Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[C:22]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].C([O-])([O-])=O.[K+].[K+]>>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:27][CH:28]=2)=[CH:8][CH:7]=1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)[C@H](Cc1ccc(OCc2ccc(C(C)(C)C)cc2)cc1)NC(=O)OC(C)(C)C
Yield: 46.9 %

Procedure:
(S)-2-Tert-butoxycarbonylamino-3-[4-(4-tert-butyl-benzyloxy)-phenyl]-propionic acid methyl ester (290 mg) was prepared from (S)-2-tert-butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionic acid methyl ester (425 mg, 1.4 mmol) and 4-tert-butylbenzyl bromide (1.6 mmol) with K2CO3 (398 mg, 2.9 mmol) as described in Procedure H and purified over silica gel (8:2, DCM-hexanes).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[O:9])=[CH:4][CH:3]=1.[N-:21]=[N+:22]=[N-:23].[Na+].C(OCC)(=O)C>CS(C)=O>[N:21]([C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[O:9])=[CH:4][CH:3]=1)=[N+:22]=[N-:23]
Reactant: O=C(NCCc1ccc(Cl)cc1Cl)c1ccc(Cl)nc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1ccc(C(=O)NCCc2ccc(Cl)cc2Cl)cn1
Temperature: 100 °C

Procedure:
6-Chloro-N-[2-(2,4-dichlorophenyl)ethyl]pyridine-3-carboxamide (1 equivalent) and sodium azide (2.6 equivalents) were suspended in anhydrous DMSO (0.6 M) under nitrogen. The mixture was heated at 100° C. for four days. Ethyl acetate was added and the organic phase washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness and the resultant residue dissolved in a 1:1 ethyl acetate/DCM mixture. This solution was purified by flash chromatography over silica (1:1 ethyl acetate/DCM). The fractions coeluting with the major band (Rf 0.53, eluent: 1:1 ethyl acetate/DCM) were combined and evaporated to dryness. The residue was recrystallized from acetonitrile to give 6-azido-N-[2-(2,4-dichlorophenyl)ethyl]-pyridine-3-carboxamide as pale yellow needles. LCMS (MH+) 336.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][C:5]=1[S:11][CH:12]([CH3:14])[CH3:13].[CH3:16][Si]([N-][Si](C)(C)C)(C)C.[K+].CI>C1COCC1.O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:16])=[N:6][C:5]=1[S:11][CH:12]([CH3:13])[CH3:14]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)c1ccc(C)nc1SC(C)C
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)OC)c(SC(C)C)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
After 2-isopropylsulfanyl-6-methyl-nicotinic acid methyl ester (105 mg, 0.46 mmol) was dissolved in THF (3 mL), KHMDS (1 mL, 0.51 mmol) was added slowly thereto at −78° C., and the mixture was stirred for 30 minutes. MeI (72 mg, 0.51 mmol) was added slowly to the reactant at −78° C., and the mixture was stirred at room temperature for 1 hour. The reactant was cooled, diluted with water, and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent EtOAc/Hex=1/5) to obtain the title compound (60 mg, 54%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C1C(=O)N([Br:16])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Br:16])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(Br)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc(Br)n1

Procedure:
A mixture of 2-bromo-6-methylpyridine (5.7 ml), NBS (8.9 g) and benzoyl peroxide (50 mg) in CCl4 (50 ml) were heated to reflux for 16 h. The reaction was filtered and the solution obtained was used without further purification in the next step. 1H NMR (400 MHz, CDCl3) δ 7.56 (1H, t, J=7.8 Hz), 7.45–7.40 (1H, m), 7.28 (1H, d, J=8.2 Hz), 4.50 (2H, s). b) (6-Bromopyridin-2-ylmethyl)dimethylamine 2-Bromo-6-bromomethyl-pyridine and NHMe2 (10 ml of 2M solution in THF) were reacted at RT for 16 h. The reaction mixture was poured into H2O, extracted into CH2Cl2 and the concentrated residue purified by column chromatography on silica, eluting with 1% MeOH/CH2Cl2 to give the title compound (440 mg). 1H NMR (400 MHz, CDCl3) δ 7.53 (1H, t, J=7.6 Hz), 7.40 (1H, d, J=7.5 Hz), 7.36 (1H, d, J=7.8 Hz), 3.57 (2H, s), 2.29 (6H, s). c) Dimethyl-{6-[3-(5-methyl-3-phenyl-isoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-α]isoindol-8-yl]pyridin-2-ylmethyl}amine Prepared in a similar manner to Example 26 using (6-bromopyridin-2-ylmethyl)-dimethylamine to give the title compound (40 mg, 39%). 1H NMR (360 MHz, CDCl3) δ 8.63 (1H, d, J=1.1 Hz), 8.13 (1H, dd, J=8.1, 1.5 Hz), 7.78 (1H, t, J=7.7 Hz), 7.67 (1H, d, J=7.7 Hz), 7.56–7.54 (2H, m), 7.47–7.34 (5H, m), 4.06 (2H, s), 3.70 (2H, s), 2.73 (3H, s), 2.37 (6H, s), m/z (ES+) 449 (M+H)+.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[Br:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][C:20]=1[CH2:21]Br)[C:10]([NH:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:11]>CN(C=O)C.COC(C)(C)C>[C:1]([O:4][CH2:21][C:20]1[CH:19]=[CH:18][C:9]([C:10](=[O:11])[NH:12][CH2:13][Si:14]([CH3:16])([CH3:15])[CH3:17])=[CH:8][C:7]=1[Br:6])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: C[Si](C)(C)CNC(=O)c1ccc(CBr)c(Br)c1
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccc(C(=O)NC[Si](C)(C)C)cc1Br
Yield: 39.1 %

Procedure:
A mixed solution of sodium acetate (2.8 g), 3-bromo-4-(bromomethyl)-N-[(trimethysilyl)methyl]benzamide (6.5 g) in DMF (30 ml) was stirred for 3 hours at 70° C. The reaction liquor was returned to room temperature and diluted with t-butyl methyl ether. The mixture was washed with water and a saturated aqueous brine, subsequently dried over magnesium sulfate. After separating the drying agent by filtration, the reaction liquor was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 2-bromo-4-{[(trimethysilyl)methyl]carbamoyl}benzyl acetate (2.4 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[NH:10][N:9]=2)=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[C@@H:51]1(O)[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:53][CH2:52]1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([C@H:51]3[C:59]4[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=4)[CH2:53][CH2:52]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)N1CCc2[nH]nc(-c3ccc(F)cc3)c2C1
Reactant: O[C@H]1CCc2ccccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CC(=O)N1CCc2c(c(-c3ccc(F)cc3)nn2[C@@H]2CCc3ccccc32)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
According to Scheme 7: A mixture of 1-[3-(4-fluoro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (3b) (0.2 g, 0.771 mmol), tri-n-butylphosphine (0.312 g, 1.54 mmol), 1,1′-(azodicarbonyl)dipiperidine (0.389 g, 1.54 mmol) and (S)-1-indanol in dry toluene (2.5 ml) was stirred at 80° C. for 2 h. Solvents were evaporated in vacuo. The crude product was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 81 mg of 1-[(R)-3-(4-fluoro-phenyl)-1-indan-1-yl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (12a)
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:51][O:52][CH3:53])[N:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:9]=1[C:10]([O:12][CH3:13])=[O:11])([CH3:4])[CH3:3].O.C(O)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)(=O)C>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:51][O:52][CH3:53])[N:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:19][CH:20]=2)[C:9]=1[C:10]([O:12][CH3:13])=[O:11])([CH3:3])[CH3:4]
Reactant: COCc1nc(C(C)(C)O)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: COCc1nc(C(C)(C)O)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
705 mg of methyl 4-(1-hydroxy-1-methylethyl)-2-methoxymethyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]-phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] were dissolved in 10 ml of a 25% aqueous solution of acetic acid, and the mixture was stirred at 60° C. for 4 hours. At the end of this time, 10 ml of water were added, whilst ice-cooling, and the trityl alcohol which appeared as crystals was filtered off. The filtrate was concentrated by distillation under reduced pressure, and then acetic acid and water were distilled off as azeotropic mixtures with benzene, to give 460 mg of the title compound as an amorphous powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1>[O-2].[Zn+2].CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:8][C:3](=[O:2])[CH3:4])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Agent: [O-2]
Agent: [Zn+2]
Solvent: CC(C)=O
Product: COc1ccc(C=CC(C)=O)cc1
Yield: 90 %

Procedure:
50 Parts of anisaldehyde, 100 parts of acetone and 15 parts of zinc oxide are heated for half an hour at 200° C and a pressure of 60 atmospheres. 46.2 parts of 4-(p-methoxyphenyl)-3-buten-2-one is obtained analogously to Example 9 in the form of yellowish crystals having a melting point of 74° C and a boiling point of 109° to 110° C at 0.1 mm. The yield is 90% of theory (based on anisaldehyde) at a conversion of 79% of theory.
Reaction SMILES: [C:1]1([CH2:9][OH:10])[CH:6]=[CH:5][C:4]([CH2:7]O)=[CH:3][CH:2]=1.S(Cl)([Cl:13])=O.C(=O)(O)[O-].[Na+].Cl>C(Cl)(Cl)Cl>[OH:10][CH2:9][C:1]1[CH:6]=[CH:5][C:4]([CH2:7][Cl:13])=[CH:3][CH:2]=1
Reactant: OCc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: OCc1ccc(CCl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
1,4-benzenedimethanol (13.8 g, 0.10 mole) was dispersed in chloroform (100 mL) in a 500 mL three-neck round bottom flask equipped with a magnetic stirring bar, an addition funnel, a nitrogen inlet and a gas scrubber. The mixture was cooled to 0° C. in an ice bath. Thionyl chloride (13.1 g, 0.11 mole) dissolved in chloroform (10 mL) was added dropwise over ten minutes with rapid stirring to the cooled mixture. As the addition proceeded, the mixture largely cleared. During the addition step, and for one hour thereafter, the reaction flask was swept with nitrogen which was then passed through the scrubber before venting to the atmosphere. The nitrogen was turned off and the scrubber disconnected. The mixture was allowed to come to room temperature and stirring was continued for 20 hours. Sufficient sodium bicarbonate was added to neutralize any residual hydrogen chloride. The mixture was filtered through a coarse glass frit and the solvent removed under reduced pressure at 35° C. A sample of the residue was chromatographed on silica gel (200 g) with an ethyl acetate:hexane (2:3) solvent. p-Hydroxymethyl-benzyl chloride was obtained in 75% yield (11.64 g). The product had a melting point of 58°-60° C. NMR spectral data were as follows: 1H NMR (CDCl3, 300 MHz): δ7.3 (m, 4H), 4.70 (s, 2H), 4.59 (s, 2H), 1.67 (s, 1H); 13C NMR (CDCl3, 75 MHz, ppm) 141.372, 135.995, 128.876, 127.366, 64.927, 46.121.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[NH:10][N:9]=1.Cl[C:19]1[N:20]=[C:21]([N:28]2[CH2:33][CH2:32][CH:31]([C:34]#[N:35])[CH2:30][CH2:29]2)[C:22]2[O:27][CH:26]=[CH:25][C:23]=2[N:24]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:19]3[N:20]=[C:21]([N:28]4[CH2:33][CH2:32][CH:31]([C:34]#[N:35])[CH2:30][CH2:29]4)[C:22]4[O:27][CH:26]=[CH:25][C:23]=4[N:24]=3)=[CH:14][CH:15]=2)[NH:10][N:9]=1
Reactant: Cc1n[nH]c2cc(N)ccc12
Reactant: N#CC1CCN(c2nc(Cl)nc3ccoc23)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1n[nH]c2cc(Nc3nc(N4CCC(C#N)CC4)c4occc4n3)ccc12
Temperature: 100 °C
Reaction time: 12 h
Yield: 28.2 %

Procedure:
A mixture of K2CO3 (0.052 g, 0.38 mmol), Pd2dba3 (0.017 g, 0.019 mmol), 3-methyl-1H-indazol-6-amine (0.028 g, 0.19 mmol, Advanced ChemBlocks), 1-(2-chlorofuro[3,2-d]pyrimidin-4-yl)piperidine-4-carbonitrile (0.050 g, 0.19 mmol) and X-phos (0.018 g, 0.038 mmol) in 1,4-dioxane (10 mL) was stirred at about 100° C. for about 12 h. The solvent was removed and the residue was purified by Prep-TLC (DCM/MeOH 20:1) to give 1-(2-(3-methyl-1H-indazol-6-ylamino)furo[3,2-d]pyrimidin-4-yl)piperidine-4-carbonitrile (0.020 g, 28%): LC/MS (Table 2, Method 1) Rt=0.63 min; MS m/z: 374 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10]1[CH:15]=[CH:14][C:13]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:33])[NH:26][C:27]3[C:32]\2=[CH:31][CH:30]=[CH:29][CH:28]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[S:6]([CH3:9])(=[O:8])=[O:7])([OH:3])=O.[Cl-].[CH3:35][NH2+:36][CH3:37].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH3:35][N:36]([CH3:37])[C:1]([CH2:4][N:5]([C:10]1[CH:15]=[CH:14][C:13]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:33])[NH:26][C:27]3[C:32]\2=[CH:31][CH:30]=[CH:29][CH:28]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[S:6]([CH3:9])(=[O:8])=[O:7])=[O:3]
Reactant: C[NH2+]C
Reactant: CS(=O)(=O)N(CC(=O)O)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN(c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1)S(C)(=O)=O

Procedure:
Prepared analogously to Example 18 from (Z)-3-{1-[4-(N-carboxymethyl-N-methylsulphonylamino)-phenylamino]-1-phenyl-methylidene}-2-indolinone, dimethylammonium chloride, HOBt, TBTU and N-ethyl-N,N-diisopropylamine in DMF.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:21]=[CH:20][C:15]([NH:16][C:17](=[O:19])[CH3:18])=[N:14][C:12]2=[O:13])[CH2:8][CH2:7]1)(=[O:3])[CH3:2]>S(C1C=CC(C)=CC=1)([O-])(=O)=O.C([N+](CC)(CC)CC)C.C(#N)C>[C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:21]=[CH:20][C:15]([NH:16][C:17](=[O:19])[CH3:18])=[N:14][C:12]2=[O:13])[CH:8]=[CH:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccn([C@H]2CC[C@@H](COC(C)=O)O2)c(=O)n1
Agent: CC[N+](CC)(CC)CC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC#N
Product: CC(=O)Nc1ccn([C@H]2C=C[C@@H](COC(C)=O)O2)c(=O)n1

Procedure:
To the catholyte reservoir was added 35.0 g (0.081 mol) of 4-(acetylamino)-1-(3'-bromo-2',5'-di-O-acetyl-β-D-xylofuranosyl-2-(1H)-pyrimidinone III(a) ##STR15## R'=CH3, and 1.0 L of 0.25M tetraethylammonium tosylate in acetonitrile. To the anolyte reservoir was added 1.0 L of 0.025M tetraethylammonium tosylate in acetonitrile. Both the catholyte and anolyte were circulated through the electrolytic cell at a flow rate of 200 ml/min/cell. The cell was divided by an anion exchange membrane and the initial current density was 2.4 mA/cm2 at -1.5V. The reaction was followed by TLC and HPLC. During the first 8 hr the desired product N-acetyl 2',3'-dideoxycytidine 5'-acetate started to precipitate from the reaction mixture. The product was removed by filtration and the reaction continued. After 16 hr, this reaction was almost complete. The catholyte mixture was collected and evaporated to dryness at room temperature and 10 mm vacuum. The dried residue was combined with the previously filtered solids. The mixture of product and electrolyte was then dissolved in 200 mL of deionized water. The mixture was extracted with 3×300 ml=900 of methylene chloride. The organic extract was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was triturated with 180 ml of tetrahydrofuran to give 18.12 g (76% yield) of N-acetyl 2',3'-didehydro-2',3'-dideoxycytidine 5'-acetate, IV, ##STR16## R'=CH3, m.p.>300° (dec); [α]D25 +14.7° (c=0.387, DMSO). The product was analyzed by HPLC to give a 99.2% assay.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:33])[N:21]([CH3:32])[CH:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24][CH2:23]3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:34].O1CCOCC1>>[ClH:34].[CH3:32][N:21]([CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1)[C:20]([C:16]1[N:15]=[C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[CH:18][CH:17]=1)=[O:33]
Reactant: CN(C(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)C1CCCc2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CN(C(=O)c1cccc(C2CCNCC2)n1)C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of 6-[methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamoyl]-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (202 mg, 0.45 mmol) was added a solution of 4M HCl in dioxane (1.13 mL, 4.5 mmol)) at RT. After stirring overnight at RT, the solvent was evaporated under reduce pressure to give 1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-6-carboxylic acid methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide hydrochloride salt (162 mg, 93%). 1H-NMR (400 MHz, d6-DMSO): δ=1.83-2.02 (m, 6H), 2.51 (s, 3H), 2.52-2.59 (m, 2H), 2.71-3.03 (m, 2H), 3.29-3.38 (m, 2H), 3.97-4.05 (m, 2H), 4.78-4.83 (m, 1H), 7.08-7.23 (m, 4H), 7.36-7.41 (m, 1H), 7.52-7.55 (m, 1H), 7.90-7.95 (m, 1H), 8.81 (br, 1H), 9.04 (br, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[Cl:35][C:36]1[CH:37]=[C:38]([CH:43]=[C:44]([Cl:53])[C:45]=1[O:46][CH2:47][CH:48]1[CH2:52][CH2:51][CH2:50][NH:49]1)[C:39]([O:41][CH3:42])=[O:40].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[Cl:35][C:36]1[CH:37]=[C:38]([CH:43]=[C:44]([Cl:53])[C:45]=1[O:46][CH2:47][CH:48]1[CH2:52][CH2:51][CH2:50][N:49]1[C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:39]([O:41][CH3:42])=[O:40]
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)c1cc(Cl)c(OCC2CCCN2)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Cl)c(OCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (385.8 mg, 0.803 mmol), methyl 3,5-dichloro-4-(2-pyrrolidinyl)methoxybenzoate (244.3 mg, 0.803 mmol), Et3N (0.13 mL, 0.964 mmol) in DMF (4 mL) was stirred for 1 hr at room temp. The mixture was diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under a reduced pressure, and the residue was chromatographed on silica-gel with n-hexane:EtOAc (1:2, v/v) as eluent to afford methyl 3,5-dichloro-4-[[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]benzoate as an oil. To a stirred solution of this compound in THF (8 mL) and H2O (2 mL) was added LiOH (57.7 mg, 2.409 mmol), and the mixture was stirred at room temp overnight. The tire was concentrated in vacuo, and the residue was diluted with CHCl3. The solution was washed with 1N HCl, brine, and dried over Na2SO4. The solvent was removed under a reduced pressure, and the obtained crude solid was recrystallized from n-hexane-MeOH—CHCl3 to afford 428.2 mg (91%) 30 as a white crystalline powder. IR (KBr) 1618, 1535, 1454, 1257, 754 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ1.83-2.24 (m, 4H), 2.24 (s, 3H), 3.50-3.58 (m, 4H), 3.84 (s, 3H), 3.98-4.05 (m, 1H), 4.15 (dd, J=2.9, 8.7 Hz, 1H), 4.29 (br m, 1H), 6.74 (d, J=8.3 Hz, 1H), 6.87 (s, 1H), 6.93 (t, J=7.3 Hz, 1H), 7.11 (d, J=7.8 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.86 (s, 1H), 7.87 (d, J=9.8 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 8.49 (s, 1H), 8.58 (s, 1H); MS (FAB) m/z 586 (M++1).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:16][C:15]=2[Cl:32])=[CH:9][C:8]=1[CH3:33])C.[OH-].[Na+].Cl>CCO>[Cl:32][C:15]1[CH:16]=[C:17]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][CH:23]=2)[CH:18]=[CH:19][C:14]=1[S:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:34])=[O:3])=[C:8]([CH3:33])[CH:9]=1
Reactant: CCOC(=O)COc1ccc(Sc2ccc(COc3ccc(C(F)(F)F)cc3)cc2Cl)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2ccc(COc3ccc(C(F)(F)F)cc3)cc2Cl)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
A 1 L round-bottomed flask was charged with compound 10.6 (43.4 g, 84.9 mmol) and EtOH (386 mL). Next, 4 N NaOH (42 mL, 168 mmol) was added dropwise, and the reaction was stirred at room temperature for 30 min. The reaction was then neutralized using 343 mL of 0.5 N HCl, deposited crystals were collected, washed with 2×100 mL of water, and dried in vacuo. Recrystallization from 508 mL of AcOEt/hexanes ({fraction (2/8)}) furnished the title compound 10 (31.1 g) as white crystals. MS APSI m/e: 481 (M−H). 1H NMR (400 MHz) (DMSO-d6) δ 12.98 (1H, brs); 7.65 (2H, d, J=8.7 Hz); 7.58 (1H, s); 7.36-7.29 (3H, m); 7.17 (2H, d, J=8.6 Hz); 6.96 (1H, d, J=8.4 Hz); 6.74 (1H, d, J=8.2 Hz); 5.14 (2H, s); 4.77 (2H, s); 2.21 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=S)[CH2:24][C:25](=O)[CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:4].Cl.[CH:35]1([NH:39][NH2:40])[CH2:38][CH2:37][CH2:36]1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:11])=[O:12])[CH2:7][N:6]1[C:23]1[N:39]([CH:35]2[CH2:38][CH2:37][CH2:36]2)[N:40]=[C:25]([CH:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[CH:24]=1)=[O:4]
Reactant: NNC1CCC1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(=O)C1CCOCC1
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C2CCOCC2)nn1C1CCC1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-[3-oxo-3-(tetrahydro-pyran-4-yl)-thiopropionyl]-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 393d) was reacted with cyclobutylhydrazine hydrochloride (CAS Reg. No. 158001-21-9) to give the title compound as yellow oil. MS (ESI): m/z=542.4 [M+H]+.