Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].Cl[S:4]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10]2)(=[O:6])=[O:5]>C(Cl)(Cl)Cl.C(Cl)Cl.C(O)C>[CH3:1][NH:2][S:4]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10]2)(=[O:6])=[O:5]
Reactant: CN
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: CCO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
Methylamine (2.7 ml of a 2.9M solution in chloroform) was added to a suspension of 5-chlorosulphonyloxindole (900 mg, 3.9 mmol), (prepared as described for the starting material in Example 60), in a mixture of methylene chloride (20 ml) and ethanol (20 ml). The mixture was stirred for 15 minutes at ambient temperature, the volatiles were removed by evaporation. The solid residue was suspended in water, collected by filtration, washed with water, ether, and dried under vacuum over phosphorus pentoxide to give 5-methylaminosulphonyloxindole (880 mg, 90%).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][C:2]1=[O:12].[N+:13]([O-])([OH:15])=[O:14].S(=O)(=O)(O)O>O>[N+:13]([C:10]1[CH:9]=[CH:8][C:7]2[NH:1][C:2](=[O:12])[CH2:3][CH2:4][CH2:5][C:6]=2[CH:11]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=C1CCCc2ccccc2N1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1CCCc2cc([N+](=O)[O-])ccc2N1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2 g of 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one are added to a solution of 25 ml of nitric acid at 70% in water and of 35 ml of sulfuric acid cooled to 0° C. The reaction medium is stirred for 15 minutes at 0° C. and then poured into water (250 ml) and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous sodium bicarbonate solution and with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is taken up with diisopropyl ether and the insoluble material is filtered off and dried under vacuum, so as to give 1.04 g of 7-nitro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in the form of a beige solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.C(#N)C.C(N(C(C)C)CC)(C)C>CCOC(C)=O.Cl>[C:10]([O:9][C:8](=[O:14])[NH:7][CH:4]1[CH2:3][CH2:2][N:1]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:6][CH2:5]1)([CH3:11])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 150 °C

Procedure:
tert-Butyl piperidin-4-ylcarbamate (1.200 g, 5.992 mmol) and 4-fluoronitrobenzene (0.705 g, 4.99 mmol) were placed in a 30 mL microwave vial then acetonitrile (20 mL) followed by diisopropylethylamine (1.778 mL, 9.986 mmol) were added. The reaction was heated under microwave irradiation at 150° C. for 15 minutes. The reaction mixture was diluted with EtOAc (200 mL) and 2 M aq. HCl (150 mL), the layers were separated and the aqueous layer was extracted with EtOAc (2×100 mL), the organics were combined and washed with brine (150 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (I74) (1.040 g, 65%) as a yellow solid; 1H NMR (400 MHz, d6-DMSO) 8.06-7.99 (m, 2H), 7.03-6.97 (m, 2H), 6.88 (d, J=7.5 Hz, 1H), 4.01-3.93 (m, 2H), 3.62-3.47 (m, 1H), 3.13-3.02 (m, 2H), 1.85-1.74 (m, 2H), 1.44-1.30 (m, 11H).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][C:21]=1[N+:30]([O-:32])=[O:31]>ClCCl>[N+:30]([C:21]1[CH:22]=[N:23][C:24]2[C:29]([C:20]=1[NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:28][CH:27]=[CH:26][CH:25]=2)([O-:32])=[O:31]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
Triethylamine (66.8 g, 0.33 mol) was added to a solution of tert-butyl N-(2-aminoethyl)carbamate (55.0 g, 0.34 mol) in anhydrous dichloromethane (500 mL). 4-Chloro-3-nitroquinoline (68.2 g, 0.33 mol) was slowly added and the reaction exothermed. The reaction mixture was allowed to stir at ambient temperature overnight. The resulting precipitate was isolated by filtration to provide product as a yellow solid. The filtrate was washed with water, dried over magnesium sulfate and then concentrated under vacuum. The resulting residue was slurried with hexane and filtered to provide additional product as a yellow solid. The two crops were combined to provide 101 g of tert-butyl N-[2-(3-nitroquinolin-4-yl)aminoethyl]carbamate as a yellow solid, m.p. 157-158.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH:10]=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:34](Br)(Br)([Br:36])[Br:35].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH:9]1[CH:10]=[C:34]([Br:36])[Br:35])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1C=C(Br)Br
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a stirred cold (minus 50°) solution of N-boc-prolinal (5.98 g, 30 mmol) and PPh3 (62.95 g, 240 mmol) in CH2Cl2 (200 mL) was slowly added a solution of CBr4 (39.80 g, 120 mmol) in CH2Cl2 (50 mL), and the stirring was continued for 1 hr at 0° C. To this mixture was added sat. NaHCO3 and the mixture was extracted with CHCl3. The extract was washed with H2O, dried over MgSO4, and evaporated. The residue was chromatographed on silica-gel with CHCl3 and n-hexane-AcOEt (4:1, v/v) as eluent to give 7.84 g (74%) 1-(tert-butoxycarbonyl)-2-(2,2-dibromoethenyl) pyrrolidine as colorless plates. mp 61–63; IR (KBr) 1693 cm−1; 1H-NMR (CDCl3) δ 1.46 (9 H, s), 1.72–2.19 (4H, m), 3.35–3.45 (2H, m), 4.35 (1H, br s), 6.36 (1H, br s); MS (FAB) m/z 352, 354, 356, 358; Anal. Calcd for C11H17NO2Br2: C, 37.21; H, 4.83; N, 3.94. Found: C, 37.14; H, 4.83; N, 4.00.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:13])[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.CC(=CC)C.Cl([O-])=[O:20].[Na+].Cl([O-])=O.P([O-])([O-])([O-])=O>O.CC(O)C.O1CCOCC1>[Br:1][C:2]1[N:3]([CH3:13])[C:4]2[C:9]([C:10]=1[C:11]([OH:20])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: [O-][Cl+][O-]
Reactant: Cn1c(Br)c(C=O)c2ccccc21
Agent: CC=C(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(C)O
Solvent: O
Product: Cn1c(Br)c(C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 87 %

Procedure:
To a vigorously stirred solution of 2.38 g (10 mmol) of 2-bromo-1-methylindole-3-carboxaldehyde [XXVI: R1 =H, R3 =CH3, X=Br], 10 mL of 2-methyl-2-butene, and 40 mL of p-dioxane at 25° C. was added dropwise over ca. 15 minutes a solution of 5 g (55 mmol) of sodium chlorite and 5 g (36 mmol) of NaH2PO4.H2O in 25 mL of water. The solution was maintained at 25° C. After 3.5 hours, the mixture was treated with an additional 2.5 g each of the chlorite and phosphate. After a total reaction time of 24 hours, the mixture was extracted 3 times with dichloromethane, then the aqueous phase was acidified to pH 2 with aqueous HCl, and extracted once more. The combined organic extracts were washed with water, dried, and evaporated to leave a solid residue that was boiled in 2 -propanol. After cooling, the solids were collected by filtration, washed with a little 2-propanol, and dried to leave 2.21 g (87%) of 2-bromo-1-methylindole-3-carboxylic acid [XXVII: R1 =H, R3 =CH3, X=Br] as a beige solid; mp ca. 198° C. (dec), in 2 crops.
Reaction SMILES: C([Al](C[CH:11]([CH3:13])[CH3:12])CC(C)C)C(C)C.[CH2:14]=[CH2:15].C[CH:17]([CH3:21])[CH2:18][CH:19]=[CH2:20]>[Ti].[Zr].C1C=CC=CC=1>[CH3:14][CH2:15][CH2:20][CH2:19][CH2:18][CH2:17][CH2:21][CH2:13][CH2:11][CH3:12]
Reactant: C=CCC(C)C
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Reactant: C=C
Agent: [Ti]
Agent: [Zr]
Solvent: c1ccccc1
Product: CCCCCCCCCC

Procedure:
The polymerization of Example 1 was repeated except that in place of the benzene-soluble organoaluminum oxy-compound, the benzene-insoluble organoaluminum oxy-compound as prepared above was used in an amount of 0.1 mg atom in terms of Al atom, 1 mmol of triisobutylaluminum was further used, the amount of the titanium catalyst component used was changed to 1×10-3 mg atom and the amount of the zirconium component used was changed to 3×10-4 mg atom, whereby 49.0 g of an ethylene/4-methyl-1-pentene copolymer having MFR of 0.05 g/10 min, a density of 0.904 g/cm3, an amount of decane-soluble portion at 23° C. of 0.12% by weight and Mw/Mn of 7.0 was obtained.
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]([C:24]([OH:26])=[O:25])[C:11](=[CH:15][C:16]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[NH:17]([C:16]1[CH:15]=[C:11]2[C:12](=[O:14])[O:26][C:24](=[O:25])[C:10]2=[CH:9][C:8]=1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cc(Nc2ccccc2)c(Nc2ccccc2)cc1C(=O)O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc(Nc3ccccc3)c(Nc3ccccc3)cc21

Procedure:
A steady stream of argon is passed through a suspension of 23.4 g (67.18 mmol) of 4,5-bis(anilino)phthalic acid in 250 ml of toluene, and 19.0 ml (201.5 mmol, 3 eq) of acetic anhydride is added. The reaction mixture is heated to 60°-65° for 90 minutes with vigorous stirring. Thereaction mixture is cooled to 10° for 30 minutes, and the yellow to orange crystals are filtered off and washed with toluene/hexane to yield the title compound in the form of yellow crystals, FAB-MS: 331 [M+ +H].
Reaction SMILES: [N+:1]([C:4]1[C:12]([NH:13]C(=O)C)=[CH:11][C:7]2[CH2:8][CH2:9][O:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH]Cl.N>CCO>[N+:1]([C:4]1[C:12]([NH2:13])=[CH:11][C:7]2[CH2:8][CH2:9][O:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OCC2
Agent: N
Agent: [CH]Cl
Solvent: CCO
Product: Nc1cc2c(cc1[N+](=O)[O-])OCC2
Yield: 99.9 %

Procedure:
A suspension of acetamide 193 (8.98 g, 40.4 mmol) and cHCl (50 mL) in EtOH (100 mL) was heated at reflux temperature for 2 h. The solution was cooled, carefully neutralized with aqueous NH3 solution, and the resulting precipitate filtered and dried to give nitroaniline 194 (7.27 g, 100%) as an orange solid: mp (H2O) 148-149° C.; 1H NMR δ 7.44 (s, 1H, H-7), 6.68 (t, J=1.2 Hz, 1H, H-4), 5.92 (br s, 2H, NH2), 4.54 (t, J=8.4 Hz, 2H, H-2), 3.18 (dt, J=8.4, 1.2 Hz, 2H, H-3); 13C NMR δ 151.8, 140.8, 139.0, 131.2, 114.4, 103.4, 71.2, 30.0. Anal. calcd for C8H8N2O3: C, 53.3; H, 4.5; N, 15.6. Found: C, 53.2; H, 4.5; N, 15.6%.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[O:13]=[C:14]1[CH2:31][CH2:30][C:17]2([CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH2:16][CH2:15]1.C(OCC)(=O)C>C(OCC)C.O>[OH:13][C:14]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:31][CH2:30][C:17]2([CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19][CH2:18]2)[CH2:16][CH2:15]1
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCC(O)(c1cccnc1)CC2
Temperature: -78 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
3-Bromopyridine (22.47 mmol, 2 eq) was dissolved in diethyl ether (10 ml) and the solution was added dropwise to a solution of n-BuLi (24.7 mmol, 2.2 eq) in diethyl ether (70 ml) at −78° C. The resulting mixture was stirred for 30 min. tert-Butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (for the synthesis see above) (11.23 mmol, 1 eq.) was dissolved in diethyl ether (10 ml), the solution was slowly added, and the reaction mixture was then stirred at −78° C. for 1 h. The reaction mixture was warmed to room temperature, ethyl acetate (150 ml) and water (80 ml) were added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×70 ml) and the combined organic phases were dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography (2% methanol in methylene chloride). Yield: 19%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN2
Temperature: 10 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
A 4-neck 22 L round bottom flask equipped with a nitrogen inlet, mechanical stirrer and thermowell was charged with commercially available 5-methoxyindole (750 g, 5.1 mol) and acetic acid (3.75 L). The resulting solution was cooled to 10° C. by ice bath. Sodium cyanoborohydride (640 g, 10.2 mol, 2 equiv) was added portionwise to maintain the reaction temperature below 25° C. Upon the completion of addition, the reaction was stirred at room temperature for 3 hours and then water was added slowly (2.2 L). The mixture was basified to pH>12 with 50% NaOH (˜5.3 L, slow addition to avoid foaming, the temperature kept below 30° C.). The resulting mixture was extracted with dichloromethane (2×12 L). The combined organic layers were dried over sodium sulfate and evaporated in vacuo to give 5-(methyloxy)-2,3-dihydro-1 H-indole (760 g, >90% purity), which was used for the next step without further purification. 1H NMR (CDCl3, 300 MHz) 6 6.76 (s, 1 H), 6.60 (s, 2H), 3.54 (t, 2H), 3.01 (t, 2H).
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=2[O:2]1.[CH3:12][N:13]([CH3:23])[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18].C(N(CC1C=CC=CC=1)C1C=CC(C2C3C(=CC(N(C)C)=CC=3)C(=O)O2)=CC=1)C>C(OC(=O)C)(=O)C>[CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]3[C:20]4[C:16](=[CH:15][C:14]([N:13]([CH3:23])[CH3:12])=[CH:22][CH:21]=4)[C:17](=[O:18])[O:7]3)=[CH:4][C:3]=2[O:2]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CN(C)c1cccc(C(=O)O)c1
Agent: CCN(Cc1ccccc1)c1ccc(C2OC(=O)c3cc(N(C)C)ccc32)cc1
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc2c(c1)C(=O)OC2c1ccc2c(c1)OCO2
Yield: 6.1 %

Procedure:
Following a procedure similar to that described in Example 1, part A above, 7.5 g of 3,4-(methylenedioxy)benzaldehyde and 9.1 g of 3-dimethylaminobenzoic acid were interacted in acetic anhydride to obtain 0.9 g of 3-(3,4-methylenedioxyphenyl)-6-dimethylaminophthalide (Formula II: R=CH3 ; X=H; Y=1-[3,4-(OCH2O)C6H3 ]) a light yellow solid melting over the range 134°-143° C.
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)(C)C)(C)(C)C.[Li]C(CC)C.CN([CH:25]=[O:26])C.Cl>C1COCC1.C1CCCCC1>[Cl:16][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[C:13]([Cl:15])[C:12]=1[CH:25]=[O:26]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(Cl)c1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: O=Cc1c(Cl)cc(O)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl-(3,5-dichlorophenoxy)-dimethylsilane (2.7 g, 9.8 mmol) in THF (20 mL) at −78° C., under a N2 atmosphere, was added dropwise sec-BuLi (7.2 mL of a 1.4 M solution in cyclohexane, 10.1 mmol). After 30 min, anhydrous DMF (1.2 mL, 15.2 mmol) was added slowly to the solution. After the addition, the solution was stirred at −78° C. for 1.5 h then 20 mL of 1N HCl was added and the suspension was warmed to ambient temperature. The aqueous layer was extracted with EtOAc and the organic layer was washed with water, brine, dried with MgSO4 and filtered. The solvent was removed under reduced pressure to give 2,6-dichloro-4-hydroxybenzaldehyde as a pale yellow solid.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.O.[CH2:20]([O:22][C:23]([CH2:25][S:26][C:27]1[S:28][C:29]([SH:32])=[N:30][N:31]=1)=[O:24])[CH3:21].P(Cl)(Cl)(OP(Cl)(Cl)=O)=O>C(#N)C>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:32][C:29]3[S:28][C:27]([S:26][CH2:25][C:23]([O:22][CH2:20][CH3:21])=[O:24])=[N:31][N:30]=3)[CH2:15][S:14][C@H:9]12
Reactant: CCOC(=O)CSc1nnc(S)s1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=P(Cl)(Cl)OP(=O)(Cl)Cl
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CSc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Yield: 91.9 %

Procedure:
The procedure was carried out in accordance with Example 22, while utilizing 1.36 g of 7-ACA, 0.36 g of water, 8.0 ml of acetonitrile, 1.54 g of 2-ethoxycarbonylmethylthio-5-mercapto-1,3,4-thiadiazole and 5.04 g of diphosphoryl tetrachloride, and there was obtained 2.06 g (91.8%) of 7-amino-3-(2-ethoxycarbonylmethylthio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [NH2:1][CH:2]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)[C:3]([N:5]([CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][N:13]=[CH:12]2)=[O:4].[CH2:36]([NH:43][C:44](=[O:52])[NH:45][C@H:46]([CH3:51])[CH2:47][C:48](O)=[O:49])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[CH2:36]([NH:43][C:44](=[O:52])[NH:45][CH:46]([CH3:51])[CH2:47][C:48]([NH:1][CH:2]([C:3](=[O:4])[N:5]([CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][N:13]=[CH:12]2)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[CH:27][CH:26]=1)=[O:49])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: C[C@H](CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(CN(Cc1cccc2cn[nH]c12)C(=O)C(N)Cc1ccc(OC(C)(C)C)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CN(Cc1cccc2cn[nH]c12)C(=O)C(Cc1ccc(OC(C)(C)C)cc1)NC(=O)CC(C)NC(=O)NCc1ccccc1)OCC
Reaction time: 0.67 h

Procedure:
To a solution of 2-Amino-3-(4-tert-butoxy-phenyl)-N-(2,2-diethoxy-ethyl)-N-(1H-indazol-7-ylmethyl)-propionamide in CH2Cl2 (50 mL) was added a solution of (3R)-3-(3-Benzyl-ureido)-butyric acid (1.44 g, 6.1 mmol), EDCI (1.17 g, 1.2 eq), HOBt (0.93 g, 1.2 eq), DIEA (2.13 mL, 12.2 mmol) in CH2Cl2 (100 mL) stirred for 40 min. The reaction mixture was stirred at room temperature for 14 h, and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The crude compound was used next step without further purification. MS ESI 701 (M+H), 723 (M+Na).
Reaction SMILES: [N:1]([C:3]1C=CC=CC=1)=O.[Br-].[Al+3].[Br-].[Br-].[C]=[O:14].[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[Rh]>[C:15]1([N:1]=[C:3]=[O:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccccc1
Reactant: O=Nc1ccccc1
Reactant: [C]=O
Agent: [Rh]
Agent: [Al+3]
Agent: [Br-]
Product: O=C=Nc1ccccc1
Temperature: 190 °C

Procedure:
The procedure of Example 14 is repeated using 12.3 parts of nitrosobenzene, 80 parts of benzene, 5 parts of rhodium on carbon and 1.41 parts of aluminum bromide. After carbon monoxide is introduced to a pressure of 3,000 p.s.i., the pressure vessel is heated at 190°C. for 5 hours. Phenyl isocyanate is obtained.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[S:24][C:16]3=[N:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:15]3[CH2:14][CH2:13]2)(=O)=O)=CC=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1.[H-].[Na+]>C(Cl)(Cl)Cl>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][CH2:11][CH:12]2[S:24][C:16]3=[N:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:15]3[CH2:14][CH2:13]2)=[CH:30][CH:29]=1
Reactant: COc1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCn3c(nc4ccccc43)S2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(NCC2CCn3c(nc4ccccc43)S2)cc1
Yield: 31 %

Procedure:
3,4-Dihydro-2-p-toluenesulfonyloxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole in the amount of 1.12 g (3 m mole) was dissolved in 30 ml of chloroform. Then, 0.44 g of p-anisidine (3.6 m mole) and a catalytic amount of sodium hydride were added under ice-cooled stirring conditions. The temperature of the mixture was allowed to rise to room temperature, and then refluxed for 12 hours. The reaction mixture was cooled and washed with water. After drying the chloroform layer over anhydrous magnesium sulfate, chloroform was evaporated under reduced pressure. The residue was chromatographed on silica gel and eluted with chloroform to obtain 0.28 g (yield: 31%) of the intended product, m.p. 155°-157° C.; IR νmaxKBr cm-1 : 3360, 3100-2800, 1430; Anal. Calcd. for C18H19N3OS: C, 66.44; H, 5.88; N, 12.91; S, 9.85; Found: C, 66.91; H, 5.90; N, 12.88; S, 9.70.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH:19]=O)[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[BH4-].[Na+].Cl>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: NCC1CCNCC1
Reactant: COC(=O)c1cc(C=O)cc(-c2cccc(C#N)c2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(CNCC2CCNCC2)cc(-c2cccc(C#N)c2)c1
Reaction time: 1 h
Yield: 70.6 %

Procedure:
In 30 ml of toluene, were dissolved 3.00 g of the compound obtained in Example 11 and 1.50 g of 4-aminomethylpiperidine. The resulting solution was refluxed for 3 hours to remove the produced water. The solvent was evaporated from the reaction solution under reduced pressure, and 10 ml of tetrahydrofuran and 20 ml of methanol were added to the residue to provide a solution. To the resulting solution, was added 0.500 g of sodium borohydride under cooling with ice. The mixture was stirred at this temperature for 1 hour, then returned to room temperature and stirred for another hour. To the resulting solution was added a 1 M hydrochloric acid to quench the reaction. The resulting solution was washed with ethyl acetate. A 1 M aqueous solution of sodium hydroxide was added to the obtained aqueous layer until the pH attained 10. The resulting solution was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine and subsequently dried over sodium sulfate, and the solvent was removed under reduced pressure to provide 2.9 g (71%) of the title compound as an oil.
Reaction SMILES: NCCNC(=O)OCC1C=CC=CC=1.[N:15]([C:18](=[CH:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][NH:28]2)[C:19]([O:21][CH3:22])=[O:20])=[N+]=[N-].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:23]1[C:24]2=[C:25]3[C:29]([CH:30]=[CH:31][C:32]2=[N:15][C:18]=1[C:19]([O:21][CH3:22])=[O:20])=[N:28][CH:27]=[CH:26]3
Reactant: COC(=O)C(=Cc1cccc2[nH]ccc12)N=[N+]=[N-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCCNC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1=Cc2c3c(ccc2=N1)=NC=C3
Temperature: 25 °C
Reaction time: 4 h
Yield: 260.6 %

Procedure:
To compound 1 (50 mg, 0.079 mmol) in DMF (2 mL) was added 2 (49 mg, 0.085 mmol) and HATU (33 mg, 0.086 mmol) followed by adding DIPEA (45 uL) and the reaction mixture was stirred for 4 hrs at room temperature. The solvent was removed under vacuo and the product was purified by Prep HPLC (SymmetrPrep C18, 7 μm, 19×150 mm column), eluted at 10 ml/min (0.01% TFA in water/acetonitrile) with a gradient: 10% acetonitrile in 5 min, 10% to 50% acetonitrile in 15 min, maintaining 50% acetonitrile in 5 min, 50% to 100% acetonitrile in 5 min, to give 3 (47 mg, 60%). MS: (M+H)+ 1003.