Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:12]([I:13])=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:14][CH3:15])[CH:2]=[CH2:3].[CH:16]([C:18]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=1)=[O:19])=[CH2:17].C(O)C>S1C=CN=C1.C(N(CC)CC)C>[CH2:1]([O:4][C:5]1[C:12]([I:13])=[CH:11][C:8]([C:9](=[O:10])[CH2:17][CH2:16][C:18]([C:20]2[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=2)=[O:19])=[CH:7][C:6]=1[O:14][CH3:15])[CH:2]=[CH2:3]
Reactant: C=CCOc1c(I)cc(C=O)cc1OC
Reactant: C=CC(=O)c1cc(OC)c(OC)c(OC)c1
Agent: c1cscn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=CCOc1c(I)cc(C(=O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc1OC
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 4-allyloxy-5-iodo-3-methoxybenzaldehyde (46 g, 0.15 mol), 3,4,5-trimethoxyphenyl vinyl ketone (38 g, 0.16 mol) and thiazole catalyst (6 g, 0.07 mol) in triethylamine (200 ml) was heated, with stirring, at 70° C. for 2 hours, and kept at room temperature overnight. Ethanol was added to the solid mass, filtered, and the filtrate was evaporated to a residue, which was purified by HPLC (hexane-ethyl acetate; 2:1, v/v) to afford 1-(4-allyloxy-5-iodo-3-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione, m.p. 113°-114° C.
Reaction SMILES: O[CH2:2][C:3]1[C:4]2[CH2:5][C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9](=[O:16])[NH:8][C:7]=3[C:17]=2[CH:18]=[CH:19][CH:20]=1.P(Br)(Br)[Br:22]>C1COCC1>[Br:22][CH2:2][C:3]1[C:4]2[CH2:5][C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9](=[O:16])[NH:8][C:7]=3[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: BrP(Br)Br
Reactant: O=c1[nH]c2c(c3ccccc13)Cc1c(CO)cccc1-2
Solvent: C1CCOC1
Product: O=c1[nH]c2c(c3ccccc13)Cc1c(CBr)cccc1-2
Reaction time: 1 h
Yield: 81 %

Procedure:
Fine powder of Compound (I)(25) (10-hydroxymethyl-5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline, 7.3 g, 27.7 mmol) was suspended in THF (150 mL). A solution of PBr3 (83 mL, 1M in dichloromethane) was added dropwise at room temperature. After the complete addition, the resultant mixture was stirred overnight and quenched by addition of water (150 mL). The suspension was stirred for 1 hour and filtered. The resultant solid was washed with water (2×100 mL) and ethyl acetate (2×100 mL) and dried in a vacuum oven to provide 10-Bromomethyl-5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline in 81% yield. 1H NMR spectrum (in DMSO-d6): δ 12.31 (s, 1H); 8.23 d, J=7.5 Hz, 1H); 7.95 (m, 1H); 7.75 (m, 2H); 7.45 (m, 2H); 4.87 (s, 2H); 3.97 (s, 2H).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1>C(O)CC(C)C>[OH:4][CH2:1][C@H:11]1[CH2:10][N:9]2[CH2:13][CH2:8][N:9]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH2:10][C@@H:8]2[CH2:13][CH2:12]1
Reactant: O=C([O-])[O-]
Reactant: Brc1ccccn1
Agent: [Na+]
Solvent: CC(C)CCO
Product: OC[C@@H]1CC[C@H]2CN(c3ccccn3)CCN2C1

Procedure:
A mixture consisting of title product of Preparation 5 (9.10 g; 53.4 mmol), sodium carbonate (14.1 g; 0.13 mol), and 2-bromopyridine (25.5 ml; 42.3 g; 0.27 mol) in isoamylalcohol (25 ml) was refluxed for 72 hours. The reaction was filtered while hot, and the filter cake washed with 50 ml of methylene chloride. The filtrate was concentrated in vacuo to an oil, which was taken up in 100 ml ethyl acetate. An equal volume of water was added, and the pH of the well-stirred mixture was adjusted to 11.5 (saturated sodium carbonate). The organic phase was separated, treated with activated carbon, dried (anhydrous sodium sulfate), and concentrated in vacuo to an oil. Flash chromatography of the entire sample (125 g silica gel, 2-63 mesh; elution with methylene chloride/methanol=7:3 by volume) with TLC monitoring of fractions [product Rf =0.26 (methylene chloride:methanol 9:1 in volume), detection by U.V. and Dragendorf's spray] afforded 7.50 g (56.6% yield) of the title compound as a pale yellow amorphous solid.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CC#N.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([F:27])([F:26])[F:15])[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cccc2cc(C=O)c(-c3ccccc3C(F)(F)F)nc12

Procedure:
Prepared according to Procedure A using 2-chloro-8-methylquinoline-3-carbaldehyde (2.0 g, 9.73 mmol), 2-(trifluoromethyl)phenylboronic acid (2.032 g, 10.7 mmol, 1.1 eq), tetrakis(triphenylphosphine)palladium (562 mg, 5% mmol), and sodium carbonate (5.15 g, 48.6 mol, 5 eq) in MeCN (75 mL) and water (25 mL). After purification, 8-methyl-2-(2-(trifluoromethyl)phenyl)quinoline-3-carbaldehyde was obtained as a white solid. 1H NMR (DMSO-d6) δ ppm 9.93 (1H, s), 9.04 (1H, s), 8.13 (1H, d, J=8.1 Hz), 7.93 (1H, d, J=7.3 Hz), 7.85 (1H, d, J=7.1 Hz), 7.72-7.82 (2H, m), 7.64-7.71 (1H, m), 7.59 (1H, d, J=7.3 Hz), 2.67 (3H, s). Mass Spectrum (ESI) m/e=316.1 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[CH:27]2[O:28][C:26]2([CH3:29])[CH:25]([OH:30])[CH2:24][C:22](=[O:23])[N:21]([CH3:31])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:32])=[CH:9][CH:8]=[CH:7][CH:6]([O:33][CH3:34])[C:5]2([OH:39])[NH:35][C:36]([O:38][CH:3]1[CH2:4]2)=[O:37].[C:40](O)(=[O:44])[CH:41]([CH3:43])[CH3:42].CC(C)N=C=NC(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Sc+3]>[CH3:1][C@H:2]1[C@H:27]2[O:28][C@@:26]2([CH3:29])[C@@H:25]([O:30][C:40]([CH:41]([CH3:43])[CH3:42])=[O:44])[CH2:24][C:22](=[O:23])[N:21]([CH3:31])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:32])=[CH:9][CH:8]=[CH:7][C@@H:6]([O:33][CH3:34])[C@:5]2([OH:39])[NH:35][C:36]([O:38][C@H:3]1[CH2:4]2)=[O:37]
Reactant: CC(C)C(=O)O
Reactant: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)C=CC=C(C)C2
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Agent: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)/C=C/C=C(\C)C2
Solvent: ClCCl
Product: COc1cc2cc(c1Cl)N(C)C(=O)C[C@H](OC(=O)C(C)C)[C@]1(C)O[C@@H]1[C@H](C)[C@@H]1C[C@@](O)(NC(=O)O1)[C@H](OC)C=CC=C(C)C2
Temperature: -8 °C
Reaction time: 0.5 h

Procedure:
A mixture of maytansinol (6.00 mg, 0.01062 mmol), isobutyric acid (23.60 mg, 0.2124 mmol), Sc(OTf)3 (3.14 mg, 0.00637 mmol) and DMAP (3.89 mg, 0.03186 mmol) in CH2Cl2 (1 mL) was stirred for 0.5 h at −8° C. DIC (29.49 mg, 0.2337 mmol) was added dropwise. The mixture was stirred till completion, quenched with diluted HCl, and extracted with CH2Cl2. The organic layer was washed with aq. NaHCO3, brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. Chromatography (silica gel, CH2Cl2/MeOH 30:1) gave the desired product ansamitocin P3. LC-MS (M+Na+) calc.: 657.3. found: 657.4.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[CH3:25])[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.CO.[OH-].[NH4+]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[CH3:25])[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c(C)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.8 %

Procedure:
To a solution of N-tert-butyl-2-(2,4-dimethylphenylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (82 mg, 175 mol) in dichloromethane (2.7 mL) was added trifluoroacetic acid (400 mg, 270 μL, 3.51 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained diluted with dichloromethane (3 mL), methanol (1.5 mL) and ammonium hydroxide (0.4 mL) and stirred at room temperature for 1 h. The mixture was concentrated and triturated with water. The solid was collected by filtration and washed with water and ether to give N-tert-butyl-2-(2,4-dimethylphenylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (7 mg, 20.7 mol, 12%) as a yellow solid. 1H NMR (400 MHz, CDCl3-d) δ ppm: 9.19 (s, 1H), 8.12 (d, J=3.0, 1 H), 7.95 (s, 1H), 7.86 (s, 1H), 7.50 (d, J=7.8, 1 H), 7.15 (s, 1H), 7.08 (d, J=8.2, 1 H), 6.33 (s, 1H), 2.38 (s, 3H), 2.34 (s, 1H), 1.49 (s, 9H); MS (EI/CI) m/z: 338.2 [M+H].
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[C:4]([O:19][CH3:20])[CH:3]=1.[CH2:21]([C:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1)[CH:22]=[CH2:23]>N1C=CC=CC=1>[CH2:21]([C:24]1([S:27]([NH:18][C:5]2[C:4]([O:19][CH3:20])=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=2[NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])(=[O:29])=[O:28])[CH2:26][CH2:25]1)[CH:22]=[CH2:23]
Reactant: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1N
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Solvent: c1ccncc1
Product: C=CCC1(S(=O)(=O)Nc2c(OC)cc(F)c(F)c2Nc2ccc(I)cc2F)CC1
Temperature: 40 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)-3-methoxybenzene-1,2-diamine (1 eq) in anhydrous pyridine (5 ml/mmole) was added 1-allyl-cyclopropanesulfonyl chloride (1-5 eq). The reaction mixture was stirred at 40° C. for 48 hours. The reaction mixture was partitioned with water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica to obtain the title product. 1H NMR (CDCl3, 300 MHz): δ 7.417 (dd, 1H), 7.309 (s, 1H), 7.25 (m, 1H), 6.89 (m, 1H), 6.52 (m, 1H), 6.427 (m, 1H), 6.03 (s, 1H), 5.668 (m, 1H), 5.11 (t, 1H), 3.9 (s, 3H), 2.75 (d, 2H), 1.21 (m, 2H), 0.767 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([OH:17])=[C:6]([O:15][CH3:16])[CH:7]=[C:8]2[CH:13]=[O:14])[CH3:2].[H-].[Na+].[CH3:20][O:21][CH2:22]Cl.O>CN(C=O)C>[CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:17][CH2:20][O:21][CH3:22])=[C:6]([O:15][CH3:16])[CH:7]=[C:8]2[CH:13]=[O:14])[CH3:2]
Reactant: COCCl
Reactant: CCc1cccc2c(C=O)cc(OC)c(O)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Reaction time: 0.17 h

Procedure:
324 g of 5-ethyl-4-hydroxy-3-methoxy-1-naphthalenecarbaldehyde was dissolved in 1 liter of N,N-dimethylformaldehyde, to which 68 g of 60% sodium hydride was gently added under ice-cooling conditions. After agitation for 10 minutes, 128 ml of chloromethyl methyl ether was gradually added so that the reaction temperature did not exceed 15° C. After agitation at room temperature for 20 minutes, the reaction solution was poured into iced water and extracted with ethyl acetate. The resultant organic phase was washed with a saturated saline solution and dried with anhydrous magnesium sulfate. The solvent was distilled off and the resultant residue was purified by silica gel column chromatography (5% ethyl acetate/hexane) to obtain 288 g of the captioned compound as a brown oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O[CH2:44][C:45]([F:48])([F:47])[F:46])(=O)=O)=CC=1.Cl>CN(C)C=O>[F:46][C:45]([F:48])([F:47])[CH2:44][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC(F)(F)F)cc1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
50 grams (0.41 mol) of 4-hydroxybenzaldehyde, 400 ml of N,N-dimethylformamide (DMF), and 5 grams of 18-crown-6 ether was added into a one-litre four-necked flask with thermometer, mechanical stirrer and reflux condenser, and then the mixture was stirred for 20 minutes. 168 grams (1.22 mol) of potassium carbonate powder was added in batch and stirred another 30 minutes. The reaction mixture was heated to 110° C., and then a solution of 115 gram (0.45 mol) of trifluoroethyl toluene-4-sulfonate in 100 ml DMF was added dropwise within about 1 hour. The reaction mixture was heated to 130° C. for 3-4 hours. The reaction was monitored by TLC. The mixture was cooled to 0° C. and was poured into cooled 600 ml of 3N hydrochloric acid, and was stirred. The mixture was extracted with 1000 ml of ether. The water layer was separated and extracted with ether (3×400 ml). The ether extracts were combined and washed with 400 ml of 3N hydrochloric acid, distilled water, brine in turn. Then it was dried over anhydrous magnesium sulfate. The ether was removed by flash distillation, and the residue was vacuum distilled to give 4-trifluoroethoxybenzaldehyde (95-97° C./10 mmHg) in a yield of 88%. 1H-NMR (ppm) δ: 9.80 (1H, s; —CHO); 7.65 (2H, m; 2,6-ArH); 6.83 (2H, m; 3,5-ArH); 4.56 (2H, q; J3H-F=7.2 Hz; —CH2CF3).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[N:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH2:31][C:32](=[O:38])[NH:33]3)=[CH:25][CH:24]=1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1/[CH:21]=[C:31]1\[C:32](=[O:38])[NH:33][C:34]2[C:30]\1=[C:29]([C:26]1[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=1)[CH:37]=[CH:36][CH:35]=2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: Cc1c(/C=C2\C(=O)Nc3cccc(-c4ccncc4)c32)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Yield: 54 %

Procedure:
The title compound was prepared under the same conditions as described in step 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d obtained from step 4 of Example 32 and 4-pyridin-4-yl-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-3-methyl-2-(2-oxo-4-pyridin-4-yl-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-piperidin -1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 54 (40 mg, yield 54%) as a yellow solid.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22](=[O:36])[CH2:23][C:24]=1[C:25]1[S:29][C:28]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[N:27][CH:26]=1)[CH:20]([NH:37]C(OC(C)(C)C)=O)[C:19]2=[O:45])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O)(=O)=O>C(#N)C>[NH2:37][CH:20]1[C:19](=[O:45])[N:18]2[CH:21]1[S:22](=[O:36])[CH2:23][C:24]([C:25]1[S:29][C:28]([C:30]3[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=3)=[N:27][CH:26]=1)=[C:17]2[C:15]([O:14][CH:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(-c4ccncc4)s3)CS(=O)C12
Agent: CS(=O)(=O)O
Solvent: CC#N
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(-c4ccncc4)s3)CS(=O)C12
Yield: 50 %

Procedure:
2-Benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-[2-(pyridin-4-yl)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene 5-oxide (6.4 g) is treated with methanesulphonic acid (6 cc) in acetonitrile (60 cc) in accordance with the procedure of Example 2 to give 7-amino-2-benzhydryloxycarbonyl-8-oxo-3-[2-(pyridin-4-yl)thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene 5-oxide (2.7 g) in the form of a hard brown foam.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].C(=O)([O-])O.[Na+]>CC(C)=O>[CH3:2][C:3]1([CH3:5])[O:4][C@@H:3]([C@H:5]2[O:6][C@H:11]([OH:12])[C@H:9]3[O:10][C:9]([CH3:11])([CH3:7])[O:8][C@@H:7]23)[CH2:2][O:1]1
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](O)O[C@@H]2[C@H]1COC(C)(C)O1
Reaction time: 3 h
Yield: 180 %

Procedure:
To 250 ml of acetone were added 10.0 g of D-mannose and 125 mg of anhydrous cupric chloride, and the mixture was stirred for 3 hours under reflux in a warm-water bath at 57° to 58° C. The refluxing solvent was continuously dried with 20 g of molecular sieves 3A which was placed between the reaction vessel and the cooling tube. After the conclusion of the reaction, a small amount of aqueous sodium hydrogencarbonate was added to the reaction mixture, and the acetone was distilled off under reduced pressure. The residue was dissolved in benzene, and the benzene solution was washed with aqueous sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. When the benzene was distilled off under reduced pressure, there was obtained 13.0 g (90%) of 2,3:5,6-di-O-isopropylidene-α-D-mannofuranose (purity of not less than 92%). The compound, when recrystallized from petroleum ether, showed a melting point of 122° to 123° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]([OH:23])[CH:7]([N:18]1[CH2:21][CH2:20][C:19]1=[O:22])[C:8]([O:10]CC1C=CC=CC=1)=[O:9])=[N+]=[N-].O.CCOCC>C(O)C.[Pd]>[NH2:1][CH2:4][CH2:5][CH:6]([OH:23])[CH:7]([N:18]1[CH2:21][CH2:20][C:19]1=[O:22])[C:8]([OH:10])=[O:9]
Reactant: [N-]=[N+]=NCCC(O)C(C(=O)OCc1ccccc1)N1CCC1=O
Agent: [Pd]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: NCCC(O)C(C(=O)O)N1CCC1=O
Yield: 29.1 %

Procedure:
Benzyl 5-azido-3-hydroxy-2-(2-oxo-azetidin-1-yl)-valerate (1.6 g, 5 mmol) as a mixture of diastereoisomers prepared as Example 1, was hydrogenated at atmospheric pressure in ethanol (45 ml) and water (7 ml) with 5% palladium on carbon catalyst (900 mg). When no more hydrogen was absorbed the reaction mixture was filtered and the filtrate evaporated to yield a gum. Trituration with ether yielded a solid which was filtered off and dried under vacuum to yield a friable foam. The foam was triturated with methanol to give a white solid and pale yellow solution. The solid was filtered off and dried to yield the less soluble diasteroisomer of the title compound (294 mg) as a white powder m.p. 152°-153.5°. νmax (KBr) 3422, 1709, 1637, 1578, 1376, 1333, 1248, 1228 and 1151; δH (D2O, 250 MHz) 1.93 (2H, m), 3.03 (2H, t, J 4 Hz), 3.21 (2H, m), 3.55 (2H, m), and 4.21 (2H, m); δC (D2O, 100 MHz) 31.06, 36.23, 37.99, 41.03, 62.49, 69.54, 172.40 and 174.74. (Found: C, 45.85, H, 6.77; N, 12.94 %; C8H14N2O4 1/2H2O requires C, 45.49; H, 7.16; N, 13.26 %).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([OH:26])[C:3]=1[OH:27].C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[Br:1][C:2]1[C:3]([O:27][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:4]([OH:26])[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc(Br)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 58.9 %

Procedure:
A suspension of 3-bromo-5-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-benzene-1,2-diol (0.390 g, 0.78 mmol) and potassium carbonate (0.108 g, 0.78 mmol) in DMF (4 mL) was stirred at 0 ° C. under a dry N2 atmosphere for 20 min. Benzyl bromide (0.093 mL, 0.78 mmol) was added dropwise to this mixture over a period of ten minutes. After the mixture was stirred at 0 ° C. for 6.5 h., the reaction mixture was quenched with aqueous hydrochloric acid to pH 1 and further diluted with water (60 mL) and aqueous mixture was extracted with methylene chloride (2×60 mL). The combined organic extracts were washed with water and dried with brine. Silica gel (5 mL) was added. Solvent was removed and the adsorbate was flash chromatographed (eluents: petroleum ether:methylene chloride 6:4 to petroleum ether:ethyl acetate 6:4) to provide a mixture (271 mg, 59%) of the title compound (87%) and 2-bromo-4-(6) -bromo-benzo[b]naphtho[2,3-d]thiophen- 11 -yl)-6-benzyloxy-phenol (13%). The mixture was used for next reaction without separation: NMR (CDCl3): δ8.35 (d, J=8 Hz, 1 H), 7.79 (d, J=8 Hz, 1 H), 7.72-7.33 (m, 9 H), 7.18 (d, J=2 Hz, 1 H), 7.17 (ddd, J=8, 7, 1 Hz, 1 H), 6.93 (d, J=2 Hz, 1H), 6.87 (d, J=8 Hz, 1 H), 5.71 (s, 1H), 5.32 (t, J=7 Hz,2 H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:3]=1.[OH:27][CH2:28][C:29]([NH:32][S:33]([C:36]1[CH:37]=[N:38][CH:39]=[C:40](Br)[CH:41]=1)(=[O:35])=[O:34])([CH3:31])[CH3:30]>>[OH:27][CH2:28][C:29]([NH:32][S:33]([C:36]1[CH:37]=[N:38][CH:39]=[C:40]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:6]3[CH:5]=[C:4]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:9]=2)[CH:41]=1)(=[O:35])=[O:34])([CH3:31])[CH3:30]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(B(O)O)c2)n1
Reactant: CC(C)(CO)NS(=O)(=O)c1cncc(Br)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cncc(S(=O)(=O)NC(C)(C)CO)c3)c2)n1

Procedure:
The title compound was prepared from 3-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-benzeneboronic acid (example G.9) (0.20 g, 0.56 mmol) and 5-bromo-pyridine-3-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example H.2) (0.173 g, 0.56 mmol) according to the general procedure VI. Obtained as a white solid (0.080 g, 26%). MS (ISP) 542.2 [(M+H)+]; mp 105° C. (dec.).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:21][C:22]1[N:26]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:25]2[CH:36]=[CH:37][CH:38]=[CH:39][C:24]=2[N:23]=1)[CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:30]1([S:27]([N:26]2[C:25]3[CH:36]=[CH:37][CH:38]=[CH:39][C:24]=3[N:23]=[C:22]2[CH2:21][N:12]([CH2:13][C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:11][CH2:10][CH2:9][CH2:8][NH2:7])(=[O:29])=[O:28])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1cccnc1CN(CCCCNC(=O)OC(C)(C)C)Cc1nc2ccccc2n1S(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccnc1CN(CCCCN)Cc1nc2ccccc2n1S(=O)(=O)c1ccccc1
Yield: 43.1 %

Procedure:
To a solution of {4-[(1-Benzenesulfonyl-1H-benzoimidazol-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester (0.202 g, 0.36 mmol) in CH2Cl2 (3 mL) was added TFA (2 mL) and the resultant solution was stirred at room temperature for 1 hour. The mixture was concentrated and the residue was portioned between CH2Cl2 (10 mL) and saturated Na2CO3 (5 mL). Solid Na2CO3 was added until the aqueous phase was basic (pH˜9) to litmus paper. The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 50:1:1 CH2Cl2-MeOH—NH4OH) provided 72 mg (42%) of COMPOUND 144 as a pale yellow oil. 1H NMR (CDCl3) δ 1.25-1.37 (m, 2H), 1.47-1.57 (m, 4H), 2.16 (s, 3H), 2.58 (t, 2H, J=7.2 Hz), 2.78 (t, 2H, J=7.5 Hz), 4.03 (s, 2H), 4.33 (s, 2H), 7.07 (dd, 1H, J=4.8, 7.5 Hz), 7.30-7.44 (m, 5H), 7.55-7.60 (m, 1H), 7.68-7.72 (m, 1H), 7.93-8.03 (m, 3H), 8.35 (d, 1H, J=4.2 Hz); 13C NMR (CDCl3) δ 18.78, 23.49, 31.79, 42.22, 52.27, 53.79, 57.83, 113.92, 120.73. 122.61, 125.01, 125.47, 127.66, 129.70, 133.28, 133.45, 134.77, 138.31, 138.69, 142.14, 146.48, 152.39, 157.18; ES-MS m/z 464 (M+H). Anal. Calcd. For C25H29N5O2S.0.7H2O: C, 63.06; H, 6.43; N, 14.71; S, 6.73. Found: C, 63.10; H, 6.48; N, 14.42; S, 6.52.