Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=O)=O.[CH:18]1[C:23]([NH:24][NH2:25])=[CH:22][CH:21]=[C:20]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:19]=1.Cl>C(O)C>[F:1][C:2]([F:17])([F:16])[C:3]1[C:5]2[CH2:14][CH2:13][C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:6]=2[N:24]([C:23]2[CH:18]=[CH:19][C:20]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:21][CH:22]=2)[N:25]=1
Reactant: O=C1c2ccccc2CCC1C(=O)C(F)(F)F
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c3c2-c2ccccc2CC3)cc1
Yield: 71.2 %

Procedure:
A 100 mL one necked round bottomed flask equipped with reflux condenser, nitrogen inlet and provisions for magnetic stirring was charged with 2-trifluoroacetyl-1-tetralone from Step 1 (1.21 g, 5.0 mmol), 4-sulfonamidophenylhydrazine hydrochloride (1.12 g, 5.0 mmol) and 25 mL of absolute ethanol. The solution was warmed to reflux for 15 hours and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water, and with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and isooctane to give 1.40 g, 71% of pure product: mp 257-258° C.; 1H NMR (CDCl3/CD3OD, 4:1) δ 2.7 (m, 2I), 2.9 (m, 2H), 6.6 (m, 1H), 6.9 (m, 1H), 7.1 (m, 1H), 7.16 (m, 1H), 7.53 (m, 2H), 7.92 (m, 2H); 19F NMR (CDCl3) 3-62.5. FAB-MS M+H=394.
Reaction SMILES: [BH4-].[Na+].O[CH:4]([C@H:9]1[C:11]([CH3:13])([CH3:12])[C@H:10]1[C:14]([OH:16])=[O:15])[C:5]([Cl:8])([Cl:7])Cl.Cl>CN(C)C=O.O>[Cl:8][CH:5]([Cl:7])[CH:4]1[CH:9]2[CH:10]([C:11]2([CH3:12])[CH3:13])[C:14](=[O:15])[O:16]1
Reactant: CC1(C)[C@H](C(O)C(Cl)(Cl)Cl)[C@@H]1C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C2C(=O)OC(C(Cl)Cl)C21
Temperature: 80 °C
Yield: 25 %

Procedure:
Sodium borohydride (0.12 mmol) was added to a solution of cis 2-(1-hydroxy-2,2,2-trichloroethyl)-3,3-dimethylcyclopropane carboxylic acid (0.12 mol) in dry dimethylformamide (0.4 ml), and the mixture was heated for 30 minutes at 80° C. An additional amount of 0.12 mmol sodium borohydride was then added and the mixture was heated for a further 15 minutes at 80° C. It was then diluted with water, acidified with concentrated HCl and extracted with deuterochloroform, CDCl3. The extract was washed with water and analysed by NMR, which showed a yield of 25% of the desired product, with 30% of unconverted starting material.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:29])[CH2:15][C@@H:16]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([F:28])[CH:22]=1)[CH2:17][N+:18]([O-])=O)C1C=CC=CC=1>CCOC(C)=O.CCO.[Ni]>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C@H:16]2[CH2:17][NH:18][C:14](=[O:29])[CH2:15]2)=[CH:22][C:23]=1[F:28]
Reactant: O=C(C[C@H](C[N+](=O)[O-])c1ccc(Cl)c(F)c1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Ni]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1C[C@@H](c2ccc(Cl)c(F)c2)CN1
Reaction time: 20 h
Yield: 50.9 %

Procedure:
To a solution of 88 (1.55 g, 3.68 mmol) in EtOAc/EtOH (1:1, 50 mL) was added a Raney Nickel suspension (0.316 g, 3.68 mmol) and the reaction mixture was purged with nitrogen then placed under 40 psi hydrogen for 20 h. A second aliquot of Raney Ni suspension (1 mL) was added and the reaction was placed under hydrogen pressure for another 24 h. A third aliquot of Raney Ni was added (1 mL) and the reaction was placed under hydrogen pressure of 45 psi for 24 h. The reaction was filtered through a plug of CELITE® and the filtrate was concentrated. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (10 to 30% EtOAc) to afford 400 mg (50.8%) of (S)-4-(4-chloro-3-fluorophenyl)pyrrolidin-2-one (90).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C(OC([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25]([NH:27][C@H:28]([C:32](OC)=O)[CH:29]([CH3:31])[CH3:30])=[O:26])[CH2:20][CH2:19]1)=O)(C)(C)C>C1(C)C=CC=CC=1.ClCCl>[CH:29]([C:28]1[NH:27][C:25](=[O:26])[N:24]([CH:21]2[CH2:20][CH2:19][NH:18][CH2:23][CH2:22]2)[CH:32]=1)([CH3:30])[CH3:31]
Reactant: COC(=O)[C@@H](NC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1)C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)c1cn(C2CCNCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diisobutylaluminum hydride (1M, 0.520 mL, 0.520 mmol) was added to a solution of methyl N-{[(1-tert-butoxycarbonylpiperidin-4-yl)amino]carbonyl}valinate (155 mg, 0.434 mmol) in toluene (3 mL) and dichloromethane (3 mL) at −78° C. and stirred for 30 min and then warmed to ambient temperature. After 1 h, the reaction was quenched with 1 N saturated potassium sodium tartrate solution (3 mL) and extracted with dichloromethane (2×). The combined organic extracts were dried over sodium sulfate, filtered, concentrated. The crude material was dissolved in dichloromethane (5 mL) and treated with trifluoroacetic acid (5 mL). After 30 min, the reaction was concentrated to give the title compound. MS 210.1 (M+1)
Reaction SMILES: [Cl:1]NC(=O)CCC(N)=O.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH:22]([C:27]2[CH:44]=[CH:43][C:30]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH:20]=[O:21])=[CH:14][CH:13]=1>C(#N)C>[Cl:1][C:17]1[CH:16]=[C:15]([CH:18]([CH:22]([C:27]2[CH:28]=[CH:29][C:30]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:32])=[CH:43][CH:44]=2)[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH:20]=[O:21])[CH:14]=[CH:13][C:12]=1[O:11][CH3:10]
Reactant: CCCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(CC=O)c1ccc(OC)cc1
Reactant: NC(=O)CCC(=O)NCl
Solvent: CC#N
Product: CCCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(CC=O)c1ccc(OC)c(Cl)c1

Procedure:
N-Chlorosuccinamide (40 mg, mmol) was added to an acetonitrile solution (2 ml) containing enantiopure tert-butyl N-(4-{1-[1-(4-methoxyphenyl)-3-oxopropyl]pentyl}benzoyl)-β-alaninate (20 mg, 0.42 mol), which was prepared following the procedure described in EXAMPLE 1. The solution was then heated in a screw cap tube for 35 minutes at 85° C. The solution was concentrated and the residue purified by PTLC using an EtOAC/hexanes eluent to give a mixture of compounds containing the title compound and the corresponding 3,5-diCl analog (˜30% by NMR). LC1 4.00 min. (M+H) 460, di Cl LC1 4.15 min. (M+H) 494 selected data 1H NMR (400 MHz, CDCl3): δ 9.35 (s, 1H); 7.72 (d, J=8.2 Hz, 2H); 7.23-7.15 (m, 3H); 6.86 (d, J=8.4 Hz, 2H); 3.88 (S, 3H); 3.68 (q, J=5.9 Hz, 2H); 3.29-3.23 (m, 1H); 2.75-2.65 (m, 1H); 2.56-2.50 (m, 2H); 2.39-2.31 (m, 1H); 1.46 (s, 9H); 0.66 (t, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=4)[NH:19][CH:18]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C([O:32]CCOCCO)C>O>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]([NH2:27])=[O:32])[CH:24]=4)[NH:19][CH:18]=3)[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1
Reactant: CCOCCOCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1

Procedure:
A mixture of 35.5 g of 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-5-cyanoindole [m.p. 167°; obtainable from the corresponding 5-formyl compound via the oxime], 27.1 g of NaOH, 520 ml of water and 420 ml of diethylene glycol monoethyl ether is stirred for 3 hours at a bath temperature of 140°. The mixture is cooled and worked up in the customary manner to give 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-5-carboxamide, m.p. 200°-205°.
Reaction SMILES: [F:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12].N1C=CC=CC=1.[CH3:24][O:25][C:26]1[C:27]([O:46][CH3:47])=[C:28]([CH:43]=[CH:44][CH:45]=1)[C:29](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C1C=CN=CC=1.CO>[CH3:24][O:25][C:26]1[C:27]([O:46][CH3:47])=[C:28]([CH:43]=[CH:44][CH:45]=1)[C:29]([O:9][CH2:8][C@H:5]1[O:4][C@@H:3]([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[C@H:2]([F:1])[C@@H:6]1[OH:7])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COc1cccc(C(Cl)(c2ccccc2)c2ccccc2)c1OC
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CO
Product: COc1cccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](F)[C@@H]2O)(c2ccccc2)c2ccccc2)c1OC
Reaction time: 3 h

Procedure:
0.5 g (about 2 mmol) of 2′-fluoro-2′-deoxyuridine is coevaporated with 10 ml of abs. pyridine twice in a 50 ml Schlenk flask. The dried nucleoside is taken up in 25 ml of abs. pyridine and, at room temperature, 0.66 g (about 2.2 mmol) of dimethoxytrityl chloride and 10 mg of 4-dimethylaminopyridine are added. After three hours, 1 ml of methanol was added to the mixture, which was then evaporated to dryness in vacuo. The remaining oil is taken up in 50 ml of methylene chloride (deacidified over aluminum oxide) and extracted three times with 50 ml of water. The organic phase is dried over sodium sulfate. After the methylene chloride had been stripped off, the crude product remained as a solid foam. To remove more highly tritylated components and the tritanol, the crude product was digested with 30 ml of abs. benzene at 40-50° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:25]=[O:26])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[BH4-].[Na+].C(O)(=O)C>CO>[CH3:1][C:2]1[NH:3][C:4]([CH2:25][OH:26])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C=O)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C1=C(C)NC(CO)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Yield: 21.3 %

Procedure:
A solution of dimethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (3.60 g) in methanol (72 ml) was cooled at 0° C., and sodium borohydride (0.2271 g) was added bit by bit thereto under cooling with stirring. The mixture was stirred at the same temperature for 15 minutes. The reaction mixture was adjusted to about pH 6 with 50% acetic acid and the methanol was distilled off under reduced pressure below 30° C. The residual solution was diluted with water (100 ml) and extracted with ethyl acetate. The extract was washed with water, an aqueous sodium bicarbonate solution and water in turn, dried over magnesium sulfate and then evaporated to dryness. The residual oil (3.70 g) was crystallized by triturating with diisopropyl ether to give crude crystals (2.74 g), which were recrystallized in first from methanol (8 ml) and then from ethyl acetate (10 ml) to give pure crystals of dimethyl 2-methyl-4-(2-nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (770 mg), mp 164.5 to 165° C. The whole mother liquor of above recrystallizations were combined together and concentrated. The crystalline residue was collected by filtration and washed with methanol (5 ml) to give additional crystals (1.72 g), which were recrystallized from ethyl acetate to give additional pure specimen of the same product obtained above, (840 mg) m.p. 164.5° to 165° C. Total yield, 1.61 g.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH3:26])[N:16]=[C:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[CH2:19]([C:17]1[CH:18]=[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:15]([CH3:26])[N:16]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cn1nc(Cc2ccccc2)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(Cc2ccccc2)cc1C1CCNCC1
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
4-(5-Benzyl-2-methyl-2H-pyrazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.032 g) was dissolved in a 25% v/v solution of trifluoroacetic acid in DCM (7 mL) and stirred for 30 minutes. The solvents were then evaporated under reduced pressure to give a clear oil which was purified by column chromatography on SCX-2 stationary phase using a gradient of DCM up to 50% 7N NH3 in MeOH in DCM as eluent. Evaporation of solvent under reduced pressure gave the title compound as a clear oil (0.018 g); NMR(CDCl3): 1.50-1.60 (qd, 2H), 1.85 (br d, 2H), 2.64 (tt, 1H), 2.66-2.76 (qd, 2H), 3.17 (br d, 2H), 3.76 (s, 3H), 3.91 (s, 2H), 5.76 (s, 1H), 7.16-7.20 (m, 1H), 7.24-7.30 (m 4H); MS: 256 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:36]1([S:42][CH2:43]Cl)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C=O)C.ClCCl>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[N:12]([CH2:43][S:42][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CN3CCOCC3)cc2c1O
Reactant: ClCSc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CSc2ccccc2)c2ccc(CN3CCOCC3)cc2c1=O
Temperature: 75 °C

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (0.21 gm) from Preparation No. 40 in DMF (4 mL) is treated with cesium carbonate (0.30 gm) and chloromethyl phenyl sulfide (0.08 mL). The mixture is tightly capped and heated to 75° C. for 8 hrs. The reaction mixture is allowed to cool to room temperature, diluted with dichloromethane (50 mL) and washed with water (2×10 mL), brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purified by flash column chromatography eluting with 2% to 4% methanol in dichloromethane and then by recrystallization from ethyl acetate-hexanes to afford 0.19 gm of the title compound as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][S:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C.C(=O)([O-])[O-].[K+].[K+].Cl>CO.O>[CH2:17]([N:8]1[C:9](=[O:16])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]1[S:6][CH2:5][C:4]([OH:24])=[O:3])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CSC1c2ccccc2C(=O)N1Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)CSC1c2ccccc2C(=O)N1Cc1ccccc1
Yield: 41.7 %

Procedure:
To a solution of compound 17 (8 gm, 24.5 mmol) in methanol (64 mL) and water (16 mL) at room temperature was added potassium carbonate (5.7 gm, 41.6 mmol) and the resulting reaction mixture was allowed to stir at reflux for 3 hours. The reaction mixture was poured onto 1N HCl and extracted with dichloromethane (3×100 mL). The combined dichloromethane extracts were filtered and the filterate dried over anhydrous sodium sulfate and concentrated in vacuo to provide 3.2 gm of 18 as a pale pink solid (7.8 gm, 41% yield).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28]([NH2:30])=[O:29])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21])C1C=CC=CC=1>C(O)C.O.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28]([NH2:30])=[O:29])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21]
Reactant: NC(=O)c1cccc(C=Cc2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: NC(=O)c1cccc(CCc2ccc(N3CC(=O)NS3(=O)=O)c(O)c2)c1

Procedure:
To a solution of 3-{2-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-vinyl}-benzamide in ethanol (2 mL) is added two equivalents of KHCO3. The mixture is diluted with 5 mL water and hydrogenated at 1 atm over 50 mg of 10% Pd/C for 18 h. The catalyst is filtered and the filtrate lyophilized. The resulting solid is purified by HPLC to give the title compound as an amorphous powder: m/z (M−1)−=374; 1H NMR (DMSO-d6) δ 7.95 (m, 1H), 7.81 (s, 1H), 7.72 (m, 1H), 7.35 (m, 4H), 6.75 (d, J=1.5 Hz 1H), 6.70 (m, 1H), 4.04 (s, 2H), 2.86 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([CH:24]=[CH2:25])[C:4]=1[CH3:26])#[N:2].Cl.[NH2:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[OH:35].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl>ClCCl.C(N(CC)CC)C>[C:1]([C:3]1[C:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:17][CH:18]=2)=[CH:10][C:6]([C:7]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[OH:35])=[O:9])=[C:5]([CH:24]=[CH2:25])[C:4]=1[CH3:26])#[N:2]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: C=Cc1c(C(=O)O)cc(Cc2ccc(-n3cccn3)cc2)c(C#N)c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1c(C(=O)N[C@@H]2CCCC[C@H]2O)cc(Cc2ccc(-n3cccn3)cc2)c(C#N)c1C
Reaction time: 16 h
Yield: 77.9 %

Procedure:
To a solution of 4-cyano-2-ethenyl-3-methyl-5-[4-(1H-pyrazol-1-yl)benzyl]benzoic acid (0.10 g), trans-2-aminocyclohexanol hydrochloride (0.06 g), 1-hydroxybenzotriazole (0.06 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.08 g) in dichloromethane (5.00 mL) was added triethylamine (0.11 g), and the mixture was stirred for 16 hr. The reaction mixture was poured into 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated aqueous sodium bicarbonate solution, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.10 g).
Reaction SMILES: CCN(CC)CC.[OH:8][C@@H:9]([CH3:28])[C@@H:10]([NH:14][C:15]([O:17][C:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2)=[O:16])[C:11]([OH:13])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:28][C@H:9]1[C@@H:10]([NH:14][C:15](=[O:16])[O:17][C:18]23[CH2:27][CH:22]4[CH2:21][CH:20]([CH2:26][CH:24]([CH2:23]4)[CH2:25]2)[CH2:19]3)[C:11](=[O:13])[O:8]1
Reactant: C[C@H](O)[C@@H](NC(=O)OC12CC3CC(CC(C3)C1)C2)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1OC(=O)[C@@H]1NC(=O)OC12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 3 h
Yield: 28.7 %

Procedure:
In a two necked round bottom flask, Et3N (0.34 ml, 2.42 mmol) was added to a solution of (2R,3S)-3-hydroxy-2-{[(tricyclo[3.3.1.13,7]dec-1-yloxy)carbonyl]amino}butanoic acid (0.240 g, 0.81 mmol) in dry CH2Cl2 (12 mL) under argon. After cooling at 0° C., HBTU (0.459 g, 1.21 mmol) was added and the mixture stirred 3 h at 0° C., then 16 h at rt. The obtained solid was filtered-off and the solvent removed under vacuum. The crude mixture was purified by typical silica gel column chromatography, eluting with Cy/AcOEt (90:10). The resulting white solid (0.093 g) was further triturated with cyclohexane to afford the pure title compound (0.065 g, 29%) as white solid. MS (ESI) m/z: 278.31 [M−H]−. Rf=0.19 (Cy/AcOEt 9:1, detection: ninhydrin). FTIR (cm−1): 3338, 2912, 2854, 1828, 1688, 1533, 1457, 1342, 1253, 1120, 1069, 1020, 970, 886, 820. 1H-NMR (CDCl3): δ 1.46 (d, 3H); 1.66 (m, 6H); 2.09 (m, 4H); 2.18 (m, 5H); 4.84 (m, 1H); 5.14 (d, 1H); 5.40 (t, 1H).
Reaction SMILES: [CH:1]1[N:5]([CH2:6][O:7][CH2:8][CH2:9][OH:10])[C:4]2[N:11]=[C:12]([NH2:16])[N:13]=[C:14]([OH:15])[C:3]=2[N:2]=1.[H-].[Na+].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=O.N>CN(C=O)C>[OH:10][CH2:9][CH2:8][O:7][CH2:6][N:5]1[C:4]2[N:11]=[C:12]3[N:13]([CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[NH:16]3)[C:14](=[O:15])[C:3]=2[N:2]=[CH:1]1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: Nc1nc(O)c2ncn(COCCO)c2n1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2ncn(COCCO)c2nc2[nH]c(-c3ccc(Cl)cc3)cn12
Reaction time: 5 h
Yield: 72 %

Procedure:
A solution of 1.4 g (6.22 mmol) acyclovir, 30 mL DMF, and 400 mg sodium hydride (80%) was stirred at room temperature for 30 min, then 0.7 mL 2-bromo-4′-chloroacetophenone was added dropwise into the solution. Changing to orange color, the solution was added 17 mL ammonia, and continuously stirred for 5 hr. The solvent was removed to obtain a residue, which was washed with water. The product, 3-(2-hydroxy-ethoxymethyl)-6-(4-chlorophenyl)-3,5-dihydro-1,3,4,5,7a-pentaaza-s-indacen-8-one, was produced and weighted 1.62 g (white solid, yield 72%).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([O:31]C)[O:11][C@@H:10]1[CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[CH2:24]([O:23][C@H:13]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@@H:10]([CH2:33][O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[O:11][CH:12]1[OH:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Product: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 80 °C
Yield: 54.9 %

Procedure:
To a solution of (2R,3R,4S,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-methoxytetrahydro-2H-pyran (28.0 g, 50.5 mmol, 1.0 equiv) in acetic acid (480 mL), was added 3M H2SO4 (120 mL, aqueous) at 0° C. The reaction was heated at 80° C. for 10 hours, cooled to room temperature, and then neutralized with saturated aqueous potassium carbonate solution. The mixture was then extracted with DCM (3×1000 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material thus obtained was purified by silica gel chromatography, eluting with 30% EtOAc in petroleum ether, to give (3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-ol as a pale yellow oil (15.0 g, 54%). 1H NMR (300 MHz, DMSO-d6) δ 7.38-7.17 (m, 20H), 6.61 (d, J=4.4 Hz, 1H), 5.14-5.07 (m, 1H), 4.77 (t, J=8.5 Hz, 3H), 4.71-4.38 (m, 6H), 3.80 (dp, J=22.8, 9.1, 8.3 Hz, 3H), 3.68-3.53 (m, 2H). ESI (M+H2O) 558.2; calc for C34H36O6 540.3.