Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of ethyl 3-(4-phenoxyphenyl)propanoate (S29, 500 mg, 1.95 mmol) in THF/MeOH (1/1, 8 mL) was treated with aqueous 4 N NaOH (0.5 mL) and was stirred for 20 h at 25° C. The reaction mixture was concentrated, diluted with aqueous 1 N HCl and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated to afford S30 (390 mg, 1.61 mmol, 82%) as a white solid: 1H NMR (CDCl3, 500 MHz) 7.34 (dd, 2H, J=8.4, 7.4 Hz), 7.18 (d, 2H, J=8.4 Hz), 7.10 (dt, 1H, J=7.7, 1.1 Hz), 7.00 (dd, 2H, J=8.8, 1.1 Hz), 6.95 (d, 2H, J=8.4 Hz), 2.96 (t, 2H, J=7.7 Hz), 2.70 (t, 2H, J=7.7 Hz); 13C NMR (CDCl3, 125 MHz) 179.2, 157.3, 155.6, 135.0, 129.7, 129.5, 123.1, 119.0, 118.7, 35.7, 29.8.
Reaction SMILES: CN(C)[CH:3]=[C:4]1[C:9](=O)[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)([CH2:11][CH2:12][CH3:13])[CH2:7][CH2:6][CH2:5]1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([NH:45][C:46]([NH2:48])=[NH:47])[CH:36]=[CH:37][C:38]=1[N:39]1[CH:43]=[C:42]([CH3:44])[N:41]=[CH:40]1>>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([NH:45][C:46]2[N:48]=[CH:3][C:4]3[CH2:5][CH2:6][CH2:7][C:8]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=4)([CH2:11][CH2:12][CH3:13])[C:9]=3[N:47]=2)[CH:36]=[CH:37][C:38]=1[N:39]1[CH:43]=[C:42]([CH3:44])[N:41]=[CH:40]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CCCC1(c2cccc(OC)c2)CCCC(=CN(C)C)C1=O
Solvent: O=[N+]([O-])O
Product: CCCC1(c2cccc(OC)c2)CCCc2cnc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc21

Procedure:
The title compound was prepared from 6-[1-dimethylamino-methylidene]-2-(3-methoxy-phenyl)-2-propyl-cyclohexanone (101 mg, 0.33 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (124 mg, 0.33 mmol) using in analogous manner the procedure described in example 45b). Obtained as white solid (24 mg, 15%). MS ISP (m/e): 484.5 [(M+H)+]. mp 166-168° C.
Reaction SMILES: [CH:1]([C@@H:4]1[C:9]([O:10][CH3:11])=[N:8][CH2:7][C:6]([O:12][CH3:13])=[N:5]1)([CH3:3])[CH3:2].[Li]CCCC.I[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C1COCC1>[CH:1]([C@@H:4]1[C:9]([O:10][CH3:11])=[N:8][C@@H:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[C:6]([O:12][CH3:13])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCCCCI
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1CCCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of (2R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (1.0 eq.) in THF at −78° C., was added dropwise over 10 min a solution of BuLi (1.6 N in hexane, 1.0 eq.) and stirring was continued at −78° C. for 45 min. A pre-cooled solution of tert-butyl 6-iodohexanoate (1.0 eq.) in THF was then added by cannula over 5 min and the reaction stirred overnight, slowly warming to RT. The reaction was then left to stir at RT for a further hour and was quenched by the addition of aqueous NH4Cl solution. The THF layer was decanted off and concentrated under reduced pressure, meanwhile and the aqueous mixture was extracted with EtOAc (3×). The EtOAc extracts were used to redissolve the oily THF residue and this solution was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude was used directly in the next step without further purification (I1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH2:9][C:8](=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:13]([CH2:15]C(O)=O)#[N:14].C([O-])(=O)C.[NH4+]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:15][C:13]#[N:14])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: N#CCC(=O)O
Reactant: COc1cccc2c1OCC2=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1C
Product: COc1cccc2c(CC#N)coc12
Yield: 30 %

Procedure:
The solution of 7-methoxy-1-benzofuran-3(2H)-one (reference) (7.5 g, 0.046 mol), cyanoacetic acid (19.55 g, 0.23 mol) and ammonium acetate (7.08 g, 0.092 mol) in xylene was refluxed for 16-18 h. using dean stark apparatus. Xylene was removed under diminished pressure. Brown black residue was taken in ethyl acetate, washed with water and concentrated. On purification on silica gel it yielded (7-methoxy-1-benzofuran-3-yl)acetonitrile (30%).
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([CH2:7][NH2:8])=[N:3]1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]([N:19]2[CH2:24][CH2:23][O:22][C@@H:21]([CH2:25][NH:26][C:27](=O)[O:28]C3C=CC([N+]([O-])=O)=CC=3)[CH2:20]2)[CH3:18])[CH:13]=[CH:14][C:15]=1[Cl:16]>>[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]([N:19]2[CH2:24][CH2:23][O:22][C@@H:21]([CH2:25][NH:26][C:27]([NH:8][CH2:7][C:4]3[N:5]=[N:6][N:2]([CH3:1])[N:3]=3)=[O:28])[CH2:20]2)[CH3:18])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: CC(c1ccc(Cl)c(Cl)c1)N1CCO[C@@H](CNC(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Reactant: Cn1nnc(CN)n1
Product: CC(c1ccc(Cl)c(Cl)c1)N1CCO[C@@H](CNC(=O)NCc2nnn(C)n2)C1

Procedure:
Prepared in similar fashion to Example 16 but using C-(2-methyl-2H-tetrazol-5-yl)-methylamine and 4-nitrophenyl {(2S)-4-[1-(3,4-dichlorophenyl)ethyl]morpholin-2-yl}methylcarbamate Isomer II (prepared as described in WO 02/26723).
Reaction SMILES: CC1(C)N([O])C(C)(C)CCC1.[OH:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])O.[Na+].[O-]Cl.[Na+]>ClCCl.O.CCOC(C)=O.CCCCCC>[CH3:24][N:16]([CH2:15][CH2:14][CH:13]=[O:12])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21]
Reactant: CN(CCCO)C(=O)OC(C)(C)C
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CN(CCC=O)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80.9 %

Procedure:
A catalytic amount of TEMPO was added to a mixture of 20 g (1 eq.) tert-butyl 3-hydroxypropyl(methyl)carbamate in 200 ml dichloromethane and 17.7 g (2 eq.) sodium hydrogen carbonate in 100 ml water at 0° C. 140 ml (7 eq.) NaOCl were then added dropwise over a period of 30 min to the solution at a temperature of 0° C. and the reaction mixture obtained was stirred for a further 15 min at 0° C. The reaction course was monitored by thin-layer chromatography (40% EtOAc/hexane). Once the conversion was complete, the reaction mixture was mixed with 150 ml water and the phases were separated. The organic phase was dried over Na2SO4. Following removal of the solvent under reduced pressure, 16 g (85%) of product were obtained in the form of a yellowish oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][CH2:7][CH2:6][O:5][C:4]2[C:9]([NH2:13])=[CH:10][CH:11]=[CH:12][C:3]1=2.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=2[C:25]([NH:27][CH2:28][CH3:29])=[O:26])[C:19]([Cl:34])=[CH:18][N:17]=1>>[Cl:34][C:19]1[C:20]([NH:22][C:23]2[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=2[C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[N:21][C:16]([NH:13][C:9]2[C:4]3[O:5][CH2:6][CH2:7][CH2:8][C:2]([CH3:14])([CH3:1])[C:3]=3[CH:12]=[CH:11][CH:10]=2)=[N:17][CH:18]=1
Reactant: CC1(C)CCCOc2c(N)cccc21
Reactant: CCNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCNC(=O)c1ccccc1Nc1nc(Nc2cccc3c2OCCCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared from 5,5-dimethyl-2,3,4,5-tetrahydro-benzo[b]oxepin-9-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-ethyl-benzamide in an analogous manner to Example 179. The product was isolated as a light brown solid (40 mg, 40%). LCMS (m/e) 466 (M+H); 1H NMR (400 MHz, CDCl3) δ 10.93 (s, 1H), 8.67 (d, 1H, J=8.6 Hz), 8.29 (d, 1H, J=7.8 Hz), 8.12 (s, 1H), 7.79 (s, 1H), 7.50 (m, 2H), 7.10 (t, 1H, J=7.6 Hz), 6.94 (m, 2H), 6.13 (m, 1H), 4.02 (t, 2H, J=4.5, 5.1 Hz), 3.52 (m, 2H), 2.08 (m, 2H), 1.70 (t, 2H, 5.6, 6.1 Hz), 1.39 (s, 6H) 1.27 (t, 3H, J=7.3 Hz).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]1[N:11]=[CH:12][NH:13][CH:14]=1.[N+:15]([O-])([OH:17])=[O:16].NC(N)=O.[OH-].[Na+]>S(=O)(=O)(O)O>[N+:15]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH:2]([C:10]1[N:11]=[CH:12][NH:13][CH:14]=1)[CH2:3]2)([O-:17])=[O:16]
Reactant: c1ccc2c(c1)CC(c1c[nH]cn1)C2
Reactant: O=[N+]([O-])O
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1ccc2c(c1)CC(c1c[nH]cn1)C2

Procedure:
5 g of 4-indan-2-yl-1H-imidazole are dissolved at 0° C. in 140 ml of pure sulphuric acid, and then 1 equivalent of urea nitrate in powder form is added in small portions. The reaction mixture is poured onto ice, rendered alkaline using sodium hydroxide solution and extracted with ethyl acetate. The expected product is obtained after evaporation.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[NH:16][C:17](=O)[CH:18]([CH3:35])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([O:30][C:31]([CH3:34])(C)C)=[O:29])=[CH:22][CH:21]=1>C1C=CC=CC=1>[CH2:12]([N:5]1[C:4](=[O:15])[C:3]2[N:16]=[C:17]([CH:18]([CH3:35])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([O:30][CH2:31][CH3:34])=[O:29])=[CH:22][CH:21]=3)[NH:1][C:2]=2[N:7]([CH2:8][CH2:9][CH3:10])[C:6]1=[O:11])[CH2:13][CH3:14]
Reactant: CCCn1c(N)c(NC(=O)C(C)Cc2ccc(OCC(=O)OC(C)(C)C)cc2)c(=O)n(CCC)c1=O
Solvent: c1ccccc1
Product: CCCn1c(=O)c2nc(C(C)Cc3ccc(OCC(=O)OCC)cc3)[nH]c2n(CCC)c1=O
Temperature: 70 °C
Yield: 94.1 %

Procedure:
Dissolve the ethyl enolate of (+)-2-[[4-[3-[(6-amino-1-propyl-1,2,3,4-tetrahydro-3-propyl-2,4-dioxo-5-pyrimidinyl)amino]-2-methyl-3-oxopropyl]phenyl]oxy]-acetic acid, 1,1-dimethylethyl ester (0.68 g, 1.28 mmol) in benzene (200 mL) and heat at 70° C. for 20 hours. Evaporate the solvent in vacuo and purify the residue by radial chromatography (30→40→50% ethyl acetate/hexane) to give (+)-2-[4-[2-(2,3,6,9-tetrahydro-1,3-dipropyl-2,6-dioxo-1H-purin-8-yl)propyl]phenoxy]acetic acid, ethyl ester (0.55 g); [α]d 20 =+54.5° (C=0.88, CHCl3).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=2)=[C:12]([CH3:30])[CH:11]=1.C(N(CC)CC)C.O>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][S:2]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=2)=[C:12]([CH3:30])[CH:11]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)COc1ccc(-c2c(C)cc(OCCO)cc2C)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(-c2c(C)cc(OCCOS(C)(=O)=O)cc2C)cc1
Temperature: 0 °C

Procedure:
Methanesulfonyl chloride (0.17 mL) was added to an ice-cooled mixture of ethyl [4′-(2-hydroxyethoxy)-2′,6′-dimethylbiphenyl-4-yloxy]acetate (0.58 g) and triethylamine (0.36 mL) in methylene chloride (5 mL) with stirring, and the mixture was stirred at room temperature for 1 hr. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford ethyl [4′-(2-methanesulfonyloxy-ethoxy)-2′,6′-dimethylbiphenyl-4-yloxy]acetate.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:56]([CH3:59])[CH2:57][CH3:58])[C@H:26]([O:54][CH3:55])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:52][CH3:53])[C@@H:36]([CH3:51])[C:37]([NH:39][CH2:40][CH2:41][C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[NH:44][CH:43]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].O=[CH:61][CH2:62][CH2:63][C:64]([OH:66])=[O:65].C([BH3-])#N.[Na+]>>[C:64]([CH2:63][CH2:62][CH2:61][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:56]([CH3:59])[CH2:57][CH3:58])[C@H:26]([O:54][CH3:55])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:52][CH3:53])[C@@H:36]([CH3:51])[C:37]([NH:39][CH2:40][CH2:41][C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[NH:44][CH:43]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12])([OH:66])=[O:65]
Reactant: O=CCCC(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1c[nH]c2ccccc12)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1c[nH]c2ccccc12)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C

Procedure:
The title compound was synthesized by analogy with the synthesis process of Example 1 by reacting 100 mg (119 μmol) N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[2-(1H-indol-3-yl)ethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetic acid salt (intermediate 24) with a 15% aqueous solution of 4-oxobutanoic acid in the presence of sodium cyanoborohydride.
Reaction SMILES: [CH:1]1([OH:13])[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH:26]([O:28][CH2:29][CH3:30])=[CH2:27]>CC(OC)(C)C>[CH2:26]([O:28][CH:29]([O:13][CH:1]1[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1)[CH3:30])[CH3:27]
Reactant: C=COCC
Reactant: OC1CCC=CCCC=CCCC1
Agent: CCOC(C)OC1CC/C=C/CC/C=C/CCC1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: OC1CC/C=C/CC/C=C/CCC1
Solvent: COC(C)(C)C
Solvent: O
Product: CCOC(C)OC1CCC=CCCC=CCCC1
Temperature: 40 °C

Procedure:
To a mechanically stirred mixture of E,E-4,8-cyclododecadien-1-ol (99% (E,E)/1% (E/Z), 2.0 g, 11 mmol), toluene sulphonic acid monohydrate (0.15 g, 2 mmol) and MTBE (methyl terbutyl ether, 20 mL) was added drop wise ethyl vinyl ether (5 g) over 15 minutes. The reaction mixture was heated at reflux at 40° C. for 1 hour, then diluted with MTBE, washed with aqueous NaHCO3, water and brine. The solvent was evaporated and the product (4.5 g) purified by flash distillation (Kugelrohr, 86° C., 0.1 mbar) and liquid chromatography (silica gel 100 g; eluent=heptane/ethyl acetate 95/5).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH2:15][OH:16])[CH:5]=[C:6]2[CH:10]=[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])[O:8][C:7]=12.C1CCCCC=1>[Pd].CCO>[OH:16][CH2:15][C:4]1[CH:5]=[C:6]2[CH:10]=[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])[O:8][C:7]2=[CH:2][N:3]=1
Reactant: C[Si](C)(C)c1cc2cc(CO)nc(Cl)c2o1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: C[Si](C)(C)c1cc2cc(CO)ncc2o1
Yield: 90 %

Procedure:
C5 (1.05 g, 4.1 mmol) and 10% Pd/C catalyst (1.05 g) are placed in 20 mL absolute EtOH. Cyclohexene (4 mL, 40.1 mmol) is added, and the reaction is refluxed for 2.5 h, and then filtered through celite. The filter cake is washed with 1:1 EtOH/CH2Cl2, and the filtrate is concentrated to a pale yellow solid. The residue is partitioned between 40 mL saturated NaHCO3 and extracted with CH2Cl2 (4×20 mL). The combined organic layer is dried over MgSO4, filtered, and then concentrated in vacuo to a pale oil (1.04 g). The pale oil is chromatographed over 50 g silica gel (230-400 mesh) eluting with 50-70% EtOAc/hexane to afford 5-hydroxymethyl-2-trimethylsilyl-furo[2,3-c]pyridine (C14) as a white solid (90% yield). MS (EI) for C11H15NO2Si, m/z: 221(M)+.
Reaction SMILES: CN(C)[CH2:3][CH:4]([CH3:14])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].S(=O)(=O)(O)O>>[F:13][C:10]1[CH:9]=[C:8]2[C:7](=[CH:12][CH:11]=1)[C:5](=[O:6])[CH:4]([CH3:14])[CH2:3]2
Reactant: CC(CN(C)C)C(=O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: CC1Cc2cc(F)ccc2C1=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 42 g. (0.20 mole) of 3-dimethylamino-4'-fluoro-2-methylpropiophenone and 100 ml. of concentrated sulfuric acid is warmed to 90°C over 1 hour and stirred at 90°C for 2 hours. The reaction is cooled and quenched in ice and the product extracted into toluene. The toluene layer is washed with aqueous sodium hydroxide and water and concentrated in vacuo to give 5-fluoro-2-methyl-1-indanone.
Reaction SMILES: [C:1]1([C:7](=[O:16])[CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([S:20][CH2:21][C:22]([OH:24])=[O:23])(=O)[NH2:18]>CN(C=O)C>[C:10]1([C:8]2[N:18]=[C:17]([S:20][CH2:21][C:22]([OH:24])=[O:23])[O:16][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)SCC(=O)O
Reactant: O=C(c1ccccc1)C(Cl)c1ccccc1
Solvent: CN(C)C=O
Product: O=C(O)CSc1nc(-c2ccccc2)c(-c2ccccc2)o1

Procedure:
23 g. of 1,2-diphenyl-2-chloroethanone is heated together with 18 g. of the ethyl ester of carbamoylmercaptoacetic acid in 150 ml. of absolute DMF for 3 hours to 70°. Then, the DMF is removed, and the residue, containing the ethyl ester of N-(1,2-diphenyl-2-oxoethyl)-carbamoylmercaptoacetic acid, is refluxed for 5 hours with a mixture of 100 g. of POCl3 and 200 ml. of benzene. The mixture is then evaporated under reduced pressure and the residue is purified by chromatography on silica gel, thus obtaining the ethyl ester of 4,5-diphenyl-2-oxazolylmercaptoacetic acid, m.p. 54°-56°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+]([O-])=O)[C:3]=1/[CH:12]=[CH:13]/[N:14](C)C.[OH-].[Na+]>C(O)(=O)C.O.[Zn]>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[CH:12]=[CH:13][NH:14]2
Reactant: CN(C)/C=C/c1c(Br)cc(F)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Fc1cc(Br)c2cc[nH]c2c1
Temperature: 85 °C
Reaction time: 4 h
Yield: 12.9 %

Procedure:
To a solution of crude[(E)-2-(2-bromo-4-fluoro-6-nitrophenyl)ethenyl]dimethylamine (D15) (6.07 g, 21.0 mmol) in acetic acid (200 mL) and water (50.0 mL) at 75° C. was added zinc powder (15.11 g, 231 mmol) portionwise over 1 hour. The mixture was heated to 85° C. and stirred for 4 hours. After cooling to room temperature, the reaction mixture was neutralised by the addition of 50% aqueous sodium hydroxide solution. The product was extracted into diethyl ether. After separation of the layers, the aqueous phase was re-extracted with diethyl ether. The combined organic layers were dried over magnesium sulphate, filtered and concentrated. The product was partially purified by silica gel chromatography eluting with 5-30% ethyl acetate in hexane. Purer fractions were combined to give the title compound (D16), (580 mg).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:37])[CH2:32][S:33]([CH3:36])(=[O:35])=[O:34]>>[CH3:36][S:33]([CH2:32][C:31]1[N:37]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:28][N:30]=1)(=[O:35])=[O:34]
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: CS(=O)(=O)CC(N)=NO
Product: CS(=O)(=O)Cc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 33 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-2-(methylsulphonyl)ethanimidamide were reacted according to the General Method 1. Yield: 50 mg (48% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:20][O:21][C:22]([C@@H:24]1[CH2:26][C@H:25]1[CH2:27]OS(C)(=O)=O)=[O:23].S([O-])(=O)(=O)C>CN(C=O)C>[CH3:20][O:21][C:22]([C@@H:24]1[CH2:26][C@H:25]1[CH2:27][O:13][C:5]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=2[O:8][C:7](=[O:12])[CH:6]=1)=[O:23]
Reactant: O=c1cc(O)c2cc(Cl)ccc2o1
Reactant: COC(=O)[C@@H]1C[C@H]1COS(C)(=O)=O
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@H]1COc1cc(=O)oc2ccc(Cl)cc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
6-chloro-4-hydroxycoumarin (5.09 mmol, 1.0 g) is dissolved in 80 mL of DMF, and Cs2CO3 (7.63 mmol, 2.49 g), and trans-2-methanesulfonyloxymethyl-cyclopropanecarboxylic acid methyl ester (6.14 mmol, 1.28 g) are added. The reaction is heated to 100° C. for 5 hrs, a further 0.2 eq of the mesylate is added, and heating is continued for an additional 2 hrs. After cooling to ambient temperature, the DMF is removed in vacuo. The residue is dissolved in EtOAc and is washed with H2O. The organic layer is dried over MgSO4, is filtered, and the EtOAc is removed under reduced pressure to afford a yellow solid which is chromatographed on SiO2 (35 g) using DCM as the eluent to afford the title compound as a white solid (0.98 g, 62%). 1H NMR (DMSO-d6, 300 MHz) δ 7.75 (2H, m), 7.45 (1H, d), 5.97 (1H, s), 4.22 (2H, m), 3.65 (3H, s), 1.90 (2H, m), 1.19 (2H, m); MS (ESI, Pos.) calcd for C15H13ClO5 m/z [M+H]=309.0, found 309.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1[CH2:16][CH:17]=[O:18].[BH4-].[Na+].[Cl-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1[CH2:16][CH2:17][OH:18]
Reactant: COc1c(C)c(CC=O)c(OC)c(OC)c1OC
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: COc1c(C)c(CCO)c(OC)c(OC)c1OC
Yield: 97.2 %

Procedure:
5.38 g of 2-(2,3,4,5-tetramethoxy-6-methylphenyl)acetaldehyde [prepared as described in step (b)-above] were dissolved in 60 ml of ethanol and reduced using 400 mg of sodium borohydride at 0° C. 150 ml of a saturated aqueous solution of sodium chloride were then added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated to dryness by evaporation under reduced pressure, to give a crude product. This crude product was then purified by column chromatography through silica gel, using a gradient elution method with mixtures of hexane and ethyl acetate ranging from 5:1 to 2:1 by volume as the eluent, to give 5.27 g of the title compound as a colorless oil.
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([CH:24]=[CH2:25])[O:12][C@H:11]1[N:26]1[C:37]2[N:36]=[C:35]([Cl:38])[N:34]=[C:30]([NH:31][O:32][CH3:33])[C:29]=2[N:28]=[CH:27]1)(=O)C1C=CC=CC=1.ClC1N=C2C(N=CN2[C@@H]2O[C@H](C(=C)O)[C@@H](OC(=O)C3C=CC=CC=3)[C@H]2OC(=O)C2C=CC=CC=2)=C(Cl)N=1.Cl>N>[Cl:38][C:35]1[N:34]=[C:30]([NH:31][O:32][CH3:33])[C:29]2[N:28]=[CH:27][N:26]([C:37]=2[N:36]=1)[C@@H:11]1[O:12][C@H:13]([CH:24]=[CH2:25])[C@@H:14]([OH:15])[C@H:10]1[OH:9]
Reactant: C=C[C@H]1O[C@@H](n2cnc3c(NOC)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: C=C(O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: Cl
Agent: N
Product: C=C[C@H]1O[C@@H](n2cnc3c(NOC)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.9 %

Procedure:
2',3'-Di-O-benzoyl-2-chloro-5'-deoxy-N-methoxy-5'-methyleneadenosine (0.2 g, 0.4 mmol), prepared by the method described in Example 25 from 2,6-dichloro-9-(2',3'-di-O-benzoyl-5'-methylene-β-D-ribofuranosyl)-9H-purine (0.5 g, 2.0 mmol) and O-methylhydroxlamine hydrochloride (0.167 g, 2.0 mmol), was treated with methanolic ammonia (10 ml) and stirred at ambient temperature for 18 h. The reaction mixture was evaporated and purified by flash chromatography eluting with a mixture of dichloromethane and 10% ammonia in ethanol (19:1) to provide the title 2-chloro-5'-deoxy-N-methoxy-5'-methyleneadenosine (0.03 g, 9%) as a foam, 1H-NMR (400 MHz, DMSO-d6) δ3.79 (3H, s, --CH3), 4.08 (1H, q, H-3'), 4.33 (1H, dt, H-2'), 4.61 (1H, m, H-4'), 5.20 (1H, dd, C=C--H), 5.31 (1H, d, C=C--H), 5.42, 5.59 (2H, 2d, 2'-and 3'-OH), 5.89 (1H, d, H-1'), 6.08 (1H, m, C=C--H), 8.44 (1H, s, H-8), 11.58 (1H, s, N--H). HPLC retention time 7.09 min. (gradient elution over 30 min; 25-45 % acetonitrile/0.1% ammonium sulfate in water), purity 98.6% at 250 nm).