Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[CH:17]=[C:15]([CH3:16])[C:13](=O)[NH:12][C:10]1=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:37]([O:41][C:42]([N:44]1[CH2:48][C@@H:47]([N:49]2[C:53](=[O:54])[C:52]3=[CH:55][CH:56]=[CH:57][CH:58]=[C:51]3[C:50]2=[O:59])[CH2:46][C@@H:45]1[CH2:60]O)=[O:43])([CH3:40])([CH3:39])[CH3:38].CC[O:64]C(/N=N/C(OCC)=O)=O.[Al]>C1COCC1>[C:37]([O:41][C:42]([N:44]1[CH2:48][C@@H:47]([N:49]2[C:50](=[O:59])[C:51]3=[CH:58][CH:57]=[CH:56][CH:55]=[C:52]3[C:53]2=[O:54])[CH2:46][C@@H:45]1[CH2:60][N:12]1[CH:13]=[C:15]([CH3:16])[C:17](=[O:64])[N:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]1=[O:11])=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N2C(=O)c3ccccc3C2=O)C[C@@H]1CO
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: Cc1cn(C(=O)c2ccccc2)c(=O)[nH]c1=O
Agent: [Al]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cn(C[C@H]2C[C@H](N3C(=O)c4ccccc4C3=O)CN2C(=O)OC(C)(C)C)c(=O)n(C(=O)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of N3 -benzoylthymine 20 (1.15 g, 5 mmol) in dry THF (70 ml) under argon was added triphenyl phosphine (2.62 g, 10 mmol) and (2R,4S)-1-(tert-Butyloxycarbonyl)-2-hydroxymethyl-4-phthalimido-pyrrolidine (1.4 g, 4.05 mmol) at room temperature. After 15 min, diethylazodicarboxylate (1.74 g, 10 mmol) was added slowly during 10 min period. The reaction mixture was covered with aluminum foil and allowed to stir at room temperature under argon for 24 h. The solvent was evaporated to dryness and the residue dissolved in EtOAc (150 ml). The organic extract was washed with 5% NaHCO3 solution (100 ml), water (100 ml) and brine (100 ml), and dried over anhydrous Na2SO4. The dried EtOAc extract was evaporated to dryness to give an orange oil. The crude product was purified by flash chromatography over silica gel using hexane→EtOAc as the eluent. The fraction having the required product was pooled and evaporated to give a pale pink oil. Yield: 2.0 g (89%). 1HNMR (CDCl3): 1.41 (s, 9H, Boc), 1.72 (s, 3H, CH3), 1.90 (dd, 1H), 2.34 (m, 1H), 3.40-3.62 (m, 3H), 4.00 (m, 2H), 4.28 (bs, 1H), 4.44 (m, 1H), 7.06 (s, 1H, C6H) and 7.20-7.60 (m, 9H, Ph).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][C:6](=[O:8])[O:5][C:3]1=[O:4].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCl>[C:10]1([NH:9][C:6]([CH2:7][C:2](=[CH2:1])[C:3]([OH:5])=[O:4])=[O:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=C1CC(=O)OC1=O
Reactant: Nc1ccccc1
Agent: CCl
Product: C=C(CC(=O)Nc1ccccc1)C(=O)O

Procedure:
A solution of 2-methylenesuccinic anhydride (500 mg, 4.46 mmol) and aniline (0.4 mL, 4.46 mmol) in CH3Cl were shaken overnight. A precipitate formed, which was filtered off, washed with hexanes, and dried under vacuum to afford 2-[(N-phenylcarbamoyl)methyl]prop-2-enoic acid.
Reaction SMILES: [CH2:1]([S:5][C:6]1[N:11]=[C:10](Cl)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[N+:13]([C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][NH:20]2)([O-:15])=[O:14].[H-].[Na+].CN1C(=O)CCC1>O>[CH2:1]([S:5][C:6]1[N:11]=[C:10]([N:20]2[C:21]3[C:17](=[C:16]([N+:13]([O-:15])=[O:14])[CH:24]=[CH:23][CH:22]=3)[CH:18]=[N:19]2)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Reactant: CCCCSc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCCSc1nccc(-n2ncc3c([N+](=O)[O-])cccc32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
To a flask loaded with 2-butylsulfanyl-4-chloro-pyrimidine (202 mg) was added 4-nitro-1H-indazole (228 mg), followed by NaH (60% dispersion in mineral oil, 84 mg) and NMP (4 mL). The resulting mixture was stirred at RT overnight, water added, and the mixture extracted with EtOAc. The combined organic extracts were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (hexane/EtOAc, 80:20) to give 1-(2-butylsulfanyl-pyrimidin-4-yl)-4-nitro-1H-indazole (156 mg).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=O.[NH2:14][C:15]([NH2:17])=[S:16].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:17][C:15]1[S:16][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[N:14]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.3 %

Procedure:
A mixture of 2-bromo-3′-nitroacetophenone (12.2 g) and thiourea (3.81 g) in ethanol (100 ml) was stirred at room temperature for 15 minutes. The reaction mixture was poured into a mixture of ethyl acetate and an aqueous sodium bicarbonate solution. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 2-amino-4-(3-nitrophenyl)thiazole (10.21 g).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[S:7][C:8]([C:11](=O)[CH2:12][Br:13])=[CH:9][N:10]=1)(=[O:3])[CH3:2].[NH2:15][C:16](=[N:18][C:19]([NH2:21])=[S:20])[NH2:17]>CC(C)=O>[BrH:13].[BrH:13].[C:1]([NH:4][CH2:5][C:6]1[S:7][C:8]([C:11]2[N:21]=[C:19]([N:18]=[C:16]([NH2:17])[NH2:15])[S:20][CH:12]=2)=[CH:9][N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1ncc(C(=O)CBr)s1
Reactant: NC(=S)N=C(N)N
Solvent: CC(C)=O
Product: Br
Product: CC(=O)NCc1ncc(-c2csc(N=C(N)N)n2)s1
Yield: 42.4 %

Procedure:
A mixture of 2-acetylaminomethyl-5-bromoacetylthiazole (6.30 g) and diaminomethylenethiourea [(H2N)2C=NCSNH2 ] (1.77 g) in acetone (90 ml) was refluxed for 10 hours with stirring. The resulting precipitate was collected by filtration to give 4-(2-acetylaminomethylthiazol-5-yl)-2-(diaminomethyleneamino)thiazole dihydrobromide (2.21 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[N+:13]([CH3:16])([O-:15])=[O:14].[OH-].[Na+].Cl>O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:16]/[N+:13]([O-:15])=[O:14])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1cc(C=O)cc(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(/C=C/[N+](=O)[O-])cc(OC)c1
Temperature: 0 °C

Procedure:
A solution of 3,5-dimethoxybenzaldehyde (34.5 g., 0.208 mole) and nitromethane (12.69 g., 0.208 mole) in 40 ml. of MeOH was cooled to 0° under N2. A solution was prepared by dissolving NaOH (8.43 g., 0.211 mole) in 10 ml. of H2O then diluting to 20 ml. with ice-water. This solution was then added dropwise to the methanol mixture. After 15 minutes the reaction was diluted with ice-H2O and added slowly to a solution of 40 ml. concentrated HCl in 60 ml. H2O. The resulting precipitate (44 g.) was filtered and recrystallized from methanol to give 28.6 g. of product, m.p. 132°; reported, J. Org. Chem. 27, p. 376 (1962), m.p. 133.5-134.5.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.[CH3:8][O:9][CH2:10][C@H:11](O)[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:8][O:9][CH2:10][C@@H:11]([O:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[CH3:12]
Reactant: Oc1ccncc1
Reactant: COC[C@@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1ccncc1
Reaction time: 0.17 h
Yield: 87 %

Procedure:
Pyridin-4-ol (10 g, 105.15 mmol), (R)-1-methoxypropan-2-ol (9.48 g, 105.15 mmol) and triphenylphosphine (30.3 g, 115.67 mmol) were added to THF (250 mL) and stirred for 10 minutes. To this was slowly added DIAD (22.49 mL, 115.67 mmol) and the reaction was stirred for 1 hour at 25° C. The solvent was evaporated and diethyl ether (100 mL) was added. To this was added a little triphenyl phosphine oxide and the reaction was stirred for 20 minutes to afford a solid, which was discarded. The solvent was evaporated and the pale yellow gum was acidified with 2.0 HCl, extracted with Et2O (1×75 mL) and the aqueous was then basified with solid KOH. This was then extracted with Et2O (3×75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford yellow gum. This was purified by distillation at 0.43 mBar, collecting fractions that distilled at 80° C. to afford the desired material as a colourless oil (15.30 g, 87% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.34 (3H, d), 3.40 (3H, s), 3.50 (1H, dd), 3.58 (1H, dd), 4.68-4.60 (1H, m), 6.82 (2H, d), 8.40 (2H, d); m/z (LC-MS, ESI+), RT=1.28 (M+H 168).
Reaction SMILES: C1(=O)N([CH:6]([S:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([OH:9])=[O:8])C(=O)CC1.[OH-].[Na+].SCC(O)=O.C(Cl)(=O)C1C=CC=CC=1>O.C1(C)C=CC=CC=1>[C:11]([S:10][CH2:6][C:7]([OH:9])=[O:8])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(SC(C(=O)O)N1C(=O)CCC1=O)c1ccccc1
Agent: O=C(O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(O)CSC(=O)c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
In advance, succinimidyl-S-benzoylmercaptoacetic acid (BMS) was synthesized as follows. Two-layer system of toluene (75 mL) and water (75 mL) was cooled in an ice-water bath, sodium hydroxide (8.86 g, 221.5 mmol) was added thereto. Next, mercaptoacetic acid (9.22 g, 100 mmol) was added dropwise and washed with 5 mL of water. Further, benzoyl chloride (14.61 g, 100.3 mmol) was added dropwise, and washed with 5 mL of toluene. The reaction was conducted with stirring at about 5° C. for 30 minutes, then at room temperature for 3.5 hours. The reaction mixture was subjected to separation, the organic layer was extracted in 3 times with 10 mL of water, and the aqueous layers were combined together. Under stirring, 12 mL of concentrated hydrochloric acid was added dropwise to the aqueous layer to adjust pH 1-2, and the crystals formed were collected by filtration. The crystals were dried in a desiccator, then washed with hexane, and dissolved in ethyl acetate. The solvent was distilled away to give S-benzoylmercaptoacetic acid (19.19 g, 97.8 mmol, 98% yield) as colorless needle-like crystals.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].OC1C=C(C=CC=1)C(=O)C=CC1C=CC2OCOC=2C=1>>[OH:21][C:17]1[CH:16]=[C:15]([C:13](=[O:14])[CH2:12][CH2:11][C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:10][O:2][C:3]=3[CH:4]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(CCC(=O)c2cccc(O)c2)cc1OC
Agent: O=C(C=Cc1ccc2c(c1)OCO2)c1cccc(O)c1
Product: O=C(CCc1ccc2c(c1)OCO2)c1cccc(O)c1
Yield: 41 %

Procedure:
Prepared in a similar manner as (7) from 3′-Hydroxy-3,4-methylenedioxy chalcone (6). Crystallization of crude material from EtOAc/hexanes afforded 4.10 g (41%) of white solids: 1H NMR (CDCl3, 300 MHz) 9.73 (s, 1H), 7.43 (d, J=7.8 Hz, 1H), 734-7.29 (m, 2H), 7.02 (dd, J=8.0 Hz, 1H), 6.88 (m, 1H), 6.80 (d, J=7.9 Hz, 1H), 6.71 (d, J=7.9 Hz, 1H), 5.96 (s, 2H), 3.26 (t, J=7.6 Hz, 2H), 2.84 (t, J=75 Hz, 2H); 13C NMR (CDCl3, 75 MHz) 199.4, 158.0, 147.5, 145.7, 138.4, 135.4, 130.1, 121.5, 120.5, 1193, 114.4, 1092, 108.4, 101.0, 402, 29.7.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:28]=[CH:27][C:11]([NH:12][C:13]2[C:18]([C:19](OCC)=[O:20])=[C:17]([CH3:24])[N:16]=[C:15]([S:25][CH3:26])[N:14]=2)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>C(O)C>[OH:20][CH2:19][C:18]1[C:13]([NH:12][C:11]2[CH:27]=[CH:28][C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[CH:9][CH:10]=2)=[N:14][C:15]([S:25][CH3:26])=[N:16][C:17]=1[CH3:24]
Reactant: CCOC(=O)c1c(C)nc(SC)nc1Nc1ccc(C(=O)OC(C)(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CSc1nc(C)c(CO)c(Nc2ccc(C(=O)OC(C)(C)C)cc2)n1
Reaction time: 4 h

Procedure:
To a suspension of compound E (30 g; 0.0743 mol) in 500 mL of anhydrous ethanol at 45° C. NaBH4 (15 g; 0.397 mol) was added portion-wise under vigorous stirring. After 4 h the reaction mixture was brought to room temperature and was poured into 2 L of iced water, vigorously stirred for 10′ and extracted with ethyl acetate (2×600 mL). The organic phase was washed with water until neutral pH, with brine and dried over anhydrous sodium sulphate. After evaporation the crude compound F (22 g; 82%) was used without further purification in the next step.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH3:22])=[C:12]([NH:14]C(=O)OC(C)(C)C)[CH:13]=2)[N:4]=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.C([O-])([O-])=O.[K+].[K+].[F:43][C:44]1([F:51])[C:47]([F:49])([F:48])[CH2:46][CH:45]1O>ClCCl.O>[CH3:22][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[N:4]=[C:3]([CH2:2][O:1][CH:46]3[CH2:45][C:44]([F:51])([F:43])[C:47]3([F:49])[F:48])[O:7][N:6]=2)=[CH:13][C:12]=1[NH2:14]
Reactant: Cc1ccc(-c2noc(CO)n2)cc1NC(=O)OC(C)(C)C
Reactant: OC1CC(F)(F)C1(F)F
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2noc(COC3CC(F)(F)C3(F)F)n2)cc1N
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
Tert-butyl (5-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)carbamate (137) (0.35 g, 1.15 mmol) was dissovled in dichloromethane (5 mL) and followed by addition of DIEA (0.6 mL, 3.45 mmol) and MsCl (197 mg, 1.72 mmol). The reaction was stirred for 10 minutes. The mixture was diluted with dichloromethane (10 mL) and washed with water. The organic layers were combined, dried over Na2SO4, filtered and concentrated to give a residue which was dissolved in 2,2,3,3-tetrafluorocyclobutanol (2 mL) and followed by addition of K2CO3(476 mg, 3.45 mmol). The reaction mixture was heated at 90° C. for 2-3 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated. To this residue was added TFA (1 mL) and stirred for 15 minutes. Then aqueous Na2CO3(2M, 20 mL) was added and extracted with EtOAc. The organic layers were dried over Na2SO4, filtered and concentrated. Purification by column chromatography on silica gel gave 2-methyl-5-(5-((2,2,3,3-tetrafluorocyclobutoxy)methyl)-1,2,4-oxadiazol-3-yl)aniline (138). 1H NMR (400 MHz, CDCl3) δ 9.36 (bs, 2H), 8.12 (d, J=1.2 Hz, 1H), 7.91 (dd, J=1.2, 8.0 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 4.95 (dd, J=14.4, 68.4 Hz, 2H), 4.51 (m, 1H), 2.95 (m, 1H), 2.51-2.68 (m, 4H). MS m/z 332.0 (M+1)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH:20]1[O:24][CH2:23][CH2:22][CH2:21]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:25]([O-])=[O:26].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:25]=[O:26])[C:5]([N:7]([CH2:19][CH:20]1[O:24][CH2:23][CH2:22][CH2:21]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: O=C(NCCCl)N(CC1CCCO1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: O=CO
Product: O=NN(CCCl)C(=O)N(CC1CCCO1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
3.7 g of 1-(2-chloroethyl)-3-tetrahydrofurfuryl-3-(D-galactopyranosyl)urea are dissolved in 15 ml of formic acid, and 2.1 g of sodium nitrite are added gradually thereto at 0° C. for one hour under stirring. The mixture is further stirred at the same temperature for 30 minutes. 100 ml of etherhexane (1:1) are added to the reaction mixture. The resultant oil is washed with ether. Then, 100 ml of ethyl acetate-methanol (10:1) are added to said oil, and insoluble materials are removed by filtration. The filtrate is evaporated to remove solvent, and the residue obtained is purified by silica gel chromatography (Solvent: ethyl acetate-chloroform-methanol (5:2:1)). 0.9 g of 1-(2-chloroethyl)-1-nitroso-3-tetrahydrofurfuryl-3-(D-galactopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: [CH3:1][O:2]/[CH:3]=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][OH:23])[CH:17]=1)/[C:5]([O:7][CH3:8])=[O:6].[Cr](O)(O)(=O)=[O:25].O>CC(C)=O>[CH3:1][O:2]/[CH:3]=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([OH:25])=[O:23])[CH:17]=1)/[C:5]([O:7][CH3:8])=[O:6]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cccc(CO)c1
Reactant: O=[Cr](=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cccc(C(=O)O)c1
Yield: 98.3 %

Procedure:
To (E)-methyl 3-methoxy-2-(2-[3-hydroxymethylphenoxy]phenyl)propenoate (2.43 g, prepared as described in Example 17) stirred in acetone (100 ml) at 5°-10° C., was added chromic acid [made by dissolving chromium trioxide (6.5 g) in 18.5 ml water containing 5.5 ml of concentrated sulphuric acid]until a reddish brown colour persisted, and GC indicated the disappearance of all the starting alcohol. The mixture was then poured into water and extracted with ether. The ether extracts were washed with water, dried and evaporated to give (E)-methyl 3-methoxy-2-(2-[3-carboxyphenoxy]phenyl)propenoate as a pale yellow oil (2.495 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH2:10]([O:12][C:13](=[O:21])[CH2:14][C:15]([CH2:17][O:18][CH2:19][CH3:20])=O)[CH3:11].[CH2:22]([O:24][C:25](=[O:30])/[CH:26]=[C:27](\[NH2:29])/[CH3:28])[CH3:23]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([I:1])[CH:3]=2)[C:26]([C:25]([O:24][CH2:22][CH3:23])=[O:30])=[C:27]([CH3:28])[NH:29][C:15]=1[CH2:17][O:18][CH2:19][CH3:20])=[O:21])[CH3:11]
Reactant: O=Cc1cccc(I)c1
Reactant: CCOCC(=O)CC(=O)OCC
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CCO
Product: CCOCC1=C(C(=O)OCC)C(c2cccc(I)c2)C(C(=O)OCC)=C(C)N1
Yield: 60 %

Procedure:
A solution of 5.8 g of 3-iodobenzaldehyde, 4.4 g of γ-ethoxyacetoacetic acid ethyl ester and 3.3 g of β-aminocrotonic acid ethyl ester in 30 ml of ethanol is heated to the boil overnight and is then cooled. After cooling, 2-ethoxymethyl-6-methyl-4-(3'-iodophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is obtained in a yield of 60% of theory in the form of light yellow crystals which melt at 124°C.
Reaction SMILES: S=[C:2]1[C@H:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6][C:5]2[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=2[NH:3]1.[CH3:24][O:25][CH:26]([O:29][CH3:30])[CH2:27][NH2:28]>O1CCCC1.[Hg](Cl)Cl>[CH3:24][O:25][CH:26]([O:29][CH3:30])[CH2:27][NH:28][C:2]1[C@H:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6][C:5]2[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=2[N:3]=1
Reactant: O=C(N[C@@H]1CCc2ccccc2NC1=S)OCc1ccccc1
Reactant: COC(CN)OC
Agent: Cl[Hg]Cl
Solvent: C1CCOC1
Product: COC(CNC1=Nc2ccccc2CC[C@H]1NC(=O)OCc1ccccc1)OC
Temperature: 25 °C
Yield: 92.2 %

Procedure:
Combine benzyl N-[(3R)-2-thioxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]carbamate (8.71 g, 26.68 mmol), mercury dichloride (HgCl2) (9.42 g, 34.69 mmol), and aminoacetaldehyde dimethyl acetal (11.65 mL, 106.73 mmol;) in tetrahydrofuran (250 mL) and heat to 55° C. for 20 minutes. Cool the mixture to ambient temperature and filter it through diatomaceous earth. Wash the cake with THF and ethyl acetate and concentrate the filtrate under reduced pressure. Dissolve the resulting oil in dichloromethane, wash with warm water (4×) and brine, dry over sodium sulfate, and concentrate the organic layer under reduced pressure to give the title compound (9.78 g, 92%) as a solid: MS (m/z): 398 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:20])([CH3:19])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17].C(N(C(C)C)[P:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])(C)C.N1C=NN=N1.OO.S(=O)(=O)(O)[O-:47].[Na+]>O1CCCC1>[P:25]([O:1][CH2:2][C:3]([CH3:20])([CH3:19])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:13])(=[O:14])[NH2:15])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:47]
Reactant: CC(C)(CO)CNc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Reactant: O=S(=O)([O-])O
Reactant: CC(C)N(C(C)C)P(OC(C)(C)C)OC(C)(C)C
Agent: OO
Agent: [Na+]
Agent: c1nnn[nH]1
Solvent: C1CCOC1
Product: CC(C)(CNc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-])COP(=O)(OC(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of EXAMPLE 4A (540 mg) in tetrahydrofuran (5 ml) was added di-tert-butyl diisopropylphosphoramidite (0.84 ml) and 0.45 M 1H-tetrazole (7.91 ml) at 0° C. The mixture was stirred at room temperature for 1.5 hours and cooled to 0° C. 30% Hydrogen peroxide (0.82 ml) was added. The mixture was stirred at room temperature for 30 minutes. Ice water and sodium bisulfate (1.1 g) were added. The resulting mixture was diluted with dicholormethane and the organic layer was washed with water extensively until the water layer became pH neutral. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography, eluting with 0-66% ethyl acetate in dichloromethane to provide the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]([NH:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[CH:6]=[N:5]1.[NH2:39][CH:40]([CH2:50][NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:41][NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46].C(N(CC)CC)C.O>CN(C)C=O>[OH:1][CH2:2][CH2:3][N:4]1[C:8]([NH:9][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:7]([NH:29][C:30]([NH:39][CH:40]([CH2:50][NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:41][NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:31])[CH:6]=[N:5]1
Reactant: O=C(Nc1cnn(CCO)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(N)CNC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)NC(=O)Nc1cnn(CCO)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.4 %

Procedure:
To a stirred solution of phenyl [1-(2-hydroxyethyl)-5-(tritylamino)-1H-pyrazol-4-yl]carbamate (1 g) in N,N-dimethylformamide (10 ml) were added di-tert-butyl (2-amino-1,3-propanediyl)biscarbamate (631 mg) and triethylamine (0.83 ml), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture and the whole mixture was extracted with ethyl acetate. The extract was washed with water and brine and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave a crude product, which was triturated with ethyl acetate-diisopropyl ether (1:3). The resulting solid was collected by filtration to give di-tert-butyl {2-[({[1-(2-hydroxyethyl)-5-(tritylamino)-1H-pyrazol-4-yl]amino}carbonyl)amino]-1,3-propanediyl}biscarbamate (435 mg).