Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:53])[C:7]([S:25][C@@H:26]1[CH2:30][CH2:29][O:28][C@@H:27]1[CH2:31][NH:32][C:33](=[O:52])[C@@H:34]([NH:38]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)[CH:35]([CH3:37])[CH3:36])=[C:8]2[C:12]([O:14]CC1C=CC([N+]([O-])=O)=CC=1)=[O:13])[CH3:3].[H][H]>[Pd].[OH-].[Pd+2].[OH-].[Pt]=O.O>[NH2:38][C@@H:34]([CH:35]([CH3:37])[CH3:36])[C:33]([NH:32][CH2:31][C@@H:27]1[C@H:26]([S:25][C:7]2[C@H:6]([CH3:53])[C@H:5]3[N:9]([C:10](=[O:11])[C@@H:4]3[C@H:2]([OH:1])[CH3:3])[C:8]=2[C:12]([OH:14])=[O:13])[CH2:30][CH2:29][O:28]1)=[O:52]
Reactant: CC(C)[C@H](NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)NC[C@H]1OCC[C@H]1SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Reactant: [H][H]
Agent: O=[Pt]
Agent: [Pd+2]
Agent: [Pd]
Solvent: O
Product: CC(C)[C@H](N)C(=O)NC[C@H]1OCC[C@H]1SC1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C

Procedure:
The 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-{[(2R,3R)-2-({[(2S)-3-methyl-2-({[(4-nitrobenzyl)oxy]carbonyl}amino)butanoyl]amino}methyl)tetrahydrofuran-3-yl]thio}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate 1 is added to the biphasic solvent system of water and organic solvent in the presence of catalyst, without the addition of an acid acceptor. Suitable catalysts include palladium-on-carbon, palladium hydroxide, platinum oxide and the like. The reaction mixture is hydrogenated by shaking in a Parr hydrogenation apparatus under hydrogen pressure, until the reaction has reached completion as shown by monitoring the progress of the reaction by analytical high pressure liquid chromatography (HPLC) and cessation of hydrogen uptake. Suitably, the reaction is maintained at 20 to 30° C. for a preferred period of about 4 hours to about 24 hours at a hydrogen pressure of about 50-60 pounds-per-square inch (psi). The water portion and organic solvent portion are separated and the (4R, 5S, 6S)-3-[[(2R,3R)-2-[[[(S)-2-amino-3-methyl-1-oxobutyl]amino]methyl]tetrahydro-3-furanyl]thio]-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid 2 isolated from the water portion by lyophilization or reverse osmosis.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[CH:2].[N:16]([CH:19]1[CH2:25][CH2:24][C:23]2[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:22]=2[N:21]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:20]1=[O:36])=[N+:17]=[N-:18]>>[F:30][C:26]1[C:23]2[CH2:24][CH2:25][CH:19]([N:16]3[CH:2]=[C:1]([CH:3]4[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]4)[N:18]=[N:17]3)[C:20](=[O:36])[N:21]([CH2:31][C:32]([F:33])([F:34])[F:35])[C:22]=2[CH:29]=[CH:28][CH:27]=1
Reactant: [N-]=[N+]=NC1CCc2c(F)cccc2N(CC(F)(F)F)C1=O
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2cn(C3CCc4c(F)cccc4N(CC(F)(F)F)C3=O)nn2)CC1

Procedure:
tert-Butyl 4-{1-[6-fluoro-2-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]-1H-1,2,3-triazol-4-yl}piperidine-1-carboxylate was prepared from tert-butyl 4-ethynylpiperidine-1-carboxylate (synthesized from tert-butyl 4-formylpiperidine-1-carboxylate and Bestmann's reagent under standard condition) and 3-azido-6-fluoro-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one under standard click chemistry condition. MS calculated 512.2 (MH+), exp 521.1 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([O:29][CH2:30][O:31][CH3:32])[C:19]=1[CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:8][O:9][Si](C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:32][O:31][CH2:30][O:29][C:18]1[CH:17]=[C:7]([CH2:8][OH:9])[CH:6]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:19]=1[CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COCOc1cc(CO[Si](C)(C)C(C)(C)C)cc(OCOC)c1C/C=C/c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COCOc1cc(CO)cc(OCOC)c1C/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.9 %

Procedure:
To a solution of [3,5-bis-methoxymethoxy-4-((E)-3-phenyl-allyl)-benzyloxy]-tert-butyl-dimethyl-silane (220d) (55 g, 0.12 mol) in THF (250 mL) was added TBAF (47.2 g, 0.18 mol) in one portion. The mixture was stirred at room temperature for 0.5 hr. TLC (EtOAc/petroleum ether=1/10) showed that the reaction was complete. The reaction mixture was washed with brine (50 mL) and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4 and concentrated in high vacuum to give the title compound (45 g, 92% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.16˜7.41 (m, 5H), 6.82 (s, 2H), 6.47 (m, 2H), 5.22(s, 4H), 4.71 (s, 2H), 3.62 (d, 2H), 3.45 (s, 6H).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([CH3:19])[C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11](N)=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1.Cl.N([O-])=[O:23].[Na+].S(=O)(=O)(O)O>O>[OH:23][C:12]1[CH:13]=[C:14]2[C:9]([C:8]3[CH:16]=[CH:17][C:5]([CH:4]([CH3:19])[C:3]([OH:2])=[O:20])=[CH:6][C:7]=3[CH2:15]2)=[CH:10][CH:11]=1
Reactant: O=N[O-]
Reactant: COC(=O)C(C)c1ccc2c(c1)Cc1cc(N)ccc1-2
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)Cc1cc(O)ccc1-2

Procedure:
The ester is dissolved in water (300 ml) containing concentrated HCl (11ml) with the aid of heat. The solution is cooled to 3°, stirred and treated dropwise with a solution of sodium nitrite (2.84 g) in water (15 ml) over a 30 minute period. The resulting diazonium solution is then added dropwise over a 1 hour period to boiling water (800 ml) containing concentrated sulfuric acid (13 ml), and then stirred for 30 minutes and cooled. The precipitate is collected by filtration and heated in 10% aqueous potassium hydroxide containing charcoal for 1 hour, cooled and acidified with 4N HCl. The solid is collected by filtration to give 8.0 g, mp 205°-207° of the tilted product. The analytical sample is prepared by sublimation, mp 218°-219°.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH3:8][O:9][CH:10]([CH:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:11]([O:13][CH3:14])=[O:12]>FC(F)(F)C(O)=O>[CH3:8][O:9][CH:10]([CH:15]([S:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(OC)C(O)c1ccccc1CCCCCCCCc1ccccc1
Reactant: COC(=O)CCS
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCSC(c1ccccc1CCCCCCCCc1ccccc1)C(OC)C(=O)OC
Reaction time: 0.17 h

Procedure:
To trifluoroacetic acid (100 ml) under argon and cooled to 0° C., was added methyl 3-mercaptopropanoate (0.5 ml, 4.5 mmoles). The mixture was stirred for 10 minutes, after which the ice bath was removed. Methyl 2-methoxy-3-hydroxy-3-[2-(8-phenyloctyl)phenyl]propanoate (1.5 g, 4 mmoles) was added and the mixture stirred for 18 hours. The reaction mixture was evaporated and diluted in methylene chloride. The organic layer was washed with 10% sodium hydroxide (ice cold) followed by ice water. The organic layer was dried over magnesium sulfate, filtered and evaporated. Flash chromatography on silica gel provided the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7](Cl)=[O:8].[CH2:13]([NH2:16])[CH:14]=[CH2:15]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([NH:16][CH2:13][CH:14]=[CH2:15])=[O:8]
Reactant: C=CCN
Reactant: O=C(Cl)C=Cc1cccc(F)c1
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: C=CCNC(=O)C=Cc1cccc(F)c1
Reaction time: 72 h

Procedure:
A solution of 3-fluorocinnamoyl chloride (3.7 g) in dry toluene (35 ml) was added with stirring to allylamine (8 ml) in dry benzene (100 ml). The reaction mixture was allowed to stand at room temperature for three days. After evaporation of the solvents under reduced pressure the residue was triturated with water containing a small amount of sodium carbonate and washed with water. Recrystallization from ethanol: water gave 3-fluoro-N-allylcinnamamide (3.3 g), m.p. 84.5-87° C. as fine white needles. Elemental analysis, nmr and ir spectra were consistent with the structure assignment.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11](Br)[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:9]1[C:25]([N:27]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:28])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:34]1(B(O)O)[CH2:36][CH2:35]1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([CH:34]2[CH2:36][CH2:35]2)[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:9]1[C:25]([N:27]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:28])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)C1CC1
Reactant: CN(CC(C)(C)C)C(=O)c1c(-c2ccc(Cl)cc2)c(Br)c(C(F)(F)F)n1Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(CC(C)(C)C)C(=O)c1c(-c2ccc(Cl)cc2)c(C2CC2)c(C(F)(F)F)n1Cc1ccccc1
Temperature: 120 °C
Yield: 99.4 %

Procedure:
To a solution of 1-benzyl-4-bromo-3-(4-chlorophenyl)-N-(2,2-dimethylpropyl)-N-methyl-5-(trifluoromethyl)pyrrole-2-carboxamide (100 mg, 0.18 mmol) in Toluene (1 mL) was added cyclopropylboronic acid (2 equiv., 0.032 g, 0.37 mmol), Palladium(II) acetate (0.1 equiv., 0.004 g, 0.018 mmol), 2-(DICYCLOHEXYLPHOSPHINO)-2′,4′,6′-TRI-I-PROPYL-1,1′-BIPHENYL (0.2 equiv., 0.01796 g, 0.03691 mmol) and POTASSIUM PHOSPHATE TRIBASIC (3 equiv., 0.1212 g, 0.04726 mL, 0.5537 mmol) in a Reactivial. The reaction was heated to 120° C. overnight. Work up: Reaction mixture cooled to room temperature and diluted with Ethyl Acetate. Filtered through celite and celite washed, through 3× Ethyl Acetate. Organics reduced under vacuum to residue. Purification: Purified via 25 g Silica Column using 0-100% Petrol Ether/(10% Ethyl Acetate/Petrol Ether) over 30 minutes collecting at 254 nm. Major peak isolated and reduced under vacuum to yield ˜90 mg (45%) white foam. Purified further via preparative HPLC using 70-95% acetonitrile/water (0.1% formic acid) over 20 min collecting at 254 nm. Pure fractions combined and reduced under vacuum.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: COc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(OC)c([N+](=O)[O-])cn1
Yield: 97.7 %

Procedure:
A solution of the product of Step 2 (950 mg, 5 mmol), sodium methoxide (695 mg, 12.5 mmol) in methanol (10 ml) was heated at reflux for 2 hours. After cooling the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried and evaporated in vacuo to give the title compound (900 mg, 98%). MS (ES+) m/e 185 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH:9](Br)[CH:10]=[C:11]([Br:13])[Br:12])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[CH:9]([CH:10]=[C:11]([Br:13])[Br:12])[CH:3]1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(C)(C)C(Br)C=C(Br)Br
Solvent: c1ccccc1
Product: CCOC(=O)C1C(C=C(Br)Br)C1(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
4.1 Parts of the so obtained ethyl 3,3-dimethyl-4,6,6tribromo-5-hexenoate was dissolved in 35 parts of dry benzene, and 1.9 parts of sodium t-butylate was added to the solution and the mixture was agitated for 1 hour under reflux of benzene. The liquid reaction mixture was poured into ice water and extracted with diethyl ether, and ether and benzene were distilled from the organic layer. The residue was subjected to distillation under reduced pressure to obtain 3.2 parts of ethyl 2,2-dimethyl-3-(2',2'-dibromovinyl)-cyclopropane-carboxylate having a boiling point of 92° - 94° C. under 0.5 mm Hg. The yield was 98%.
Reaction SMILES: O[CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[S:8]([N:11]([CH3:26])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)(=[O:10])=[O:9].C(N(CC)CC)C.CS([Cl:38])(=O)=O.O>O1CCCC1>[Cl:38][CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[S:8]([N:11]([CH3:26])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)(=[O:10])=[O:9]
Reactant: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1CCl
Temperature: 25 °C
Reaction time: 10 h
Yield: 85 %

Procedure:
To a solution of 2-(hydroxymethyl)-N-methyl-N-[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]thiophene-3-sulfonamide (405 mg) and triethylamine (167 μL) in tetrahydrofuran (5 mL) was added methanesulfonyl chloride (93 μL). The reaction mixture was stirred at room temperature for 10 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was crystallized from diethyl ether-hexane to give the title compound (360 mg, yield 85%) as colorless crystals. melting point 190° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][O:34][CH3:35])[C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:18]([O:20]CC4C=CC([N+]([O-])=O)=CC=4)=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[OH-].[K+].Cl>C(O)C.O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][O:34][CH3:35])[C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(N)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 39.9 %

Procedure:
p-Nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer: 7.8 g.) was suspended in a mixture of ethanol (60 ml.) and water (60 ml.) 1 N Aqueous solution of potassium hydroxide (45 ml.) was added dropwise to the stirred suspension under ice-cooling over 10 minutes and stirred at 5° C. for 15 minutes. The resultant solution was adjusted to pH 7.0 with conc. hydrochloric acid, washed with ethyl acetate and the concentrated under reduced pressure to half of its initial volume. The concentrated solution was adjusted to pH 5.0 and subjected to column chromatography on macroporous, non-inonic adsorption resin "Diaion HP-20" (Trade mark; manufactured by Mitsubishi Chemical Industries Ltd.; 80 ml.), and eluted with 5% aqueous solution of isopropyl alcohol. The fractions containing the object compound were collected and adjusted to pH 3.2 with 10% hydrochloric acid. The precipitating crystals were collected by filtration, and dried to give 7-[2 -(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-isomer: 2.3 g.).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([Cl:14])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)C.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[Cl:14][C:8]1[C:9]([O:11][CH2:12][CH3:13])=[CH:10][C:5]([CH2:4][OH:3])=[CH:6][C:7]=1[O:15][CH2:16][CH3:17]
Reactant: CCOC(=O)c1cc(OCC)c(Cl)c(OCC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CCOc1cc(CO)cc(OCC)c1Cl
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of 4-chloro-3,5-diethoxy-benzoic acid ethyl ester (5.0 g, 18.33 mmol, 1.0 equiv) in dichloromethane (25 mL) was added slowly over a time period of 15 min under slight cooling to −30° C. a solution of diisobutylaluminium hydride (55.0 mL, 55.00 mmol, 3.0 equiv; 1 M solution in THF). After 30 min the excess hydride was quenched by cautious addition of methanol (10 mL) and water (2 mL). The mixture was stirred for 30 min, a solution of 1 M HCl was added and the aqueous layer extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure providing 4.0 g (95%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.45 (t, J=7.0 Hz, 6H), 1.93 (br s, 1H), 4.09 (q, J=7.0 Hz, 4H), 4.62 (s, 2H), 6.57 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 14.74, 64.96, 65.18, 104.30, 110.65, 140.29, 155.66. MS (ISP): 231.4 [M+H]+.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[N:10]=[C:9](Cl)[C:8]([F:12])=[C:7]([CH3:13])[N:6]=1.CO.O>ClCCl>[Cl:4][C:5]1[N:10]=[C:9]([O:2][CH3:1])[C:8]([F:12])=[C:7]([CH3:13])[N:6]=1
Reactant: C[O-]
Reactant: Cc1nc(Cl)nc(Cl)c1F
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COc1nc(Cl)nc(C)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
Sodium methoxide (446.53 mg, 8.27 mmol) is added portion wise to a stirred solution of 2,4-dichloro-5-fluoro-6-methyl-pyrimidine (1.7 g, 7.51 mmol) in methanol (8 mL, 197.66 mmol) at 0° C. The mixture is then stirred at room temperature for 1 hour. Water (20 mL) is added to the reaction mixture followed by dichloromethane. The layers are separated and the aqueous layer is re-extracted with dichloromethane. The combined organic extracts are dried over magnesium sulfate and the solvents are evaporated under reduced pressure to give an 8:1 of mixture of product to starting material. The crude material is purified by silica gel chromatography using a 0-99% gradient of dichloromethane in iso-hexanes to give the title compound (1.16 g, 87%). 1H NMR (CDCl3) δ 4.09 (s, 3H), 2.45 (d, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][C:14]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26]Cl)=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1)=[O:7].[I-].[K+].[CH2:31]([NH:34][CH2:35][CH:36]=[CH2:37])[CH:32]=[CH2:33]>O1CCCC1>[CH2:31]([N:34]([CH2:35][CH:36]=[CH2:37])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][C:14]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][N:34]([CH2:35][CH:36]=[CH2:37])[CH2:31][CH:32]=[CH2:33])=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1)=[O:7])[CH:32]=[CH2:33]
Reactant: C=CCNCC=C
Reactant: O=C(CCCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCCl)ccc1S2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCN(CC=C)CCCCC(=O)c1ccc2c(c1)Cc1cc(C(=O)CCCCN(CC=C)CC=C)ccc1S2
Temperature: 120 °C
Reaction time: 24 h

Procedure:
A mixture of 22.3 g (0.05 mole) of 2,7-bis(5-chlorovaleryl)thioxanthene, 1 g of potassium iodide, 100 ml of diallylamine and 200 ml of tetrahydrofuran is placed in a Paar bomb and heated to 120°C with stirring for 24 hours. Upon cooling, the mixture is filtered and the filtrate evaporated to dryness. The resulting residue is dissolved in dilute HCl and extracted with ether. The aqueous portion is made basic, extracted with methylene chloride, dried over magnesium sulfate and filtered. The filtrate is heated to boiling, treated with charcoal, filtered and filtrate evaporated to dryness. The residue is chromatographed on a column of alumina and eluted with methylene chloride. The resulting oil is dissolved in diethyl ether, dried over molecular sieves, filtered and the ether evaporated. This process is repeated several times to yield 2,7-bis(5-diallylaminovaleryl)thioxanthene.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.CS[C:32]1[N:33](C(OCC)=O)[CH2:34][CH2:35][N:36]=1.CC(O)=O.C([O-])(O)=O.[Na+]>CCO>[NH:36]1[CH2:35][CH2:34][N:33]=[C:32]1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCN=C1SC
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)Nc1nc(CCc2ccc(NC3=NCCN3)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Yield: 10.3 %

Procedure:
A mixture of N-{4-[2-(4-aminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (150 mg), ethyl 2-(methylthio)-4,5-dihydro-1H-imidazole-1-carboxylate (78.9 mg), AcOH (0.3 ml) and EtOH (3 ml) was refluxed for 7 hours under N2 atmosphere. After cooled to r.t., the reaction mixture was made basic with saturated NaHCO3. The mixture was extracted with AcOEt. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by preparative silica gel chromatography with CHCl3/MeOH (10:1) as an eluent. The amorphous substance was solidified with ethyl ether to give N-{4-{2-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (17.9 mg) as an off-white amorphous solid.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:6][CH2:7][C:8]1[C:9](=[O:13])[CH2:10][CH2:11][CH:12]=1)(=[O:3])[CH3:2].[OH:19]O.[OH-].[Na+]>CO>[C:1]([O:4][CH:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:6][CH2:7][C:8]12[O:19][CH:12]1[CH2:11][CH2:10][C:9]2=[O:13])(=[O:3])[CH3:2]
Reactant: CCCCCC(CCC1=CCCC1=O)OC(C)=O
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC(CCC12OC1CCC2=O)OC(C)=O
Reaction time: 18 h

Procedure:
A stirred solution of 2-(3-acetoxyoctyl)cyclopent-2-enone (31.8 g.) [prepared as described in (f) above] in methanol (700 ml.) was treated slowly with aqueous hydrogen peroxide solution (45 ml. of "100 vol." solution) and aqueous 4N sodium hydroxide solution (15 ml.) at 5° to 10° C. and allowed to stand at room temperature for 18 hours. The solution was concentrated in vacuo (to about 100 ml. volume), and water (100 ml.) was added to the residue. The mixture was extracted with chloroform and the chloroform extract was washed with water and dried over magnesium sulphate. The solvent was removed in vacuo to give 2-(3-acetoxyoctyl)-2,3-epoxycyclopentanone (26.4 g.) which was used as starting material in the following preparation (h) of 5-acetoxy-2-(3-acetoxyoctyl)cyclopent-2-enone without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][SH:12])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[CH2:14][C:15](=[O:17])[CH3:16].[OH-].[Na+]>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][S:12][CH2:14][C:15](=[O:17])[CH3:16])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(=O)CCl
Reactant: SCCc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)CSCCc1ccc2c(c1)OCO2
Yield: 84.9 %

Procedure:
10 g of 2-(1,3-benzodioxol-5-yl)ethanethiol and 5.1 g of 1-chloro-2-propanone were dissolved in 200 ml of 90% ethanol. 2.2 g of sodium hydroxide was added to the solution and the mixture was heated under reflux for 10 min to conduct the reaction. The reaction mixture was concentrated under reduced pressure. 200 ml of ethyl acetate was added thereto to obtain a solution, which was washed with water three times. After drying over anhydrous sodium sulfate, the solvent was distilled off and the residue was purified according to silica gel column chromatography (benzene/ethyl acetate=30:1) to obtain 11.1 g of the intended compound in the form of a colorless oil.