90° C. for 20 h, cooled to RT and then diluted with DCM. The solids were filtered off and the filtrate was evaporated. The product was purified on two occasions by preparative HPLC (Kromasil, C8) eluting with a gradient of acetonitrile and a mixture of acetic acid and water (0.2%). The pure fractions were combined and concentrated. The aqueous residues were extracted with DCM and the organic solutions were evaporated. There was obtained 162 mg (72%) of the title compound as a solid. 1H NMR (500 MHz, CDCl3): δ 2.66 (s, 3H), 4.34 (d, 1H), 4.69 (dd, 1H), 4.76 (d, 1H), 5.17 (m, 2H), 6.64 (d, 1H), 6.72 (dd, 1H), 7.53 (t, 2H), 7.59 (t, 1H), 7.78 (d, 1H), 8.15 (d, 1H), 10.14 (s, 1H), MS (APCI+) m/z 364 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15](=[O:17])[CH3:16])[C:5]([Cl:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:32]=[CH:31][C:23]2[N:24]([CH3:30])[C:25](=[O:29])[CH2:26][CH2:27][CH2:28][C:22]=2[CH:21]=1.Cl>CC(O)C.O1CCOCC1>[C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6]1[C:5]([Cl:18])=[CH:4][N:3]=[C:2]([NH:19][C:20]2[CH:32]=[CH:31][C:23]3[N:24]([CH3:30])[C:25](=[O:29])[CH2:26][CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:7]=1)(=[O:17])[CH3:16]
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Reactant: CC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3C)ncc1Cl
Yield: 77.7 %

Procedure:
1-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenyl]-ethanone (37.0 mg, 0.132 mmol) and 7-amino-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (27.7 mg, 0.146 mmol) were slurried in iPrOH (1.5 mL) prior to adding ˜0.2 mL of 4N HCl in dioxane. This mixture was heated in a microwave reactor (sealed vessel) at 120° C. for 40 min. After quenching with saturated aqueous NaHCO3 solution (2 mL), the resulting precipitate was collected by filtration, successively washed with iPrOH (2×2 mL) water (4×2 mL) and iPrOH (2×2 mL) to afford product (44.7 mg, 78%) as a white powder that had the following properties: m.p.=215-217° C.; LC/MS (ESI+): 436 (M+H); 1H-NMR (DMSO-d6, 400 MHz): δ 11.79 (s, 1H), 9.60 (s, 1H), 8.90 (m, 1H), 8.30 (s, 1H), 8.13 (d, 1H, J=8.1), 7.65-7.59 (m, 2H), 7.57 (s, 1H), 7.25-7.20 (m, 2H), 3.22 (s, 3H), 2.70 (s, 3H), 2.58 (m, 2H), 2.16 (m, 2H), 2.04 (m, 2H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.Br[C:16]1[C:17]([CH:38]([CH3:40])[CH3:39])=[N:18][N:19]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=2)[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1>CN(C=O)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[N:19]([C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)[N:18]=[C:17]([CH:38]([CH3:40])[CH3:39])[C:16]=2/[CH:3]=[CH:2]/[C:1]([O:5][CH2:6][CH3:7])=[O:4])=[CH:22][CH:23]=1
Reactant: CC(C)c1nn(-c2ccc3ccccc3n2)c(-c2ccc(F)cc2)c1Br
Reactant: C=CC(=O)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1c(C(C)C)nn(-c2ccc3ccccc3n2)c1-c1ccc(F)cc1
Yield: 86.9 %

Procedure:
Ethyl acrylate (4.9 mL, 45 mmoles) and bis-triphenyl phosphine palladium (II) chloride (0.25 g, 0.36 mmoles) were suspended in a 1:1 mixture of triethyl amine and DMF. This mixture was heated to reflux under an atmosphere of N2. When the suspension had completely dissolved, 2-[4-bromo-5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-1-yl]quinoline (3.70 g, 9.0 mmoles) was carefully added. The resulting yellow solution was refluxed for 16 hours, then cooled and partitioned between H2O and Et2O. The ether layer was dried over MgSO4, filtered, and evaporated to give a yellow solid which was recrystallized from hexanes to give 3.36 g (87%) of the title compound as a tan solid, mp 140°-143° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.O[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N:12]1([CH2:11][CH2:10][O:8][C:4]2[CH:3]=[C:2]([I:1])[CH:7]=[CH:6][CH:5]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: OCCN1CCOCC1
Reactant: Oc1cccc(I)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Ic1cccc(OCCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a stirred solution of 3-iodophenol (2.2 g, 10 mmol), N-(2-hydroxyethyl)morpholine (2 eq. 2.4 mL) and Ph3P (2 eq. 5.24 g) in THF (90 mL)at 0° C. was added dropwise a solution of diisopropylazodicarboxylate (2 eq. 3.96 g) in THF (20 mL). The resulting solution was stirred at room temperature overnight and was then quenched with NaHCO3. The product was extracted with EtOAc and the EtOAc layer was washed with NaCl (sat.), dried over sodium sulfate. The crude mixture was then purified on a silica gel column with 25% acetone in hexane to give 3-(2-morpholin-4-ylethyloxy)iodobenzene (2.8 g, 84% yield).
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:13]1[C:14](=[O:28])[CH2:15][C:16]([CH3:27])([CH3:26])[CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]=1[OH:19])(=O)[CH2:9][CH2:10][CH3:11].Cl.[CH2:30]([O:33][NH2:34])[CH:31]=[CH2:32]>C(O)C>[CH2:30]([O:33][N:34]=[C:8]([C:13]1[C:14](=[O:28])[CH2:15][C:16]([CH3:27])([CH3:26])[CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]=1[OH:19])[CH2:9][CH2:10][CH3:11])[CH:31]=[CH2:32]
Reactant: CCCC(=O)C1=C(O)C(c2ccccc2)C(C)(C)CC1=O
Reactant: C=CCON
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=CCON=C(CCC)C1=C(O)C(c2ccccc2)C(C)(C)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
Triethylamine (1.2 g) was added to a solution of 2-butyryl-5,5-dimethyl -3-hydroxy-4-phenyl cyclohex-2-ene-1-one (2.8 g) and O-allylhydroxylamine hydrochloride (1.2 g) in ethanol (50 ml). After stirring at ambient temperature overnight, the ethanol was evaporated in vacuo, water was added to the residue and the aqueous solution extracted with methylene chloride. After drying the organic extracts over anhydrous magnesium sulphate, the methylene chloride was evaporated in vacuo. The residue was chromatographed on a silica gel column using 5% (v/v) diethyl ether-methylene chloride as eluant to give the title compound (2.1 g) as a viscous, colourless oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=2)O1.Br[C:35]1[C:36]([NH2:41])=[N:37][CH:38]=[CH:39][CH:40]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[C:14]([N:12]1[CH:13]=[C:9]([C:35]2[C:36]([NH2:41])=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:10]=[N:11]1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ncccc1Br
Reactant: CC1(C)OB(c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)OC1(C)C
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: Cc1ccccc1
Solvent: CCO
Product: Nc1ncccc1-c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
4-(4,4,5,5-Tetramethyl-(1,3,2)dioxaborolan-2-yl)-1-trityl-1H-pyrazole (3.2 g, 7.33 mmol) described in Manufacturing Example 32-1-2, 3-bromo-pyridine-2-ylamine (1.14 g, 6.60 mmol), tetrakis(triphenylphosphine)palladium (0) (424 mg, 0.37 mmol), toluene (40 mL), 2 M aqueous sodium carbonate solution (10 mL) and ethanol (20 mL) were stirred for 1 hour at 95° C. The reaction solution was allowed to room temperature, and partitioned into water and ethyl acetate. The ethyl acetate layer was washed with water once, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel chromatography (heptane:ethyl acetate=1:2) to obtain the title compound (2.3 g, 78.0%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([C:19]3[CH:30]=[CH:29][C:22]([CH2:23]OS(C)(=O)=O)=[CH:21][CH:20]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][O:32][C:33](=[O:45])[C@H:34]([CH2:43][SH:44])[NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[CH3:31][O:32][C:33](=[O:45])[CH:34]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:40])[CH3:41])=[O:37])[CH2:43][S:44][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([C:9]2[N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)OCc1ccc(-c2nc(-c3ccccc3)cc(-c3ccccc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(CSCc1ccc(-c2nc(-c3ccccc3)cc(-c3ccccc3)n2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of Methanesulfonic acid 4-(4,6-diphenylpyrimidin-2-yl)-benzyl ester, 0.15 g (0.36 mmol), N-(tert-Butoxycarbonyl)-L-cysteine methyl ester, 0.08 mL (0.36 mmol), cesium carbonate, 235 mg (0.72 mmol), and 10 mL of N,N-dimethylformamide was stirred at room temperature for 4 h. The mixture was diluted with 10 mL of water and extracted with 2×50 mL of ethyl acetate. The organic layer was washed with 2×50 mL portions of aq. LiCl, sat. aq. NaHCO3, sat. aq. NaCl, and dried (MgSO4). After the solution was concentrated, the residue was purified by column chromatography (eluted with 7% EtOAc-Heptane) to afford the desired product in 0.18 g (90%) as a white solid. 1H NMR (CDCl3) 8.67 (d, 2H, J=9.0 Hz), 8.30-8.27 (m, 4H), 8.02 (s, 1H), 7.61-7.55 (m, 6H), 7.47 (d, 2H, J=9.0 Hz), 5.30 (d, 1H, J=7.7 Hz), 4.63-4.52 (m, 1H), 3.82 (s, 2H), 3.76 (s, 3H), 2.93 (dd, 1H, J=15.7, 6.0 Hz), 2.84 (dd, 1H, J=15.7, 6.7 Hz), 1.47 (s, 9H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.Cl[C:10]1[C:15]([C:16]2[N:24]3[C:19]([CH2:20][CH2:21][CH2:22][CH2:23]3)=[C:18]([C:25]#[N:26])[CH:17]=2)=[CH:14][CH:13]=[CH:12][N:11]=1>ClCCCl>[Br:1][C:17]1[C:18]([C:25]#[N:26])=[C:19]2[N:24]([C:16]=1[C:15]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[CH2:23][CH2:22][CH2:21][CH2:20]2
Reactant: N#Cc1cc(-c2cccnc2Cl)n2c1CCCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCCl
Product: N#Cc1c(Br)c(-c2cccnc2)n2c1CCCC2
Yield: 68 %

Procedure:
2.42 g of N-bromosuccinimide are added with stirring to a solution of 3.5 g of 3-(2-chloro-3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile in 50 cm3 of 1,2-dichloroethane. The mixture is refluxed for 20 hours. After cooling, the reaction mixture is concentrated at reduced pressure (2.7 kPa) at a temperature close to 60° C. The residue is taken up with 100 cm3 of ethyl acetate and washed 3 times with 70 cm3 of an aqueous solution of sodium bicarbonate at a concentration of 5%. The organic extracts are combined and dried over anhydrous magnesium sulphate, filtered and concentrated to dryness at reduced pressure (2.7 kPa) at a temperature close to 50° C. A mixture of products is thus obtained, which is chromatographed on a column of 1.8 cm diameter containing 90 g of silica (0.04-0.0063). Elution is carried out with dichloromethane at a total pressure of 1.5 bar and with 20-cm3 fractions being collected. The homogeneous fractions are combined and concentrated at reduced pressure (2.7 kPa) at a temperature close to 60° C. 2.79 g of 2-bromo-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile are thus obtained in the form of white crystals melting at 188° C.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C@@H:9]([OH:17])[CH2:10][C:11](=[O:16])[C:12]=1[CH2:13][C:14]#[CH:15].[Cl:18][C:19]([Cl:29])=[CH:20][C@@H:21]1[C@@H:23]([C:24](Cl)=[O:25])[C:22]1([CH3:28])[CH3:27].[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Cl:18][C:19]([Cl:29])=[CH:20][C@@H:21]1[C@@H:23]([C:24]([O:17][C@H:9]2[CH2:10][C:11](=[O:16])[C:12]([CH2:13][C:14]#[CH:15])=[C:8]2[CH3:7])=[O:25])[C:22]1([CH3:27])[CH3:28]
Reactant: C#CCC1=C(C)[C@@H](O)CC1=O
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@H]1C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C#CCC1=C(C)[C@@H](OC(=O)[C@@H]2[C@@H](C=C(Cl)Cl)C2(C)C)CC1=O
Yield: 78.3 %

Procedure:
3.4 Grams of pyridine was added to a mixture of 5.0 g of (S)-2-methyl-4-oxo-3-(2-propynyl)-cyclopent-2-enyl alcohol, 8.0 g of (1R)-trans-3-(2, 2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid chloride and 50 ml of toluene under ice-cooling. The resulting mixture was allowed to react at room temperature for 12 hours. Thereafter, about 50 ml of a saturated aqueous ammonium chloride solution was added to the resultant reaction solution, which was then extracted with three 50-ml portions of diethyl ether. The combined diethyl ether layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography followed by recrystallization from a mixed solvent of hexane and ethyl acetate to obtain 8.9 g (yield: 78%) of (S)-2-methyl-4-oxo-3-(2-propynyl)-cyclopent-2-enyl (1R)-trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate (the present compound).
Reaction SMILES: O[CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]1=2.C1C=CC(P([N:34]=[N+:35]=[N-:36])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[N:34]([CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]1=2)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Oc1ccc2c(c1)CCCC2O)C(F)(F)F
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NC1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Temperature: 0 °C

Procedure:
To a solution of trifluoro-methanesulfonic acid 5-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl ester (11.2 g, 37.9 mmol, 1.0 eq) in THF (150 mL) at RT was added DPPA (Aldrich, 11.1 mL, 51.6 mmol, 1.36 eq). The resulting mixture was cooled to 0° C., then DBU (Aldrich, 7.7 mL, 51.6 mmol, 1.36 eq) was added slowly through a syringe. The reaction was warmed to RT and stirred over the weekend. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc (400 mL), washed with saturated NH4Cl (twice), water, and brine, dried over Na2SO4, and concentrated in vacuo. The crude was purified by flash chromatography (5% EtOAc-hexane) to provide the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7][OH:8])[NH2:6].CCN(CC)CC.Cl[C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[OH:8][CH2:7][C@@H:5]([NH:6][C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:4]([O:3][CH3:2])=[O:9]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@H](N)CO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 96.2 %

Procedure:
(S. Bhatia and J. Hajdu, Tetrahedron Lett. 1998, 29, 31-34). To a solution of D-serine methyl ester hydrochloride (20.00 g, 0.13 mol) and Et3N (35.82 mL, 0.26 mol) in CH2Cl2 (80 mL) at 0° C., was added in one portion a solution of TrCl (36.53 g, 0.13 mol) in CH2Cl2 (80 mL). The mixture was allowed to stir at 0° C. (24 h) under Ar and then successively washed with 10% aqueous citric acid (120 mL) and saturated aqueous brine (120 mL). The organic layer was dried (Na2SO4) and evaporated in vacuo to yield 45.20 g (97%) of crude desired product as a pale yellow crystalline solid. The product was used for next step without further purification: Rf=0.50 (1/1 EtOAc/hexanes); 1H NMR (CDCl3) δ 2.29 (br s, 1H), 2.98 (br s, 1H), 3.29 (s, OCH3), 3.51-3.60 (m, CHH′OH, CH), 3.64-3.74 (m, CHH′OH), 7.16-7.30 (m, 9 PhH), 7.47-7.50 (m, 6 PhH).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:19].[Cl-].[NH4+]>C(Cl)Cl>[CH2:1]([NH:8][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CNCc1ccccc1)c1ccc(F)cc1
Yield: 62.8 %

Procedure:
To a solution of benzylamine (1.29 g, 12.1 mmol) in methylene chloride was added triethylamine (7.6 g, 75.0 mmol), and then 2-bromo-1-(4-fluorophenyl)ethanone (3.27 g, 15.1 mmol) was added thereto. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was partitioned. The organic layer was dried over sodium sulfate and concentrated to give crude 2-(benzylamino)-1-(4-fluorophenyl)ethanone (1.85 g) as an oil. The oil (1.50 g) was dissolved in a mixed solvent of methanol (9 mL) and water (1 mL), and sodium borohydrogen (0.8 g) was added at room temperature. The reaction mixture was concentrated and extracted with tert-butyl methyl ether, and the organic layer was concentrated. Isopropyl acetate (4 mL) and heptane (4 mL) were added to the residue, and the mixture was refluxed. The precipitated crystals were collected by filtration and dried to give racemic 1-(4-fluorophenyl)-2-(benzylamino)ethanol (0.21 g). 1-(4-fluorophenyl)-2-(benzylamino)ethanol: 1H-NMR (CDCl3) δ: 2.70-2.73 (1H, m), 2.91-2.94 (1H, m), 3.80-3.88 (2H, m), 4.68-4.71 (1H, m), 7.00-7.52 (9H, m)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][NH2:21])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:21][CH2:20][CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: NCCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Br)cc1NCCc1cccc(F)c1
Temperature: 80 °C

Procedure:
A mixture of 4-bromo-2-fluoronitrobenzene (500 mg, 2.27 mmol), 2-(3-fluorophenyl)ethylamine (411 mg, 2.95 mmol), and potassium carbonate (1.0 g, 7.24 mmol) in 7 mL N,N-dimethylformamide was heated at 80° C. for 1 hour. The mixture was diluted with ethyl acetate, rinsed with brine (three times), dried over magnesium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[CH2:19]1[CH:23]([CH2:24][OH:25])[CH2:22][CH:21]([NH2:26])[CH2:20]1.[OH-].[Na+]>C(N(CC)CC)C.C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:26][C@H:21]2[CH2:20][CH2:19][C@@H:23]([CH2:24][OH:25])[CH2:22]2)[N:3]=1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reactant: NC1CCC(CO)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nc(N[C@H]2CC[C@@H](CO)C2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 25 °C

Procedure:
A solution of (±)-cis-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (530 mg, 2.00 mmol) from Example 4, 3-aminocyclopentyl-1-methanol (276 mg, 24 mmol), triethylamine (1.12 g, 10.98 mmol), and ethanol (20 mL) was stirred at reflux for 5 hours. An additional amount of triethylamine (1.17 g) was then added and the solution was refluxed for 8 additional hours. The solution was allowed to cool to room temperature and 2 mL of 1 N NaOH was added. The solution was concentrated and the residues were placed on silica gel column which was eluted with 10% methanol-chloroform (0.36 g, 52%). Recrystallization of such a sample from ethanolacetonitrile gave title compound as white powder, m.p. 177-180° C.