Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2].B(F)(F)F.CCOCC.[N+](=[C:66]([CH3:68])[CH3:67])=[N-]>CCOCC>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH:66]([CH3:68])[CH3:67])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2]
Reactant: CC(C)=[N+]=[N-]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Agent: FB(F)F
Solvent: CCOCC
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC(C)C)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg) in ether (6 ml) is added boron trifluoride etherate (10 μl) followed by freshly prepared 2-diazopropane (100 fold excess). The mixture is stirred at room temperature for 15 min and quenched with sat'd aqueous sodium bicarbonate solution. The organic layer is separated, washed (sat'd. aqueous NaCl) and dried over anhydrous magnesium sulfate. Removal of solvent followed by preparative tlc on silica gives the title compound and its 4"-isomer.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[C:18]1([C:24]2[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([C:24]2[CH:25]=[CH:26][C:27]([C:28]([NH:1][C:2]3[CH:3]=[C:4]4[C:12](=[CH:13][CH:14]=3)[NH:11][C:10]3[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]4=3)=[O:29])=[CH:31][CH:32]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc(-c5ccccc5)cc4)cc3c2C1
Yield: 71.1 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 15 mg (0.051 mMol) 4-phenylbenzoyl chloride, 13.4 mg (71%) of the title compound were recovered as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[CH2:14][CH2:15][C:16]([OH:18])=[O:17].S(=O)(=O)(O)O.[CH3:24]O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17]
Reactant: CO
Reactant: O=C(O)CCc1cnoc1-c1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(Cl)cc1Cl
Yield: 94 %

Procedure:
A mixture of 3-[5-(2,4-dichlorophenyl)-4-isoxazolyl]propionic acid (3.00 g), conc. sulfuric acid (0.1 ml) and methanol (50 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(2,4-dichlorophenyl)-4-isoxazolyl]propionate (2.96 g, yield 94%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio). NMR (CDCl3) δ: 2.46–2.58 (2H, m), 2.71–2.81 (2H, m), 3.66 (3H, s), 7.35–7.42 (2H, m), 7.54–7.58 (1H, m), 8.28 (1H, s).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Si:7]([O:14][C@H:15]1[C:20](=[CH2:21])[C@H:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:18][C:17](CO)([OH:30])[CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>CO.[Cl-].[Na+].O>[Si:7]([O:14][C@H:15]1[C:20](=[CH2:21])[C@H:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:18][C:17](=[O:30])[CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(O)(CO)C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium periodate saturated water (2.2 mL) was added to a solution of the diol 4 (146 mg, 0.36 mmol) in methanol (9 mL) at 0° C. The solution was stirred at 0° C. for 1 h, poured into brine and extracted with ether and benzene. The organic extracts were combined, washed with brine, dried (MgSO4) and evaporated. An oily residue was dissolved in hexane (1 mL) and applied on a silica Sep-Pak cartridge. Pure 4-methylenecyclohexanone derivative 5 (110 mg, 82%) was eluted with hexane/ethyl acetate (95:5) as a colorless oil: 1H NMR (CDCl3) δ 0.050 and 0.069 (6H and 6H, each s, 4× SiCH3), 0.881 (18H, s, 2× Si-t-Bu), 2.45 (2H, ddd, J=14.2, 6.9, 1.4 Hz), 2.64 (2H, ddd, J=14.2, 4.6, 1.4 Hz), 4.69 (2H, dd, J=6.9, 4.6 Hz), 5.16 (2H, s); MS m/z (relative intensity) no M+, 355 (M+-Me, 3), 313 (M+-t-Bu, 100), 73 (76).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]1[C@@H:13]([OH:14])[CH2:12][CH2:11][C@H:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@H:9]1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[F:25][C:26]([F:47])([F:46])[C:27]1[CH:28]=[C:29]([C@@H:37](OC(=N)C(Cl)(Cl)Cl)[CH3:38])[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1>>[F:25][C:26]([F:46])([F:47])[C:27]1[CH:28]=[C:29]([C@H:37]([O:14][C@H:13]2[CH2:12][CH2:11][C@H:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@@H:9]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C@@H:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH3:38])[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1
Reactant: CCOC(=O)[C@H]1[C@H](c2ccccc2C)[C@@H](O)CC[C@@H]1C(=O)OCC
Reactant: C[C@H](OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CCOC(=O)[C@H]1[C@H](c2ccccc2C)[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC[C@@H]1C(=O)OCC

Procedure:
The title compound was prepared from the first eluting isomer diethyl (1S,2S,3R,4S)-3-(2-methylphenyl)-4-hydroxycyclohexane-1,2-dicarboxylate (step G) and (1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl-2,2,2-trichloroethanimidoate (Example 6, step E) according to the procedure of Example 6, step F. 1H-NMR (CDCl3): δ: 7.65 (1H, s), 7.15 (2H, s), 7.08–6.92 (4H, m), 4.25 (1H, q, J=6.0 Hz), 4.20–4.10 (2H, m), 3.85–3.66 (2H, m), 3.42 (1H, m), 3.21 (1H, t), 2.90–2.79 (2H, m), 2.35 (1H, m), 2.25 (1H, m), 2.22 (3H, s), 1.69–1.56 (2H, m), 1.30 (3H, d, J=6.0 Hz), 1.23 (3H, t, J=7.2 Hz), 0.77 (3H, t, J=7.2 Hz). Unreacted starting alcohol could be recovered by flushing the column with EtOAc and reused in the above reaction.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.[OH:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>O>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:19][C:18]1[C:13]([C:39]2[CH:40]=[CH:41][C:36]([OH:35])=[CH:37][CH:38]=2)=[N:14][C:15]([CH3:34])=[CH:16][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: OB(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccc(O)cc3)c2cc1OC
Temperature: 70 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonate solution (0.5 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 4-hydroxyphenylboronic acid (81 mg) under an argon atmosphere, and the mixture was stirred at 70° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (34 mg, yield 75%).
Reaction SMILES: CC([CH:5]1[CH2:10][N:9]([CH2:11][CH:12]2[C:21]3[C:16](=[C:17]([O:24][CH3:25])[C:18]([C:22]#[N:23])=[CH:19][CH:20]=3)[CH2:15][CH2:14][O:13]2)[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][O:24][C:17]1[C:18]([C:22]#[N:23])=[CH:19][CH:20]=[C:21]2[C:16]=1[CH2:15][CH2:14][O:13][CH:12]2[CH2:11][N:9]1[CH2:10][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: COc1c(C#N)ccc2c1CCOC2CN1CCN(C(=O)[O-])C(C(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(C#N)ccc2c1CCOC2CN1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1,1-dimethylethyl-4-{[6-cyano-5-(methyloxy)-3,4-dihydro-1H-isochromen-1-yl]methyl}piperazine-1-carboxylate (30 mg, 0.08 mmol) in 5 mL of DCM was added 5 mL of TFA was stirred at room temperature for 1 hours, and the reaction was concentrated. The resulting crude 5-(methyloxy)-1-(piperazin-1-ylmethyl)-3,4-dihydro-1H-isochromene-6-carbonitrile was directly used in next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]([C:14]#[N:15])[C:7]2=O)([O-:3])=[O:2].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=[CH:9][C:8]=1[C:14]#[N:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c[nH]c2ccc([N+](=O)[O-])cc2c1=O
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl

Procedure:
A mixture of 31.3 g (0.147 mol) of 6-nitro-4-oxo-1,4-dihydro-3-quinolinecarbonitrile and 160 mL of phosphorous oxychloride was refluxed for 5.5 h. The phosphorous oxychloride was removed in vacuo and the residue was poured over ice and neutralized with sodium bicarbonate. The product was collected, washed with water and dried in vacuo (500° C.). There was obtained 33.5 g of tan solid; solid: mass spectrum (electrospray, m/e): M+H 234.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[N+:10]([O-])([OH:12])=[O:11]>ClCCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:1][C:2]1[C:3]([F:9])=[CH:4][C:5]([OH:8])=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(Cl)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: ClCCCl
Product: O=[N+]([O-])c1cc(Cl)c(F)cc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.8 %

Procedure:
4-chloro-3-fluorophenol (2.38 g, 16.2 mmol) was dissolved in DCE (32 mL) and tetrabutylammonium bromide (0.524 g, 1.62 mmol) was added. HNO3 70% (2.1 mL, 32 mmol) was diluted with H2O (18.9 mL) to make a 7% HNO3 solution. This solution was added to the reaction mixture which was then stirred at rt for 4 h at which time the reaction was judged complete by TLC. The reaction was poured into H2O and extracted with DCM (3×). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was adsorbed onto silica gel and flash chromatographed to give the title compound of step A (2.29 g, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.76 (br. s., 1H), 8.18 (d, J=8.1 Hz, 1H), 7.10 (d, J=10.6 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[S:6])[NH2:5].Br[CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11].S([O-])([O-])(=O)=O.[Mg+2]>CC(C)=O>[CH3:1][O:2][CH2:3][C:4]1[S:6][CH:8]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:5]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: COCC(N)=S
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(COC)n1
Temperature: 25 °C
Yield: 56.7 %

Procedure:
A solution containing the product from Example 6B (7 g, 66.6 mmol) in acetone (270 mL) was treated with ethyl bromopyruvate (8.4 mL, 66.6 mmol) and magnesium sulfate (7.9 g, 66.6 mmol), heated at reflux for 16 hours, cooled to 25° C., filtered and concentrated. The residue was chromatographed on silica gel eluting with chloroform to give the title compound (7.6 g, 57% yield).
Reaction SMILES: Br[C:2](Br)=[CH:3][CH2:4][CH:5]([CH3:7])[CH3:6].C([Li])CCC.Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1COCC1>[CH2:18]([O:17][C:15](=[O:16])[C:2]#[C:3][CH2:4][CH:5]([CH3:7])[CH3:6])[CH3:19]
Reactant: CC(C)CC=C(Br)Br
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C#CCC(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
1,1-Dibromo-4-methyl-pent-1-ene 6 (40 g, 165.9 mmol) was dissolved in dry THF (120 mL) and cooled to −78° C. While stirring, n-butyllithium (1.6 M solution in hexane, 190.8 mL, 305 mmol) was added dropwise in a few minutes. After 1 hour, ethyl chloroformate (15 mL, 154.5 mmol) was added, and the reaction was stirred overnight during which it warmed to room temperature. It was poured onto water and extracted with ether (3×250 mL), dried on magnesium sulfate and evaporated. The light oil was flash chromatographed on a silica gel column, and the compound was eluted with 10% ether in pet ether to afford 5-methyl-hex-2-ynoic acid ethyl ester 7 (23.6 g, 92%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24])C(OC(C)(C)C)=O)([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+]>C1(C)C=CC=CC=1.CO>[C:1]([O:5][C:6](=[O:26])[NH:7][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc([N+](=O)[O-])c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.1 %

Procedure:
To a solution of N-(5-methoxy-2-nitrophenyl)-N-t-butoxycarbonylcarbamic acid t-butyl ester (10.6 g) in toluene (5 ml) and methanol (30 ml) was added 24% sodium methoxide in methanol (3.1 ml) and the mixture was stirred at 25° C. for 3 hours. At the end of this time the reaction mixture was cooled to 0° C. and the precipitated crystals were filtered to give the title compound (5.8 g, yield 75%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:11]([OH:12])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([OH:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:21])[CH:8]=2)[O:3]1.[CH:23](O)=[O:24]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[CH:11]([OH:12])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([OH:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:21][CH:23]=[O:24])[CH:8]=2)[O:3]1
Reactant: O=CO
Reactant: CC1(C)Oc2ccc(N)cc2C(Oc2ccnc(O)c2)C1O
Solvent: c1ccncc1
Product: CC1(C)Oc2ccc(NC=O)cc2C(Oc2ccnc(O)c2)C1O

Procedure:
A solution of 1 g of 2,2-dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-amino-3-chromanol in 15 ml of HCOOH and 1 ml of pyridine is boiled for 19 hours and evaporated. After customary working up, 2,2-dimethyl-4 - (2-hydroxy-4-pyridyloxy)-6-formamido-3-chromanol is obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]([CH2:11][CH2:12][CH2:13][C@@H:14]([NH:59]C(OC(C)(C)C)=O)[C:15]([O:17][C@H:18]1[C@@H:22]([OH:23])[C@H:21]([N:24]2[CH:32]=[N:31][C:30]3[C:25]2=[N:26][CH:27]=[N:28][C:29]=3[NH2:33])[O:20][C@H:19]1[CH2:34][O:35][P:36]([O:39][C@H:40]1[CH2:44][C@H:43]([N:45]2[CH:50]=[CH:49][C:48]([NH2:51])=[N:47][C:46]2=[O:52])[O:42][C@@H:41]1[CH2:53][O:54][P:55]([OH:58])([OH:57])=[O:56])([OH:38])=[O:37])=[O:16])=[N+:9]=[N-:10]>ClCCl>[NH2:59][C@H:14]([CH2:13][CH2:12][CH2:11][N:8]=[N+:9]=[N-:10])[C:15]([O:17][C@H:18]1[C@@H:22]([OH:23])[C@H:21]([N:24]2[CH:32]=[N:31][C:30]3[C:25]2=[N:26][CH:27]=[N:28][C:29]=3[NH2:33])[O:20][C@H:19]1[CH2:34][O:35][P:36]([O:39][C@H:40]1[CH2:44][C@H:43]([N:45]2[CH:50]=[CH:49][C:48]([NH2:51])=[N:47][C:46]2=[O:52])[O:42][C@@H:41]1[CH2:53][O:54][P:55]([OH:58])([OH:57])=[O:56])([OH:38])=[O:37])=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCN=[N+]=[N-])C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=NCCC[C@@H](N)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 86.5 %

Procedure:
Trifluoroacetic acid (0.09 mL) was added to a solution of (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-azido-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk71) (24.5 mg, 0.028 mmol) in dichloromethane (1 mL), and the mixture was stirred at room temperature for 25 minutes. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-amino-5-azidopentanoate (Orn(N3)-pdCpA) (Compound tk72) (18.8 mg, 87%).
Reaction SMILES: [C:1]([CH:3]([OH:18])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1)#[N:2].[CH3:19][C:20]1([CH3:35])[C@@H:22](/[CH:23]=[CH:24]\[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C@H:21]1[C:32](O)=[O:33]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:19][C:20]1([CH3:35])[C@@H:22](/[CH:23]=[CH:24]\[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[C@H:21]1[C:32]([O:18][C@H:3]([C:1]#[N:2])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=1)=[O:33]
Reactant: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#CC(O)c1ccc(F)c(Oc2ccccc2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2ccc(F)c(Oc3ccccc3)c2)C1(C)C
Temperature: 20 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
A solution of 30 g of (RS)α-cyano-3-phenoxy-4-fluoro-benzyl alcohol, 300 mg of 4-dimethylamino-pyridine and 50 ml of methylene chloride was added all at once at -5° C. to a solution of 30 g of (1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-tert.-butoxy-1-propenyl]-cyclopropane-carboxylic acid in 100 ml of methylene chloride and the mixture was stirred at 0° C. for 30 minutes and at 20° C. for 3 hours. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 n-hexane-ethyl acetate mixture to obtain 53.9 g of (S)α-cyano-3-phenoxy-4-fluoro-benzyl(1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-tert.-butoxy-1-propenyl]-cyclopropanecarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].O=[C:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]#[N:17].[Cl-].[Ca+2].[Cl-]>>[F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][C:11]1[CH2:15][CH2:14][CH2:13][C:12]=1[C:16]#[N:17]
Reactant: N#CC1CCCC1=O
Reactant: Nc1cc(F)ccc1F
Agent: [Ca+2]
Agent: [Cl-]
Product: N#CC1=C(Nc2cc(F)ccc2F)CCC1

Procedure:
2,5-Difluoro-aniline (2.6 g, 20.0 mmol) (Aldrich Chemicals) cyano-ketone (Example 11) (2.2 g, 20.2 mmol), calcium chloride (2.5 g, 22.5 mmol) and T.H.F. (30 ml) were heated under reflux for 22 hours. After cooling, the mixture was filtered and the solvent evaporated. Kugelrohr distillation (160° C., 0.9 mmHg) gave the produce as white crystals.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10]CC)=O)[C:3](OCC)=[O:4].[CH3:13][NH:14][NH:15][CH3:16].C[O-].[Na+]>CO>[OH:10][C:8]1[N:14]([CH3:13])[N:15]([CH3:16])[C:3](=[O:4])[C:2]=1[CH3:1]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: CNNC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(O)n(C)n(C)c1=O

Procedure:
Diethyl methylmalonate and N,N'-dimethylhydrazine are heated under reflux for 170 hours in methanol in the presence of sodium methylate under an atmosphere of nitrogen. 3-Hydroxy-1,2,4-trimethyl-5-pyrazolone is obtained in the form of colorless crystals which, after recrystallization from ethyl acetate, melt at 87°-89° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]>C1COCC1>[Cl:1][C:2]1[C:7]([CH:21]([C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[Cl:18])[OH:22])=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1
Reactant: CSc1nccc(Cl)n1
Reactant: O=Cc1ccccc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ncc(C(O)c2ccccc2Cl)c(Cl)n1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-chloro-2-(methylthio)pyrimidine (Aldrich) (20 g, 124.51 mmol) in dry THF (300 mL) at −78° C. under argon was slowly added a solution of 2.0 M lithium diisopropyl amide, i.e., LDA, (109 mL, 1.75 eq) in THF via a cannula. After addition was complete, the resulting mixture was stirred at −78° C. for an additional 15 minutes, after which 2-chlorobenzaldehyde (Aldrich) (29.5 mL, 2.1 eq) was added dropwise via syringe. The reaction mixture was stirred for an additional 30 minutes at −78° C. and then quenched with saturated ammonium chloride solution. Ethyl acetate was added, the mixture was allowed to warm to room temperature, and the layers were partitioned and separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine solution. The ethyl acetate layers were combined, dried over magnesium sulfate, filtered and concentrated to give the crude product as an oil. Purification using Flash Column Chromatography on Silica Gel, eluting with a gradient of 5%-20% ethyl acetate in hexanes gave the title compound (10.8 g, (M+H)+=301) as an orange-yellow semi-solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:7][CH2:6]1)=[O:4].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([C:15]2[CH:14]=[CH:13][C:12]([O:17][CH3:18])=[C:11]([CH:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C:2]([F:1])([F:19])[F:20])[CH2:6][CH2:7]3)[CH:16]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COc1ccccc1C1CCN(C(=O)C(F)(F)F)CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(S(=O)(=O)c2ccc(Cl)cc2)cc1C1CCN(C(=O)C(F)(F)F)CC1

Procedure:
To a solution of 2,2,2-trifluoro-1-[4-(2-methoxyphenyl)piperidin-1-yl] ethanone (0.285 g; 1 mmol), prepared as in Example 1 Step 1, and 4-chlorobenzenesulfonyl chloride (0.210 g; 1 mmol) in 1,2-dichloroethane (2 mL) at 0° C. under nitrogen atmosphere was added, in small portions, aluminum chloride (0.134 g; 1 mmol), and the mixture was refluxed for 18 h. After cooling to 0° C. a solution of 2N HCl (2 mL) was added and the mixture was extracted into dichloromethane (20 mL). The organic phase was dried (Na2SO4), concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with hexane-ethyl acetate (7:3, v/v) to give 1-{4-[5-(4-chloro-benzenesulfonyl)2-methoxyphenyl]piperidin-1-yl}2,2,2-trifluoro-ethanone (31) as white solid (0.077 g; 17%).