Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([OH:25])[CH:19]=[CH:18]2)[CH2:2][CH2:3][CH2:4][CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CC(C)=O>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][O:25][C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][CH:24]=[C:15]([C:7]3[O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:6]=3[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:16]=2)[CH:21]=1)[CH3:38]
Reactant: CCCCCc1c(-c2ccc3cc(O)ccc3c2)oc2ccccc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCCCCc1c(-c2ccc3cc(OCC(=O)OCC)ccc3c2)oc2ccccc12
Yield: 93.6 %

Procedure:
Following the procedure described in Method B, Step 5 of Example 1, the title compound was prepared from 6-(3-pentyl-benzofuran-2-yl)-naphthalen-2-ol (0.33 g, 1 mmol), cesium carbonate (0.75 g, 2.3 mmol), ethyl bromoacetate (0.16 mL, 1.4 mmol) in acetone (20 mL). Crystallization from hexane furnished the title compound as a white solid (0.39 g), mp 84-86° C. Mass spectrum (+APCl, [M+H]+) m/z 417. 1HNMR (300 MHz, DMSO-d6): δ8.25 (s, 1H), 8.00 (d, 1H, J=9.1 Hz), 7.94-7.84 (m, 2H), 7.69-7.66 (m, 1H), 7.60 (d, 1H, J=7.5 Hz), 7.35-7.25 (m, 4H), 4.93 (s, 2H), 4.20 (q, 2H, J=7.1 Hz), 2.98 (t, 2H, J=7.3 Hz), 1.72 (p, 2H, J=7.3 Hz), 1.43-1.28 (m, 4H), 1.23 (t, 3H, J=7.2 Hz), and 0.83 ppm (t, 3H, J=7.1 Hz). Elemental Analysis for C27H28O4.0.5H2O: Calculated: C, 76.21; H, 6.87; N, 0.00. Found: C, 76.48; H, 6.69; N, 0.12.
Reaction SMILES: C(OC([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH:8](Cl)[CH2:7]1)=O)C.[O-]CC.[Na+]>C(O)C>[CH3:21][C:17]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=[C:9]2[CH:8]=[CH:7][NH:6][CH2:20][CH2:19][C:18]=12
Reactant: CCOC(=O)N1CCc2c(nc3ccccc3c2C)C(Cl)C1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c2c(nc3ccccc13)C=CNCC2
Reaction time: 2 h

Procedure:
A mixture of 3 gm (5.42 millimols) of 5-chloro-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester, 45 millimols of sodium ethoxide and 150 ml of ethanol was boiled for 2 hours. After distilling off the ethanol, the residue was dissolved in water, the solution was extracted with chloroform, the extract was dried with sodium sulfate, the solvent was evaporated, and the residue was recrystallized from ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:12]([NH:27][C:28]([NH:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[S:29])([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.I[CH3:40].O>CN(C=O)C>[C:31](/[N:30]=[C:28](\[S:29][CH3:40])/[NH:27][C@:12]([C:4]1[CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=[C:2]([F:1])[CH:3]=1)([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(NC(=S)N[C@@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1)c1ccccc1
Reactant: CI
Solvent: O
Solvent: CN(C)C=O
Product: CS/C(=N\C(=O)c1ccccc1)N[C@@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.4 %

Procedure:
To a solution of (S)-N-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethylcarbamothioyl)benzamide (70 mg, 0.13 mmol), prepared by method described in Procedures 22, 23, 24 and 9, in DMF (0.5 mL), was added iodomethane (10 μL, 0.15 mmol). The reaction vessel was sealed and stirred at room temperature for 18 h, followed by the addition of H2O. The aqueous layer was extracted with EtOAc. The separated organic portion was dried over MgSO4, filtered and concentrated to give (S,Z)-methyl N′-benzoyl-N-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)carbamimidothioate as a white solid (58 mg, 81% yield). LCMS: RT=4.49 min [M+H] 554.92 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[C:10]([NH2:13])[S:11][CH:12]=1)[C:5]([OH:7])=O.P(Cl)(Cl)(Cl)=O.C[Si](CC(N)=O)(C)C.[CH3:27][CH:28]1[CH:33]=[C:32]([C:34]([OH:36])=[O:35])[N:31]2[C:37](=[O:40])[CH:38]([NH2:39])[C@H:30]2[S:29]1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CC(C)=O.O.CN(C)C=O>[CH3:27][CH:28]1[CH:33]=[C:32]([C:34]([OH:36])=[O:35])[N:31]2[C:37](=[O:40])[CH:38]([NH:39][C:5](=[O:7])[C:4](=[N:3][O:2][CH3:1])[C:8]3[N:9]=[C:10]([NH2:13])[S:11][CH:12]=3)[C@H:30]2[S:29]1
Reactant: CON=C(C(=O)O)c1csc(N)n1
Reactant: CC1C=C(C(=O)O)N2C(=O)C(N)[C@H]2S1
Agent: CON=C(C(=O)O)c1csc(=N)[nH]1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(N)n1
Temperature: 5 °C

Procedure:
A suspension of 2-methoxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer), which can be represented as 2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetic acid (syn isomer), (26 g.) in ethyl acetate (250 ml.) was cooled to 5° C., and phosphorus oxychloride (25 g.) was added dropwise thereto with stirring under ice-cooling, and then the mixture was stirred for 30 minutes at 4° to 6° C. To the mixture was added dropwise a solution of trimethylsilylacetamide (22 g.) in ethyl acetate (20 ml.) with stirring under ice-cooling, and the mixture was stirred for 30 minutes at 4° to 6° C., and then phosphorus oxychloride (25 g.) was further added thereto with stirring under ice-cooling. The mixture was stirred for 15 minutes at the same temperature, and dimethylformamide (10.6 g.) was added dropwise thereto at the same temperature. The mixture was stirred for 40 minutes at the same temperature, and the resulting clear solution was cooled to -10° C. On the other hand, to a solution of 2-methyl-7-amino-3-cephem-4-carboxylic acid (23.9 g.) in a solution of sodium bicarbonate (25 g.) and water (400 ml.) was added acetone (300 ml.), and the mixture was cooled to -5° C. To the mixture was added dropwise the above prepared clear solution at -5° to 0° C., and then the mixture was stirred for 2 hours, all the while the mixture was kept to pH 6 with 15% aqueous sodium bicarbonate solution. Insoluble materials were filtered off, and the aqueous layer was separated. The aqueous layer was adjusted to pH 3 with 20% hydrochloric acid, and precipitated crystals were collected by filtration, washed with water and acetone in turn and then dried under reduced pressure to give 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7 -[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (39.4 g.). This object compound was identified with the object compound prepared in Example 6 by IR and NMR determination.
Reaction SMILES: [F:1][C:2]1[C:3](=O)[NH:4][CH:5]=[N:6][C:7]=1[C:8]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:11]2=[N:12][CH:13]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:15]=[C:10]2[CH:9]=1.P(Cl)(Cl)([Cl:32])=O>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:20]2[C:11]3=[N:12][CH:13]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:15]=[C:10]3[CH:9]=[C:8]2[C:7]2[C:2]([F:1])=[C:3]([Cl:32])[N:4]=[CH:5][N:6]=2)=[CH:23][CH:24]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1cnc2c(c1)cc(-c1nc[nH]c(=O)c1F)n2Cc1ccc(F)cc1
Product: CS(=O)(=O)c1cnc2c(c1)cc(-c1ncnc(Cl)c1F)n2Cc1ccc(F)cc1

Procedure:
A mixture of 5-fluoro-6-(1-(4-fluorobenzyl)-5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3H-pyrimidin-4-one obtained in Example 36 (4) (20 mg) and phosphorus oxychloride (1 ml) was heated under reflux for 3 hours. The mixture was concentrated under reduced pressure, diluted with dichloromethane, washed with water, dried and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (methanol:dichloromethane=1:99) to obtain the desired product (13 mg) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:16])/[CH:11]=[CH:12]/[N:13](C)C.Cl.NO>CO>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:16][N:13]=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccccc1C(=O)/C=C/N(C)C
Agent: Cl
Agent: NO
Solvent: CO
Product: COC(=O)c1ccccc1-c1ccno1
Yield: 52 %

Procedure:
To a solution of 2-((E)-3-dimethylamino-acryloyl)-benzoic acid methyl ester (1.295 mg, 5.552 mmol) in methanol (21 mL) is added hydroxylamine hydrochloride (964.5 mg, 13.88 mmol). The reaction mixture is heated to reflux for 1.5 hours. After this time, the reaction mixture is loaded onto silica gel and purified using silica gel flash column chromatography with 1-10% MeOH in CH2Cl2 as the eluent to give 2-isoxazol-5-yl-benzoic acid methyl ester (587 mg, 52%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[N:5]([CH2:14][C:15]([O:17]CC)=[O:16])[CH2:6][CH2:7][C:8]1[S:9][C:10](Br)=[CH:11][CH:12]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([N:5]([CH2:14][C:15]([OH:17])=[O:16])[CH2:6][CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)=[O:20])[CH3:2]
Reactant: CCOC(=O)CN(CCc1ccc(Br)s1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)N(CCc1cccs1)CC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
To solution of ethyl(ethoxycarbonyl)methyl-2-(5-bromothiophen-2-yl)ethylcarbamate (30.0 g, 105.26 mmol) in ethanol at 0° C. was added dropwise 200 mL of 1N NaOH. The reaction mixture was warmed to RT and stirred for 24 hours. The reaction mixture was extracted with Et2O to remove unreacted starting material and the aqueous layer acidified to pH=1 with 1N HCl. The aqueous solution was extracted with ethyl acetate (2×500 mL) and the combined organics were washed with brine solution, dried (Na2SO4), filtered, and evaporated to obtain crude product. 2-(N-(Ethoxycarbonyl)-N-(2-(thiophen-2-yl)ethyl)amino)acetic acid (74% yield) was obtained as a colorless solid after washing the crude product with pentane; ES-MS: 258.2 (M+H).
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:6])[CH2:4][Cl:5].B(F)(F)F.CCOCC.[CH2:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[Cl:1][CH2:2][CH:3]([O:6][CH:26]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[CH3:27])[CH2:4][Cl:5]
Reactant: OC(CCl)CCl
Agent: C=CCCCCCCCCCC
Agent: FB(F)F
Solvent: CCOCC
Product: CCCCCCCCCCC(C)OC(CCl)CCl
Temperature: 95 °C

Procedure:
To a 1000 ml round bottom flask equipped with condenser, overhead stirrer, and nitrogen inlet system is added 526.2 g of 1,3-dichloro-2-propanol, 7.8 ml of boron trifluoride diethyl etherate, and 101 g of 1-dodecene at room temperature. The mixture is heated to 95° C. for 1 hour. The reaction mixture is cooled to room temperature and then transferred to a 1000 ml separation funnel. 200 ml of heptane is added and two phases are separated. The lower phase containing the excess dichloropropanol, ether products, unreacted and isomerized olefins, and the catalyst is extracted with 200 ml of heptane three more times. The heptane solutions are combined and heptane is removed on a rotary evaporator. Distillation under reduced pressure affords 46.3 g of dodecene isomers mixture and 91.6 g of sec-dodecyl 1,3-dichloro-2-propyl ether and isomers. Yield=51.3% (based on 1-dodecene).
Reaction SMILES: Cl.[NH:2](C(OC(C)(C)C)=O)[C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH2:10])=[O:9]>O1CCOCC1>[NH2:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH2:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(N)=O)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)NCCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
10 mL of 4N HCl in dioxane were added to the 200 mg (0.200 g) Boc-Cit-Amp. The mixture was stirred at room temperature for 6 hours and solvent was removed.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>C1COCC1.[Cu]I>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])=[N:10][CH:11]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(Br)cn1
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
1.15 g (1.63 mmol) of tetrakistriphenylphosphine palladium, 0.311 g (1.63 mmol) of copper (1) iodide, and 50 mL of triethylamine are added to a solution of 20 g (81.89 mmol) of 2,5-dibromopyridine in 250 mL of absolute THF under an argon atmosphere. At 17° C., a solution of 13 mL (90.14 mmol) of trimethylsilylacetylene in 20 mL of THF is immediately added dropwise to this reaction mixture. After ten minutes, the cooling is removed. After 20 minutes, the temperature is 30° C. The mixture is then cooled to 20° C. and briefly stirred. The reaction mixture is evaporated down, the residue is taken up in ethyl acetate and extracted twice with sodium hydrogen carbonate solution. The combined organic phases are dried over magnesium sulfate. The purification is carried out by column chromatography on silica gel (eluant: petroleum ether). Yield: 20.4 g (98% of theory); C10H12BrNSi (M=254.20); calc.: molecular ion peak (M+H)+: 254/256; found: molecular ion peak (M+H)+: 254/256; Rf value: 0.72 (silica gel, petroleum ether).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])=[O:27])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: CCNCC
Product: CCN(CC)C(=O)CN(c1cccc(N(C)C)c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with diethylamine
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[S:11][CH2:10][CH2:9][S:8][C:7]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:28])=[C:20]([CH:27]=1)[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22].Cl>C1(C)C=CC=CC=1.N1C=CC=CC=1.C(Cl)Cl>[Cl:28][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:12]([C:7]2[S:8][CH2:9][CH2:10][S:11][C:6]=2[CH3:5])=[O:14])=[CH:27][C:20]=1[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]
Reactant: CC1=C(C(=O)O)SCCS1
Reactant: CC(C)OC(=O)c1cc(N)ccc1Cl
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC1=C(C(=O)Nc2ccc(Cl)c(C(=O)OC(C)C)c2)SCCS1
Reaction time: 24 h
Yield: 57 %

Procedure:
Thionyl chloride (6.5 g, 0.055 mole) was added slowly to a stirred solution of 5,6-dihydro-3-methyl-1,4-dithiin-2-carboxylic acid (3 g, 0.017 mole) in toluene (15 ml) at room temperature. The mixture was heated under reflux for 4 hours. The excess toluene and thionyl chloride were removed in a rotary evaporator, yielding the crude acid chloride. 1-Methylethyl 5-amino-2-chlorobenzoate (3 g, 0.014 mole) in pyridine (20 ml) was added slowly to a stirred solution of the crude acid chloride (3 g) in methylene chloride (20 ml) at 20° C. The mixture was stirred for 24 hours, poured onto ice and concentrated hydrochloric acid, washed twice with water, dried with magnesium sulfate, and the methylene chloride evaporated. Recrystallization from 95% ethanol yielded the title compound, m.p. 122°-124° C. (3 g, 57% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5][C:4](=O)[CH:3]=1.[NH2:15][OH:16]>NC1C=CC=CN=1.NC1C=CC=C(C)N=1>[OH:16][N:15]1[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:7][C:2]([CH3:1])=[CH:3][C:4]1=[O:5]
Reactant: NO
Reactant: Cc1cc(C2CCCCC2)oc(=O)c1
Agent: Cc1cccc(N)n1
Agent: Nc1ccccn1
Product: Cc1cc(C2CCCCC2)n(O)c(=O)c1
Reaction time: 216 h
Yield: 36.6 %

Procedure:
2 g of 4-methyl-6-cyclohexyl-2-pyrone and 1 g of hydroxylamine were dissolved in a mixture of 1.5 g of 2-aminopyridine and 4.5 g of 2-amino-6-methylpyridine and stored for 9 days at room temperature. After the usual working up, there were obtained 0.79 g (37 %) of 1-hydroxy-4-methyl-6-cyclohexyl-2-pyridone melting at 143° C.
Reaction SMILES: C([Li])CCC.O1CCCC1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=1.[Cl:20][C:21]1[N:26]=[C:25](Cl)[CH:24]=[CH:23][N:22]=1>O>[Cl:20][C:21]1[N:26]=[C:25]([O:17][CH2:16][C:15]2[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=2)[CH:24]=[CH:23][N:22]=1
Reactant: OCc1ccc(F)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(COc2ccnc(Cl)n2)cc1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
n-Butyl lithium (2.6 M n-hexane solution, 10.1 mL) was added to tetrahydrofuran solution (12 mL) of 4-fluorobenzyl alcohol (3.08 mL) at −78° C., and stirred at the same temperature for 30 minutes. This reaction liquid was gradually added to tetrahydrofuran suspension (24 mL) of 2,4-dichloropyrimidine (4.0 g) and stirred at room temperature for 2 hours. After addition of water, the reaction liquid was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the residue was crystallized from mixed solvent of chloroform and hexane to provide the title compound (4.36 g, 68%).
Reaction SMILES: [C:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]3[C:17](=[O:24])[CH:18]=[C:19]([C:21]([OH:23])=[O:22])[O:20][C:15]=3[C:14]=2[CH2:27][CH2:28][CH3:29])=[C:6]([CH2:32][CH2:33][CH3:34])[C:5]=1[OH:35])(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+:40].O>C(O)C>[C:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]3[C:17](=[O:24])[CH:18]=[C:19]([C:21]([O-:23])=[O:22])[O:20][C:15]=3[C:14]=2[CH2:27][CH2:28][CH3:29])=[C:6]([CH2:32][CH2:33][CH3:34])[C:5]=1[OH:35])(=[O:3])[CH3:2].[Na+:40]
Reactant: CCCc1c(OCCCOc2ccc3c(=O)cc(C(=O)O)oc3c2CCC)ccc(C(C)=O)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCc1c(OCCCOc2ccc3c(=O)cc(C(=O)[O-])oc3c2CCC)ccc(C(C)=O)c1O

Procedure:
To 5.0 parts of 7-[3-(4-acetyl-3-hydroxy-2-propyl phenoxy) propoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid dissolved in 200 parts of hot ethanol was added a solution of 0.870 parts of sodium bicarbonate in 30 parts of water. The solution was evaporated under reduced pressure to dryness, dry benzene was added and the mixture was again evaporated to dryness. The resulting buff solid was ground to a powder and dried to afford 5.0 parts of sodium 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CCCCCC.[C:17]([C:20]1[N:21]=[CH:22][N:23]2[C:27]([CH3:28])=[CH:26][S:25][C:24]=12)(=[O:19])[CH3:18].C([Li])CCC.CCCCCC.[CH2:40]([Sn:44](Cl)([CH2:49][CH2:50][CH2:51][CH3:52])[CH2:45][CH2:46][CH2:47][CH3:48])[CH2:41][CH2:42][CH3:43].P([O-])([O-])([O-])=O>C1COCC1.CCOCC>[C:17]([C:20]1[N:21]=[CH:22][N:23]2[C:27]([CH3:28])=[C:26]([Sn:44]([CH2:45][CH2:46][CH2:47][CH3:48])([CH2:49][CH2:50][CH2:51][CH3:52])[CH2:40][CH2:41][CH2:42][CH3:43])[S:25][C:24]=12)(=[O:19])[CH3:18]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(=O)c1ncn2c(C)csc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1sc2c(C(C)=O)ncn2c1C
Reaction time: 0.25 h
Yield: 80.2 %

Procedure:
A 1.0 N lithiumbis(trimethylsilyl)amide/n-hexane solution (2.2 ml) was added dropwise to a solution of 0.360 g of 7-acetyl-3-methylimidazo[5,1-b]thiazole in THF (20 ml) at −70° C. The mixture was stirred for 15 min. A 1.6 N n-butyllithium/n-hexane solution (2.8 ml) was added dropwise to the reaction solution at the same temperature. The mixture was stirred for one hr. A solution (4 ml) of 0.846 g of tri-n-butylstannyl chloride in THF was added dropwise to the reaction solution. The mixture was stirred at −40° C. for 30 min. The reaction solution was added under ice cooling to a mixed solution composed of ether (50 ml) and 0.2 N phosphate buffer (pH 7) (50 ml) with thorough stirring. The organic layer was separated, washed with 0.2 N phosphate buffer (pH 7) (30 ml), and dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was subjected to separation and purification by flash column chromatography on silica gel (ethyl acetate) to give 0.752 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1([C:5]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[O:6])[CH2:4][CH2:3]1.IC.[CH2:27](N(CC)CC)C>C(Cl)Cl>[CH3:27][NH:1][C:2]1([C:5]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[O:6])[CH2:4][CH2:3]1
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccccc1-c1ccc(CNC(=O)C2(N)CC2)cc1
Solvent: ClCCl
Solvent: CI
Product: CNC1(C(=O)NCc2ccc(-c3ccccc3C(=O)OC)cc2)CC1
Yield: 34.8 %

Procedure:
Methyl 4′-({[(1-aminocyclopropyl)carbonyl]amino}methyl)-1,1′-biphenyl-2-carboxylate (200 mg, 0.62 mmol), prepared according to Example 1, was dissolved in 5 mL of DCM along with iodomethane (130 mg, 0.93 mmol) and triethylamine (75 mg, 0.74 mmol). After no reaction was observed at ambient temperature, the reaction mixture was heated to reflux for about two days. After the first day, additional iodomethane was added (ca. 3–5 equiv.). After two days >50% of the starting material was consumed. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel chromatography eluting with 1–10% MeOH in DCM to afford 73 mg of methyl 4′-[({[1-(methylamino)cyclo-propyl]carbonyl}amino)methyl]-1,1′-biphenyl-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[C:16](OC)(=[O:19])[C:17]#[CH:18]>C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:18]=[CH:17][C:16]([OH:19])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: C#CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Oc1ccn(-c2ccc(Cl)cc2)n1
Reaction time: 1 h
Yield: 74.2 %

Procedure:
A solution of 57.5 g of 4-chlorophenylhydrazine hydrosulfate in 1,000 ml of tert-butanol was first treated in portions with 100.8 g of potassium tert-butoxide and then (after stirring for 10 min) in the course of 45 min at 45° C.-50° C. with a solution of 27.7 g of methyl propiolate in 90 ml of tertbutanol. After 1 h at boiling point, the mixture was allowed to cool and the solvent was removed under reduced pressure. The residue thus obtained was dissolved in 1,200 ml of water. The aqueous phase was first washed with methylene chloride and then acidified, the product being deposited as a solid. 47.6 g of the title compound were obtained, m.p.: 185°-187° C.