Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH:17]([CH3:19])[CH3:18])[CH:11]=[C:10]2[C:5]=1[C:6](=[O:28])[CH:7]=[C:8]([S:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[O:9]2)[CH3:2].C(OC([N:36](C(OC(C)(C)C)=O)[CH2:37][C:38](O)=[O:39])=O)(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:63]>ClCCl.C(OCC)(=O)C>[ClH:63].[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH:17]([CH3:19])[CH3:18])[CH:11]=[C:10]2[C:5]=1[C:6](=[O:28])[CH:7]=[C:8]([S:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:38](=[O:39])[CH2:37][NH2:36])=[CH:23][CH:22]=1)[O:9]2)[CH3:2]
Reactant: CCOc1c(OC)c(OC(C)C)cc2oc(Sc3ccc(O)cc3)cc(=O)c12
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOc1c(OC)c(OC(C)C)cc2oc(Sc3ccc(OC(=O)CN)cc3)cc(=O)c12
Reaction time: 1 h

Procedure:
300 ml in dichloromethane of 11.35 g of 5-ethoxy-2-(4-hydroxyphenylthio)-7-isopropoxy-6-methoxychromone obtained in Example 18, 5.43 g of N-t-butoxycarbonyl(Boc)glycine, and 6.40 g of dicyclohexylcarbodiimide (DCC) was stirred over 5.5 hours at room temperature. The solution thus reacted was gravitationally filtered. The solvent was distilled out from the filtrate, so that N-t-butoxycarbonyl(Boc)glycine ester was obtained. This product was dissolved in 100 ml of ethyl acetate. Then, hydrochloric acid gas was introduced and bubbled in the solution for 10 min., followed by stirring for 1 hour. Subsequently, 200 ml ether was added and the resulting crystals were collected by filtration and dried, whereby 11.28 g of 5-ethoxy-2-(4-glycyloxyphenylthio)-7-isopropoxy-6-methoxychromone hydrochloride with the following physicochemical properties was obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14]>C1CCN2C(=NCCC2)CC1.C1CCCCC1>[CH3:17][O:16][C:12](=[O:15])[CH2:13][CH2:14][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])([C:3](=[O:10])[CH:2]([CH3:1])[CH3:11])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: C=CC(=O)OC
Reactant: CCOC(=O)CC(=O)C(C)C
Solvent: C1CCCCC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(CCC(=O)OC)(CCC(=O)OC)C(=O)C(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 112.5 %

Procedure:
12.0 g (0.08 mol) of ethyl 4-methyl-3-oxo-pentanoate and 0.5 g (0.003 mol) of DBU were placed in a three necked round bottom flask, equipped-with dropping funnel and reflux condenser. At room temperature, 16.0 g (0.18 mol) of methyl acrylate was slowly added drop by drop. After the exothermal behavior of the reaction leveled off, the reaction mixture was stirred at 60° C. for an additional two hours. The mixture was poured into cyclohexane and was washed with diluted hydrochloric acid and was subsequently washed with distilled water until the aqueous layer was neutral. The organic layer was dried over sodium sulfate, the solvent was removed, and the addition product was isolated by fractional distillation in a vacuum. 15.0 g (0.045 mol) of 4-(ethoxycarbonyl)-4-(2-methyl-1-oxopropyl)-heptanedioic acid 1,7-dimethyl ester was obtained (yield: 56%; boiling point: 145° C. at 0.02 mbar; colorless).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](F)[CH:24]=3)[C:19](=[O:27])[N:18]([CH3:28])[CH:17]=2)[CH2:3][CH2:2]1.C[O-].[Na+].C[C:33](=O)[O:34]CC>CN(C)C(=O)C.CO.CCCCCC>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:34][CH3:33])[CH:24]=3)[C:19](=[O:27])[N:18]([CH3:28])[CH:17]=2)[CH2:3][CH2:2]1
Reactant: CCOC(C)=O
Reactant: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)c2cc(F)ccc2c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: CCCCCC
Product: COc1ccc2c(=O)n(C)cc(-c3cc(S(C)(=O)=O)ccc3OCC3CC3)c2c1
Temperature: 85 °C
Yield: 74 %

Procedure:
The title compound of Example 90, step 2 (30 mg, 0.075 mmol) in N,N-dimethylacetamide was treated with excess 25% sodium methoxide in methanol and heated at 85° C. until complete. Silica gel chromatography (40-80% EA in hexane over 8 min, then isocratic) gave the title compound 23 mg, 0.056 mmol, 74%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.06-0.20 (m., 2H) 0.27-0.43 (m, 2H) 0.83-1.05 (m, 1H) 3.22 (s, 3H) 3.53 (s, 3H) 3.73 (s, 3H) 3.83-4.16 (m, 2H) 6.47 (s, 1H) 7.04-7.20 (m, 1H) 7.36 (d, J=8.59 Hz, 1H) 7.50 (s, 1H) 7.81 (s, 1H) 7.96 (d, J=6.82 Hz, 1H) 8.23 (d, J=8.59 Hz, 1H). LCMS: 414 (M+H)+
Reaction SMILES: I[C:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:3]=1.[CH3:15][CH:16]([O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.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>[CH:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:6]([CH:7]=[O:8])=[CH:5][N:4]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[N:3]=2)=[CH:21][CH:20]=1)([CH3:17])[CH3:15]
Reactant: O=Cc1cn(C2CCCCO2)nc1I
Reactant: CC(C)Oc1ccc(B(O)O)cc1
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: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(-c2nn(C3CCCCO3)cc2C=O)cc1
Temperature: 98 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of 3-iodo-1-(oxan-2-yl)-1H-pyrazole-4-carbaldehyde (6 g, 19.60 mmol, 1.00 equiv), [4-(propan-2-yloxy)phenyl]boronic acid (7.0 g, 38.89 mmol, 1.98 equiv), Pd(PPh3)4 (2.2 g, 1.90 mmol, 0.10 equiv) and sodium carbonate (6.2 g, 58.50 mmol, 2.98 equiv) in toluene (60 mL) and water (5 mL) was stirred under nitrogen at 98° C. overnight. The reaction was cooled to room temperature then diluted with 600 mL of ethyl acetate. The resulting mixture was washed with 3×300 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 3.0-6.5% ethyl acetate in petroleum ether to give 4.5 g (73%) of 3-(4-isopropoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbaldehyde as yellow oil. 1H NMR (300 MHz, CDCl3) δ: 9.98 (s, 1H), 8.23 (s, 1H), 7.70-7.65 (m, 2H), 7.26 (s, 1H), 6.98-6.93 (m, 2H), 5.45-5.41 (m, 1H), 4.65-4.57 (m, 1H), 4.13-4.09 (m, 1H), 3.78-3.73 (m, 1H), 2.21-2.03 (m, 3H), 1.71-1.63 (m, 3H), 1.36 (d, J=6.0 Hz, 6H) ppm. LCMS (method D, ESI): RT=1.57 min, m/z=315.0 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[C:10]([CH2:13][C:14]([OH:16])=[O:15])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]2[CH:17]=[CH:18][S:19][C:3]1=2.C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29].O>CN(C)C=O.CCCCCC>[CH3:31][O:30][C:28](=[O:29])[CH2:27][O:15][C:14](=[O:16])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]2[O:6][CH2:5][C:4]3[CH:17]=[CH:18][S:19][C:3]=3[C:2](=[O:1])[C:8]=2[CH:9]=1
Reactant: COC(=O)CBr
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1sccc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: COC(=O)COC(=O)Cc1ccc2c(c1)C(=O)c1sccc1CO2
Temperature: 60 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
A mixture of 12.54 g (0.046 m) of 4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetic acid in 100 ml of dimethylformamide (DMF) and 3.18 g (0.033 m) of K2CO3 was warmed to 60° C. for 1 hour in an atmosphere of nitrogen. To this mixture 7.7 g (0.05 m) of methyl bromoacetate was added dropwise and the mixture was held at 60° C. overnight (about 16 hours). The reaction mixture was poured into water and extracted with ether. The ether extract was washed with 5% NaHCO3 and water, dried over Na2SO4, filtered and evaporated to give an oil which solidified. Trituration with hexane gave 12.5 g (78%) of methyl(4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-yl)acetoxyacetate, m.p. 78°-80° C.
Reaction SMILES: [CH:1]([OH:3])=O.[CH3:4][C:5]1[C:10](C#N)=[CH:9][N:8]=[C:7]([NH:13][CH2:14][CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[N:6]=1>[Ni].O>[CH3:4][C:5]1[C:10]([CH:1]=[O:3])=[CH:9][N:8]=[C:7]([NH:13][CH2:14][CH2:15][CH2:16][CH:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)[N:6]=1
Reactant: Cc1nc(NCCCC2CCN(C)CC2)ncc1C#N
Reactant: O=CO
Agent: [Ni]
Solvent: O
Product: Cc1nc(NCCCC2CCN(C)CC2)ncc1C=O
Temperature: 12.5 °C
Reaction time: 1 h

Procedure:
A vessel at room temperature was charged with formic acid (800 mL) and 4-methyl-2-(3-(1-methylpiperidin-4-yl)propylamino)pyrimidine-5-carbonitrile (100 g) and the resulting mixture stirred to yield a clear solution, then cooled to 10-15° C. Water (200 mL) was added and the resulting mixture cooled to −2 to 0° C. To the resulting mixture was then added RANEY® nickel (160 g) maintaining the temperature at −2 to 0° C. and then stirred at this temperature for 2-3 hours. The resulting mixture was then filtered to remove the RANEY® nickel and the filtercake washed with water (100 mL), The filtrate was cooled to 0-5° C. and then slowly treated with 50% sodium carbonate solution in water (3.0 L) to adjust the pH of the solution to pH˜10. Toluene (400 mL) was added and the resulting mixture stirred at room temperature for about 30 minutes, then allowed to settle for about 1 hour. The resulting layers were separated and the aqueous layer washed with toluene (400 mL×2). The combined toluene layer and washed were distilled at 55-60° C. to remove the toluene, to yield the title compound as an oily residue.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:6]CCO1.S([O-])(OCCCCCCCCCCCC)(=O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:43]([CH:45]([CH2:49][CH2:50][CH2:51][CH3:52])[CH2:46][Mg]Br)[CH3:44]>O.C(OCC)C>[CH2:43]([CH:45]([CH2:49][CH2:50][CH2:51][CH3:52])[CH2:46][C:2]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)([OH:6])[CH3:1])[CH3:44]
Reactant: CC1(c2ccccc2)OCCO1
Reactant: CCCCC(CC)C[Mg]Br
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCCCC(CC)CC(C)(O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.6 %

Procedure:
2-Methyl-2-phenyl-1,3-dioxolane (0.25 g, 1.5 mmol), sodium dodecyl sulfate (0.1 g, 0.35 mmol) and a stir bar were added to the inside of a PDMS thimble. p-Toluene sulfonic acid monohydrate (72.4 mg, 0.38 mmol) dissolved in 2 mL water was added to the inside of the PDMS thimble followed by 1 mL of hexanes. The reaction was stirred at 25° C. for 4 hours. Hexanes (2.5 mL) was added to the outside of the PDMS thimble followed by 12 mL of 1 M 2-ethylhexyl-magnesiumbromide (2.6 g, 12 mmol). The reaction was stirred for an additional 12 hours after which 5 mL water was added. The PDMS thimble was swelled with 20 mL hexanes and 2×20 mL diethyl ether. The organics were combined and dried over MgSO4. The product was purified by column chromatography, eluting with 100% hexanes to yield a colorless oil (0.28 g, 80% yield). 1H NMR (CDCl3): δ 0.68-0.86 (m, 6H), 1.08-1.29 (m, 9H), 1.57 (s, 3H), 1.63 (s, 1H), 1.70-1.75 (m, 2H), 7.19-7.46 (m, 5H). 13C NMR (CDCl3): δ 10.43, 10.49, 14.00, 14.05, 22.86, 22.95, 26.95, 27.12, 28.48, 28.61, 30.45, 30.72, 33.82, 34.04, 34.62, 34.68, 47.99, 48.01, 75.07, 75.09, 124.82. 124.84, 126.27, 126.31, 127.88, 148.32, 148.38. HRMS: Calculated for C16H26O: 234.1984.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[N:13])[CH:8]=2)[O:3]1.C(O)C.N>CO.[Ni]>[NH2:13][CH2:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:14])([CH3:1])[CH:11]=[CH:10]2
Reactant: CC1(C)C=Cc2cc(C#N)ccc2O1
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: CO
Product: CC1(C)C=Cc2cc(CN)ccc2O1
Temperature: 60 °C
Yield: 97.9 %

Procedure:
Add 2,2-dimethyl-2H-chromene-6-carbonitrile (1.5 g, 8.1 mmol) and ethanol wet Raney® activated nickel (0.4 g) to a Parr pressure vessel. Immediately add 7N ammonia in methanol (170 mL) and seal the vessel. Purge the reaction vessel with nitrogen, pressurize the reaction mixture with hydrogen (3400 KPa), seal the vessel, agitate the reaction and heat to 60° C. for 20 h. Turn off the heat and allow the reaction mixture to cool to ambient temperature. Vent the excess hydrogen from the vessel and purge the vessel with nitrogen. Filter the reaction mixture to remove the Raney® nickel. Purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol (9:1) to obtain the title compound (1.5 g, 97%). MS (ES+) m/z: 175 M+H−NH3)+.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(NC(C)C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[CH3:9][N:8]([CH3:10])[C:6](=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:3][CH:4]=1
Reactant: CN(C)C(=O)c1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 57 °C

Procedure:
To a mixture under Ar of 4-Iodo-N,N-dimethyl-benzamide (237 mg), trimethylsilylacetylene (169 mg), [PdCl2(PPh3)2] (30 mg) and copper(i) iodide (15 mg) is added a degassed mixture of THF (4.5 ml) and diisopropylamine (4.5 ml). After stirring over night at 57° C. and aqueous work up, the organic layer is dried over Na2SO4 and the solvent is evaporated. Flash chromatography (silica gel, CH2Cl2/MeOH/25% NH4OH 97:3:0.3) yields N,N-Dimethyl-4-trimethylsilanylethynyl-benzamide as a brown oil, 1H-NMR (300 MHz): 0.25 (s, 3H); 2.96 (s, 3H); 3.10 (s, 3H); 7.35 (d, J=8.5, 2H); 7.49 (d, J=8.5, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH:21]1[CH2:25][NH:24][C:23](=[O:26])[CH2:22]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:29](I)[CH3:30]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH:21]1[CH2:25][N:24]([CH2:29][CH3:30])[C:23](=[O:26])[CH2:22]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C1CNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CC([C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)CC1=O
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a solution of (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(2-pyrrolidon-4-yl)pyrrolidine (38.5 g, 0.1 mol, the compound of Reference Example 1-6) in tetrahydrofuran (200 ml) was added 60% sodium hydride in oil (4.2 g, 0.1 mol) under ice-cooling, and the mixture was stirred for 1 hour. To the mixture was added ethyl iodide (8 rag, 0.1 mol), and after stirring at room temperature overnight, the reaction mixture was concentrated. The residue was extracted with ethyl acetate (500 ml), and the mixture was washed with water (200 ml) followed by a saturated sodium chloride aqueous solution. After the extract was dried over anhydrous magnesium sulfate, the solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (Wakogel™ C-300, chloroform) to obtain (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(N-ethyl-2-pyrrolidon-4-yl)pyrrolidine (40.3 g, yield: 97.7%).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13]NC(NC)=S)[N:9]=1)[C:2]([NH2:4])=[NH:3].[C:19]([OH:26])(=[O:25])/[CH:20]=[CH:21]\[C:22]([OH:24])=[O:23].C[I:28]>C(O)C>[IH:28].[C:19]([OH:26])(=[O:25])/[CH:20]=[CH:21]\[C:22]([OH:24])=[O:23].[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH:11]([NH:9][C:5](=[N:1][CH3:2])[S:6][CH3:7])[CH2:12][CH3:13])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CNC(=S)NCCCCc1csc(NC(=N)N)n1
Reactant: CI
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Product: CCC(Cc1csc(NC(=N)N)n1)NC(=NC)SC
Product: I

Procedure:
A solution of 2-guanidino-4-[4-(3-methylthioureido)butyl]thiazole in ethanol (15 ml.) is treated with the appropriate amount of maleic acid to give a solution containing 0.42 g. of the hydrogen maleate salt. This solution is treated with methyl iodide (0.17 g.) and the mixture heated under reflux for 1.5 hours. Concentration of the reaction mixture to 5 ml. and collection of the precipitated solid gives 2-guanidino-4-[2-(2,3-dimethylisothioureido)butyl]thiazole hydrogen maleate hydriodide.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1.[C:17](=O)(O)[O-].[Na+]>CO>[CH3:6][O:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1
Reactant: O=C([O-])O
Reactant: COC1CCC(C(=O)O)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCC(OC)CC1
Temperature: 25 °C

Procedure:
1.8 ml of concentrated sulphuric acid were added to a solution of 4.00 g (25.3 mmol) of 4-methoxycyclohexanecarboxylic acid in 32 ml of methanol, and the resulting reaction solution was heated under reflux overnight. The mixture was cooled to room temperature and the pH was adjusted to 7-8 using saturated aqueous sodium bicarbonate solution. The mixture was then extracted three times with 70 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product corresponded to the title compound. Yield: 4.30 g (99% of theory)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)nc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)nc1

Procedure:
To a solution of methyl 6-methylnicotinate (50 g, 331 mmol) in carbon tetrachloride (625 mL), was added N-bromosuccinimide (59 g, 331 mmol). Further 1.0 g of benzoyl peroxide was added, the mixture was reacted at a temperature from 40 to 50° C. for 24 hours with irradiation of light from a projector.
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.[Si:10]([O:17][C:18]1[C:23]([CH2:24][CH3:25])=[CH:22][C:21]([CH:26]([C:28]2[N:29]([CH3:39])[N:30]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:32]=2)O)=[C:20]([F:40])[CH:19]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].CCN(CC)CC.[C:48]([O:52][C:53]([N:55]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[C:56]1[C:65]2[C:60](=[CH:61][C:62]([NH2:66])=[CH:63][CH:64]=2)[CH:59]=[CH:58][N:57]=1)=[O:54])([CH3:51])([CH3:50])[CH3:49]>C(Cl)Cl.O>[Si:10]([O:17][C:18]1[C:23]([CH2:24][CH3:25])=[CH:22][C:21]([CH:26]([C:28]2[N:29]([CH3:39])[N:30]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:32]=2)[NH:66][C:62]2[CH:61]=[C:60]3[C:65](=[CH:64][CH:63]=2)[C:56]([N:55]([C:53]([O:52][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:54])[C:67]([O:69][C:70]([CH3:71])([CH3:72])[CH3:73])=[O:68])=[N:57][CH:58]=[CH:59]3)=[C:20]([F:40])[CH:19]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CCc1cc(C(O)c2nc(-c3ccccc3)nn2C)c(F)cc1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)c2nc(-c3ccccc3)nn2C)c(F)cc1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
Methanesulfonic anhydride (184 mg, 1.3 mmol) was added to a solution of Intermediate 386.4 (292 mg, 0.66 mmol) and Et3N (0.30 mL, 2.2 mmol) in CH2Cl2 (5 mL) at 0° C. The mixture was stirred 1 h at 0° C., 1-(di-(tert-butyloxycarbonyl)amino)-6-aminoisoquinoline (475 mg, 1.3 mmol) was added and it was stirred 16 h at ambient temperature. Water (10 mL) was added and the mixture was extracted with EtOAc (3×25 mL). The organics were combined, washed with brine, dried (Na2SO4) and concentrated. Purification by flash chromatography (hexanes, EtOAc) yielded 280 mg of Intermediate 386.5 as a yellow solid. LCMS 783.53 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH3:10])[CH2:7][S:8][C@H:3]12.C(=O)(O)[O-].[Na+].[Cl:27][CH:28]([Cl:32])[C:29](Cl)=[O:30].Cl>C(OCC)(=O)C.CC(C)=O.O>[Cl:27][CH:28]([Cl:32])[C:29]([NH:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:13][N:14]=[N:15][N:16]=3)[CH3:10])[CH2:7][S:8][C@H:3]12)=[O:30]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(Cl)C(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)C(Cl)Cl)[C@H]2SC1
Yield: 34.2 %

Procedure:
7-Amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (3.28 g) was suspended in a mixture (60 ml) of water and acetone (1:1) and sodium bicarbonate was added to the suspension little by little to give a solution. Dichloroacetyl chloride (3 g) was added dropwise to the solution at -5° C under stirring and the mixture was stirred at the same temperature for 30 minutes. Ethyl acetate (50 ml) was added to the reaction mixture and the mixture was adjusted to pH 2 with diluted hydrochloric acid under stirring and filtered. The ethyl acetate layer was separated from the filtrate, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and then treated with activated charcoal powder. Ethyl acetate was distilled off from the solution under reduced pressure. Ether was added to the residue and the mixture was stirred overnight. Precipitates were collected by filtration to give pale yellow powder of 7-dichloroacetamido-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (1.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH2:10]([O:12][C:13](=[O:24])[CH2:14][C:15](=[O:23])[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:11].[CH:25](OCC)(OCC)OCC>C(O)C>[CH2:10]([O:12][C:13]([CH:14]([C:15](=[O:23])[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:25]=[N:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:24])[CH3:11]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CCC(=O)CC(=O)OCC
Reactant: COc1ccccc1N
Solvent: CCO
Product: CCOC(=O)CCC(=O)C(C=Nc1ccccc1OC)C(=O)OCC
Temperature: 20 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
A mixture consisting of 5.0 g (0.041 mole) of o-anisidine (available from the Aldrich Chemical Company, Inc. of Milwaukee, Wis.), 8.86 g (0.041 mole) of β-ketoadipic acid diethyl ester (available from Sigma Chemical Company of St. Louis, Mo.) and 6.07 g (0.041 mole) of triethyl orthoformate (also available from Aldrich) was placed in an open reaction flask and heated to 140° C. for a period of three hours, at which point no further amount of ethanol by-product formation could be observed to evolve from the reaction mixture. Upon completion of this step, the spent reaction mixture was allowed to cool to ambient temperatures (ca. 20° C.) on standing overnight for a period of approximately 16 hours. The resulting residual solid was thereafter triturated with petroleum ether and filtered to give 11.53 g (82%) of pure o-[2-ethoxycarbonyl-2-(3-ethoxycarbonylpropionyl)-1-ethylideneamino]anisole. The pure product was characterized by means of mass spectrum (MS) analysis and nuclear magnetic resonance (NMR) data.