Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH2:30])(=[O:29])=[O:28])=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH:30][C:34](=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:29])=[O:28])=[O:19])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1S(=O)(=O)NC(=O)c1ccccc1)c1cccc(OCc2ccccc2)c1
Reaction time: 1 h
Yield: 65.1 %

Procedure:
In a stream of nitrogen and under ice-cooling, 88 mg (0.78 mmol) of potassium t-butoxide was added to an anhydrous tetrahydrofuran (10 ml) solution containing 300 mg (0.78 mmol) of 2-(3-benzyloxybenzamido)benzenesulfonamide produced in Reference Example 1, and the mixture was stirred for 1 hour. This solution was mixed with 111 mg (0.78 mmol) of benzoyl chloride and stirred at room temperature for 3 hours. After completion of the reaction, this was neutralized by adding an ammonium chloride aqueous solution and then the solvent was evaporated. The resulting residue was extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 247 mg (yield: 65%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[CH:22][O:23][CH:24]=2)=[CH:16][CH:15]=1)C1C=CC=CC=1.C1CC=CCC=1>CO.[Pd]>[O:23]1[CH:24]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][NH2:10])=[CH:15][CH:16]=2)[N:21]=[CH:22]1
Reactant: O=C(NCCOc1ccc(-c2cocn2)cc1)OCc1ccccc1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CO
Product: NCCOc1ccc(-c2cocn2)cc1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A stirred mixture of 234.0 g (0.692 mol) of [2-(4-oxazol-4-yl-phenoxy)-ethyl]-carbamic acid benzyl ester, 295.1 ml (3.097 mol) of 1,4-cyclohexadiene, and 93.60 g of 10% Pd/C (50% water wet) in 5.6 l of methanol was stirred at room temperature for about twenty-two hours. The mixture was filtered through a pad of diatomaceous earth (13×3 cm), and the filter cake was then washed with 12 l of 100:1 v/v methanol/triethylamine. The filtrate was evaporated in vacuo, and to the residual solid was added 250 ml of toluene. The mixture was stirred at room temperature for about thirty minutes, 2.5 l of hexanes was then added over a period of about five to ten minutes, and the resulting slurry was then stirred for about one hour. The mixture was filtered, and the filter cake was then washed with a mixture of 1:10 toluene/hexanes (3×100 ml), and the solid was dried under vacuum at about 50° C. for about eighteen hours. The title compound (115 g, 81.5% yield) was obtained as a white powder.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:34])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](=[O:33])[C:19]([C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=4)=[CH:20][O:21]3)=[CH:16][CH:15]=2)[CH:7]=1)[CH:2]=[CH2:3].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1.O>[NH2:30][C:27]1[CH:26]=[CH:25][C:24]([C:19]2[C:18](=[O:33])[C:17]3[C:22](=[CH:23][C:14]([O:13][CH2:12][C:8]4[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=4)[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:34])=[CH:15][CH:16]=3)[O:21][CH:20]=2)=[CH:29][CH:28]=1
Reactant: C=CCOC(=O)c1cccc(COc2ccc3c(=O)c(-c4ccc([N+](=O)[O-])cc4)coc3c2)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)c1cccc(COc2ccc3c(=O)c(-c4ccc(N)cc4)coc3c2)c1
Temperature: 62.5 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
A suspension of 3-[3-(4-nitrophenyl)-4-oxo-4H-chromen-7-yloxymethyl]benzoic acid allyl ester (164.6 mg, 0.36 mmol), prepared as described in Example 5d, and sodium dithionite (188 mg, 1.08 mmol) in tetrahydrofuran (8 ml) and water (4 ml) was heated at 60-65° C. for 1 hour. Additional sodium dithionite (1.13 g, 6.48 mmol) was added in 5 portions over 2 hours. The reaction mixture was stirred at 60-65° C. overnight. 1H NMR of the reaction mixture showed that the product was obtained without starting material. The reaction mixture was mixed with silica gel (2 g), solvent removed under reduced pressure, and the mixture applied to a column. The silica gel mixture was purified by flash chromatography, eluting with methylene chloride/methanol (98/2) to give prop-2-enyl 3-{[3-(4-aminophenyl)-4-oxochromen-7-yloxy]methyl}benzoate as a yellow solid (99.6 mg, 65%); (ESI) m/z 428 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.ClCCl>[Pt].CO>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNc1c(N)cnc2ccccc12
Reaction time: 8 h
Yield: 86 %

Procedure:
A solution of tert-butyl 2-[(3-nitroquinolin-4-yl)amino]ethylcarbamate (20.0 g, 60.2 mmol) in a 2:1 mixture of dichloromethane:methanol (500 mL) was added to a Parr vessel. The system was purged with nitrogen, and 5% platinum on carbon (7.04 g, 36.1 mmol) was added. The vessel was placed under hydrogen pressure (50 psi, 3.4×105 Pa) and shaken overnight. The reaction mixture was filtered and concentrated under reduced pressure to provide 15.65 g of tert-butyl 2-[(3-aminoquinolin-4-yl)amino]ethylcarbamate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]1[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCOCC>[O:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=[C:11]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: BrCCCCCCOCCc1nc2ccccc2o1
Solvent: CCOCC
Product: c1ccc(CNCCCCCCOCCc2nc3ccccc3o2)cc1

Procedure:
A solution of 2-[2-[(6-bromohexyl)oxy]ethyl]benzoxazole (1.55 g) in benzylamine (6 ml) was heated at 125° for 2 h under nitrogen, cooled, diluted with ether (100 ml) and the ether suspension washed with 8% sodium bicarbonate solution (25 ml). The organic phase was dried and evaporated in vacuo. Benzylamine was removed by bulb to bulb distillation (b.p. 130°/25 mm) to leave a product which was purified by chromatography over silica (Merck 60) eluting with System B (89:10:1) to afford the title compound as a red oil (250 mg), t.l.c. (System A 39:10:1) Rf 0.55.
Reaction SMILES: S(O[CH2:12][CH2:13][CH:14]1[O:19][C:18]2[CH:20]=[C:21]([Cl:25])[C:22]([Cl:24])=[CH:23][C:17]=2[O:16][CH2:15]1)(C1C=CC(C)=CC=1)(=O)=O.[NH:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:36][CH2:35][NH:34][C:33]2=[O:37])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[Cl:24][C:22]1[C:21]([Cl:25])=[CH:20][C:18]2[O:19][CH:14]([CH2:13][CH2:12][N:26]3[CH2:27][CH2:28][CH:29]([N:32]4[CH2:36][CH2:35][NH:34][C:33]4=[O:37])[CH2:30][CH2:31]3)[CH2:15][O:16][C:17]=2[CH:23]=1
Reactant: O=C1NCCN1C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3cc(Cl)c(Cl)cc3O2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=C1NCCN1C1CCN(CCC2COc3cc(Cl)c(Cl)cc3O2)CC1

Procedure:
The mixture of 4.0 g of 2-(2-tosyloxyethyl)-6,7-dichloro-1,4-benzodioxan, 1.69 g of 1-(4-piperidyl)-2-imidazolidinone, 10 g of ahydrous sodium carbonate and 100 ml of 4-methyl-2-pentanone is stirred and refluxed for 2 days. It is filtered, evaporated and the residue recrystallized from acetone, to yield the 1-[1-[2-(6,7-dichloro-1,4-benzodioxan-2-yl)-ethyl]-4-piperidyl]-2-imidazolidinone melting at 165°.
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]([NH:5][CH2:6][CH2:7][NH:8][C:9]([C:11]1[N:16]=[C:15]([CH2:17][N:18]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[CH:14]=[C:13]([C:41]2[C:46]([O:47][CH3:48])=[CH:45][C:44]([O:49][CH3:50])=[CH:43][C:42]=2[O:51][CH3:52])[CH:12]=1)=[O:10])=[O:4]>FC(F)(F)C(O)=O>[N:18]1([CH2:17][C:15]2[N:16]=[C:11]([C:9]([NH:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:53])([F:1])[F:54])=[O:10])[CH:12]=[C:13]([C:41]3[C:42]([O:51][CH3:52])=[CH:43][C:44]([O:49][CH3:50])=[CH:45][C:46]=3[O:47][CH3:48])[CH:14]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: COc1cc(OC)c(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)CC3)nc(C(=O)NCCNC(=O)C(F)(F)F)c2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(-c2cc(CN3CCNCCNCC3)nc(C(=O)NCCNC(=O)C(F)(F)F)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 17 (1.0 g; 1.3 mmol) was dissolved in trifluoroacetic acid (25 mL) and the mixture was stirred at room temperature for 30 min. Solvent was evaporated to dryness. ESI-MS: [M+H]+ 569.28 calc. for C26H36F3N6O5+ 569.27
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:26])[C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([CH:17]=1)[CH2:7][N:8](C)[C:9](=O)OC(C)(C)C.[ClH:27]>ClCCl>[ClH:27].[CH2:19]([O:18][C:5]1[C:6]([CH2:7][NH:8][CH3:9])=[CH:17][C:2]([NH2:1])=[CH:3][C:4]=1[F:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CN(Cc1cc(N)cc(F)c1OCc1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: CNCc1cc(N)cc(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
17F (2.566 g, 7.12 mmol) was dissolved in dichloromethane (40 mL), then HCl (4M in dioxane) (10 mL, 40.0 mmol) was added. The reaction mixture was stirred for 1 h at rt. The solvent was removed under reduced pressure, and the residue was dried under high vacuum to give 17G (2.265 g, 6.80 mmol, 95% yield) as an off-white solid. MS (ESI) m/z: 261.1 [M+1]+. 1H NMR: (400 MHz, CD3OD) δ ppm 7.30-7.53 (7H, m), 5.33 (2H, s), 4.07 (2H, s), 2.65 (3H, s).
Reaction SMILES: C([N:3](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[Cl:25][C:26]1[N:31]=[C:30](C(O)=O)[C:29]2[C:35]([O:57][CH3:58])=[N:36][N:37]([C:38]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:28]=2[CH:27]=1>O1CCOCC1.O>[Cl:25][C:26]1[N:31]=[C:30]([NH2:3])[C:29]2[C:35]([O:57][CH3:58])=[N:36][N:37]([C:38]([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:28]=2[CH:27]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(=O)O)c12
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(N)c12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Triethylamine (370 μl, 2.66 mmol) followed by diphenylphosphoryl azide (447 μl, 2.068 mmol) were added to 6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carboxylic acid (36B, 790 mg, 1.681 mmol) in 1,4-dioxane (16.5 ml) a 100 ml roundbottom flask attached to a reflux condenser. The mixture was allowed to stir at 100° C. overnight. Room temperature was attained and the reaction mixture was diluted with water and extracted into EtOAc. The organic layer was washed with NaHCO3, brine, dried over NaSO4, and concentrated in vacuo. The material was loaded onto silica gel and purified by MPLC 0-25% EtOAc/hexanes gave 6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-amine MS: [M+H]+ m/z 441.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:11]2[C@@H:6]([S:7][C@@H:8]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9][CH2:10]2)[CH2:5][C@H:4]1[O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1.C(N(C(C)C)CC)(C)C.N1C=CC=CC=1.S(=O)(=O)=O.O>C(OCC)(=O)C.CS(C)=O>[CH:2]([C@@H:3]1[C@@H:11]2[C@@H:6]([S:7][C@@H:8]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9][CH2:10]2)[CH2:5][C@H:4]1[O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)=[O:1]
Reactant: COC(=O)CCC[C@H]1CC[C@@H]2[C@@H](CO)[C@H](OC3CCCCO3)C[C@@H]2S1
Agent: O=S(=O)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: COC(=O)CCC[C@H]1CC[C@@H]2[C@@H](C=O)[C@H](OC3CCCCO3)C[C@@H]2S1
Reaction time: 0.17 h
Yield: 100.5 %

Procedure:
The compound 10 (200 mg) was dissolved in ethyl acetate (1.7 mL) and dimethyl sulfoxide (0.84 mL), diisopropylethylamine (0.39 mL) was added, and the mixture was cooled in an ice bath. Sulfur trioxide-pyridine (256 mg) was added, and the mixture was stirred for 10 minutes, then poured into water, and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline, dried with anhydrous magnesium sulfate, and then concentrated to obtain a titled compound (200 mg) having the following physical property values.
Reaction SMILES: FC1C=CC(S(N(S(C2C=CC(N3CC[C@@H](O)C3=O)=CC=2)(=O)=O)C2SC=CN=2)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[Cl:57][C:58]1[CH:59]=[C:60]([CH:65]2[O:70][CH2:69][CH2:68][NH:67][CH2:66]2)[CH:61]=[C:62]([Cl:64])[CH:63]=1>C(Cl)Cl>[Cl:64][C:62]1[CH:61]=[C:60]([C@@H:65]2[O:70][CH2:69][CH2:68][NH:67][CH2:66]2)[CH:59]=[C:58]([Cl:57])[CH:63]=1
Reactant: Clc1cc(Cl)cc(C2CNCCO2)c1
Agent: O=C1[C@H](O)CCN1c1ccc(S(=O)(=O)N(c2nccs2)S(=O)(=O)c2ccc(F)cc2)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(Cl)cc([C@H]2CNCCO2)c1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Synthesized according to General procedure 31, Method A. A stirring suspension of ((R)-4-fluoro-N-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)phenylsulfonyl)-N-(thiazol-2-yl)benzenesulfonamide (1.07 g, 2.15 mmol), N,N-diisopropylethylamine (1.15 mL, 6.50 mmol), and CH2Cl2 (10.0 mL), under N2, was cooled to −20° C. Triflic anhydride (545 μL, 3.25 mmol) was added dropwise over 10 minutes. The suspension was stirred at −20° C. for 1 hour. A solution of (S)-2-(3,5-dichlorophenyl)morpholine (500 mg, 2.15 mmol) [this enantiomer of 2-(3,5-dichlorophenyl)morpholine was obtained by preparative SFC separation of its racemic mixture: Chiralpak AD-H column (2×15 cm), 50% ethanol (0.1% DEA)/CO2, 50 mL/min)] and CH2Cl2 (2.0 mL) was added dropwise over 5 minutes. The mixture was stirred at −20° C. for 1.5 hours. Morpholine (375 μL, 4.30 mmol) was added dropwise over 5 minutes. The mixture was stirred at −20° C. for 2 hours. The solution was allowed to warm to room temperature and concentrated to dryness under reduced pressure. The residue was purified via silica gel chromatography using 2% MeOH in CH2Cl2 to obtain the desired lactam as a white solid (814 mg, 1.48 mmol, 69% yield). 1H-NMR (400 MHz, DMSO) δ 7.85-7.78 (m, 4H), 7.54 (t, J=1.9 Hz, 1H), 7.42 (d, J=1.8 Hz, 2H), 7.25 (d, J=4.6 Hz, 1H), 6.82 (d, J=4.6 Hz, 1H), 4.53 (dd, J=1.9, 9.9 Hz, 1H), 3.97 (d, J=9.9 Hz, 1H), 3.80-3.65 (m, 4H), 3.01-2.89 (m, 2H), 2.70-2.65 (m, 1H), 2.51-2.45 (m, 1H), 2.27-2.22 (m, 1H), 2.12-2.07 (m, 1H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=553.3; tR=1.44 min. SFC (Chiralpak AS-H, (0.46×25 cm), 55% methanol (1% DEA)/CO2, 3 mL/min): tR=6.8 min.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8](C(Cl)(Cl)Cl)[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1.[F:22][CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[F:22][CH2:23][CH2:24][O:25][C:8]1[N:7]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=2)[C:6]2[CH:21]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=2[N:9]=1
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(I)cc32)n1
Reactant: OCCF
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1nccc(-n2c(OCCF)nc3ccc(I)cc32)n1
Yield: 17.1 %

Procedure:
A solution of 4-[6-iodo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (1 g, 2.20 mmol), 2-fluoroethan-1-ol (900 mg, 14.05 mmol) and cesium carbonate (4.3 g, 13.20 mmol) in N,N-dimethylformamide (10 mL) was stirred for 14 hr at room temperature. The reaction mixture was diluted with 50 mL of ethyl acetate then washed with 5×10 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column (ethyl acetate/petroleum ether, 10:1) to afford 150 mg (17%) of 4-[2-(2-fluoroethoxy)-6-iodo-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine as brown oil: LC-MS: m/z=400 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[C@:15]([CH3:17])([OH:16])[C@H:14]([OH:18])[C@@H:13]([CH2:19][OH:20])[O:12]2)=[C:4]([O:21][CH3:22])[N:3]=1.C([Mg]Cl)(C)(C)C.Cl[C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]=1[O:40][P:41](=[N:43][C@@H:44]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:45]([O:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1)=[O:46])=[O:42]>C1COCC1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[O:12][C@H:13]([CH2:19][O:20][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:31]=3[O:40][P:41](=[N:43][C@@H:44]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:45]([O:47][CH:48]3[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]3)=[O:46])=[O:42])[C@@H:14]([OH:18])[C@:15]2([OH:16])[CH3:17])=[C:4]([O:21][CH3:22])[N:3]=1
Reactant: COc1nc(N)nc2c1ncn2C1O[C@H](CO)[C@@H](O)[C@@]1(C)O
Reactant: O=C(OC1CCCCC1)[C@@H](N=[P+]([O-])Oc1c(Cl)ccc2ccccc12)c1ccccc1
Agent: CC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1nc(N)nc2c1ncn2C1O[C@H](COc2ccc3ccccc3c2O[P+]([O-])=N[C@H](C(=O)OC2CCCCC2)c2ccccc2)[C@@H](O)[C@@]1(C)O
Yield: 52.8 %

Procedure:
Using the general procedure (Method B) for the synthesis of nucleoside 5′-phosphoramidates to a solution of 250 mg of (3R,4R,5R)-2-(2-amino-6-methoxy-9H-purin-9-yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol in 5 mL of THF was added tert-BuMgCl (1.61 mL) followed by (2S)-cyclohexyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)-2-phenylacetate (1.10 g) in THF (5 mL). After workup and silica gel column chromatography, 310 mg of (2S)-cyclohexyl 2-((((2R,3R,4R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)-2-phenylacetate was obtained (53% yield). HPLC tR=21.47, 21.65 min (column: Varian Pursuit XRs 5, C18, 150×4.6 mm; method: linear gradient of ACN (10% to 100%) in H2O in 30 min).
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][CH:13]([C:17]1([CH:22]([CH2:24][CH2:25][CH3:26])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18]1)[CH2:14][CH2:15][CH3:16].S(C1C=CC(C)=CC=1)(O[CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])(=O)=O>O1CCCC1.O>[CH3:34][N:33]([CH2:32][CH2:31][C:18]1[C:17]([CH:13]([CH2:14][CH2:15][CH3:16])[CH3:12])([CH:22]([CH2:24][CH2:25][CH3:26])[CH3:23])[CH:21]=[CH:20][CH:19]=1)[CH3:35]
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)C)cc1
Reactant: CCCC(C)C1(C(C)CCC)C=CC=C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC(C)C1(C(C)CCC)C=CC=C1CCN(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under a nitrogen atmosphere, a solution of n-butyllithium in hexane (24.0 ml; 1.6 mol/L; 38 mmol) was added dropwise to a cooled (0° C.) solution of di-(2-pentyl)cyclopentadiene (7.82 g; 38.0 mmol) in dry tetrahydrofuran (125 ml) in a 250 mL three-necked round-bottomed flask provided with a magnetic stirrer and a dropping funnel. After 24 hours of stirring at room temperature, 2-dimethylaminoethyl tosylate (38.0 mmol) prepared in situ was added. After 18 hours of stirring, the conversion was found to be 92%, and water (100 ml) was carefully added dropwise to the reaction mixture and the tetrahydrofuran was then distilled off. The crude product was extracted with ether, and the combined organic phase was then dried with sodium sulphate, and evaporated to dryness. The residue was purified on a silica gel column, which resulted in 8.2 g of (dimethylaminoethyl)-di(2-pentyl)cyclopentadiene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.O[CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:30]4[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]4)=[CH:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: CCN1CCC(O)CC1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCN1CCC(Oc2ccc(C(=O)c3c(-c4ccc(OC)cc4)sc4cc(OC)ccc34)cc2)CC1
Yield: 55 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)benzo[b]thiophene (1.17 g, 3.00 mmol), 4-hydroxy-1-ethylpiperidine (775 mg, 6.00 mmol), triphenylphosphine (1.57 g, 6.00 mmol), and DEAD (6.00 mmol) were converted to product by the procedure of Example 1 to give 827 mg of the title compound. Yield: 55%. MS(FD) 501(M+). EA calculated for C30H31NO4S: C, 71.83; H, 6.23; N, 2.79. Found: C, 71.61; H, 5.94; N, 2.69.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[C:10]([O:19][CH2:20][C:21]2[CH:22]=[N:23][C:24]([O:27][CH2:28][C:29]3[N:30]=[C:31]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[O:32][C:33]=3[CH3:34])=[CH:25][CH:26]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[C:10]([O:19][CH2:20][C:21]2[CH:22]=[N:23][C:24]([O:27][CH2:28][C:29]3[N:30]=[C:31]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[O:32][C:33]=3[CH3:34])=[CH:25][CH:26]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2CC(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
A mixture of ethyl [1-benzyl-3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]acetate (648 mg), 1 N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (3 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [1-benzyl-3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]acetic acid (539 mg, yield 88%), which was then recrystallized from ethyl acetate-hexane. melting point: 87–88° C.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:20])[C:7]([C:18]#[N:19])=[C:8]([CH3:17])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)CCC.C(OC(=O)C(C#N)=C(C1C=CC=CC=1)C1C=CC=CC=1)C.C(OC(=O)C(C#N)=C(C1C=CC=CC=1)C1C=CC=CC=1)CCCCC(C)C>>[CH3:1][O:5][C:6](=[O:20])[C:7]([C:18]#[N:19])=[C:8]([CH3:17])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1
Reactant: CCCCOC(=O)C(C#N)=C(C)c1ccc(OC)cc1
Agent: CC(C)CCCCCOC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Agent: CCOC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Product: COC(=O)C(C#N)=C(C)c1ccc(OC)cc1

Procedure:
a-cyano-β-methyl-4-methoxy cinnamic acid butyl ester; a-cyano-β-phenyl cinnamic acid ethyl ester; a-cyano-β-phenyl cinnamic acid isooctyl ester; and the like.