Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[N:6][CH:7]=1.Cl.N([O-])=O.[Na+].[I-:28].[K+]>O.CC(C)=O>[I:28][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[N:6][CH:7]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(N)cn1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(I)cn1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 119.9 %

Procedure:
To a mixture of 5-amino-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]pyridine (10.0 g), conc. HCl (8.47 ml) and acetone (100 ml) was added dropwise a solution of sodium nitrite (NaNO2) (2.46 g) in water (10 ml) at temperatures below 10° C. The mixture was stirred for 30 minutes at 10° C, to which was dropwise added a solution of potassium iodide (KI) (2.46 g) in water (10 ml) at 10° C. The reaction mixture was stirred for further one hour at temperatures raging from 30° to 35° C. and for another one hour at temperatures ranging from 35° to 40° C., followed by concentration under reduced pressure. The concentrate was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off under reduced pressure. The residual oily product was subjected to a silica gel chromatography. From the fractions eluted with ethyl acetate--hexane (1:3, v/v) was obtained 5-iodo-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]pyridine (7.22 g, 52%). Recrystallization from ethyl acetate--hexane gave colorless crystals, m.p.105°-106° C.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]([O:17][CH2:18]Cl)(=[O:16])[CH2:13][CH2:14][CH3:15].C(N(CC)CC)C.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[C:12]([O:17][CH2:18][O:10][C:1](=[O:11])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: O=C(O)C=Cc1ccccc1
Reactant: CCCC(=O)OCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCC(=O)OCOC(=O)C=Cc1ccccc1
Temperature: 70 °C
Yield: 72.1 %

Procedure:
To a stirred solution of cinnamic acid (10 g, 67 mmol) and chloromethyl butyrate (9.5 g, 1 eq) in dry dimethylformamide (25 mL) under nitrogen was dropwise added triethylamine (12 mL, 8.5 g, 1.2 eq). The reaction mixture was heated at 70° C. for 3 h; during that time a large amount of precipitate formed and TLC (ethyl acetate:hexane 1:4) showed that all the acid has reacted. The precipitate was filtered and washed with ethyl acetate. The filtrate was partitioned between water and ethyl acetate. The aqueous phase was washed with a small amount of ethyl acetate, and the combined organic phase was washed with water (3×), 5% solution of NaHCO3 (2×) and brine (2×) dried with MgSO4 and evaporated to give the crude product as an orange oil (15 g), which was distilled at 150° C./0.1-0.2 mm Hg. The pure product was obtained as a colorless oil (12 g, 72% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1.[NH2:28][CH2:29][CH2:30][CH2:31][OH:32]>>[CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13]([NH:28][CH2:29][CH2:30][CH2:31][OH:32])[C:12]=2[CH2:11][CH2:10]1
Reactant: Cc1cc(F)ccc1N1CCc2c(Cl)nc3c(OC(F)(F)F)cccc3c21
Reactant: NCCCO
Product: Cc1cc(F)ccc1N1CCc2c(NCCCO)nc3c(OC(F)(F)F)cccc3c21

Procedure:
1-(2-Methyl-4-fluorophenyl)-4-chloro-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(500 mg, 1.3 mmol) was dissolved in 3-amino-1-propanol(10 ml) in the pressure tube, then reacted at the same condition of Step 3 in the Example 16 to obtain 485 mg of desired compound as solid in 95% of yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11]#[N:12])[CH:6]=[CH:7][CH:8]=1.[NH2:14][NH2:15]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([NH2:12])[NH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(=O)CC#N)c1
Reactant: NN
Solvent: CCO
Product: COc1cccc(-c2cc(N)[nH]n2)c1

Procedure:
3-(3-Methoxy-phenyl)-3-oxo-propionitrile (2.0202 gms.) is then suspended in 55 mL of anhydrous EtOH. This suspension is treated with 0.73 mL of anhydrous hydrazine and subsequently heated to refluxing temperature for 1 day. The reaction mixture is concentrated in vacuo. The residue is then triturated with isopropanol to precipitate out the 5-(3-methoxy-phenyl)-2H-pyrazol-3-ylamine as a white solid.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[N+:21]([O-])=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C>[C:4]([C:17]1[C:16]([NH2:21])=[C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10]2)[CH:20]=[CH:19][N:18]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCCN(c2ccncc2[N+](=O)[O-])C1
Solvent: CCO
Product: CC(C)(C)c1nccc(N2CCC[C@H](O[Si](C)(C)C(C)(C)C)C2)c1N

Procedure:
Following Method 2 of Example 49, (R)-4-(3-(tert-butyl dimethylsilyloxy)piperidin-1-yl)-3-nitropyridine in ethanol was reduced yielding tert-butyl (S)-4-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)pyridin-3-amine. LCMS (m/z): 308.2 (MH+); LC Rt=3.47 min.
Reaction SMILES: [NH2:1][CH:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:17]=1)[CH:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[OH:4].[C:29]1([C:40](O)=[O:41])[CH:30]=[CH:31][CH:32]=[C:33]2[CH2:39][CH2:38][CH2:37][CH:36]=[CH:35][C:34]=12.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(#N)C.C(OCC)(=O)C>[C:29]1([C:40]([NH:1][CH:2]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:27])([F:28])[CH:24]([F:25])[F:26])[CH:17]=2)[CH:3]([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[OH:4])=[O:41])[C:34]2[CH:35]=[CH:36][CH2:37][CH2:38][CH2:39][C:33]=2[CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccc(C(O)C(N)Cc2cccc(OC(F)(F)C(F)F)c2)cc1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(C(O)C(Cc2cccc(OC(F)(F)C(F)F)c2)NC(=O)c2cccc3c2C=CCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
While stirring methyl 4-[(1RS,2SR)-2-amino-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl]benzoate (10.80 g, 26.91 mmol), 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (5.06 g, 26.9 mmol) and 1-hydroxybenzotriazole hydrate (4.12 g, 26.9 mmol) in acetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.16 g, 26.9 mmol) was added and the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and passed through silica gel. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from diisopropyl ether to give the objective substance.
Reaction SMILES: O.O.O.O.O.[OH-].C[N+](C)(C)C.CN(C=O)C.[C:17]([OH:20])(=[O:19])[CH3:18].[CH2:21]([O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]Br)=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=[O:25])[CH3:22]>CCOCC>[CH2:21]([O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][O:20][C:17](=[O:19])[CH3:18])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=[O:25])[CH3:22]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCCCCCCCCCBr)cc2)cc1
Reactant: CC(=O)O
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCCCCCCCCCOC(C)=O)cc2)cc1
Reaction time: 1 h
Yield: 66.9 %

Procedure:
60 m moles (10.9 g) of tetramethylammonium hydroxide pentahydrate was added to a DMF solution of 60 m moles (3.6 g) of acetic acid, and stirred for one hour, then 50 m moles (24.5 g) of the above 4'-(12-bromododecyloxy)biphenyl-4-carboxylic acid ethyl ester was added thereto, and stirred for 12 hours. After the reaction, the reaction solution was ether extracted. The extrate was concentrated, and then purified by column chromatography, to obtain 15.7 g of 4'-(12-acetyloxydodecyloxy)biphenyl-4-carboxylic acid ethyl ester [m.p. 80.1°-81.5° C⟧ (yield: 67%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=[O:17])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.O.[Sn](Cl)Cl>C(O)C>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=[O:17])=[CH:3][C:2]=1[F:1]
Reactant: O=c1ccccn1-c1ccc([N+](=O)[O-])c(F)c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
1.8 g (7.7 mmol) 1-(3-fluoro-4-nitro-phenyl)-1H-pyridin-2-one are dissolved in 360 ml of ethanol, combined with 8.7 g (38.4 mmol) tin(II)chloride-hydrate and refluxed for 45 min. The mixture is cooled and concentrated to dryness. The residue is combined with equal amounts of 1N sodium hydroxide solution and ethyl acetate. The precipitate is filtered off, water is added to the filtrate, the organic phase is separated off and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated to dryness.
Reaction SMILES: C(OC([N:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N+:15]([O-:17])=[O:16])[CH2:7]1)=O)C.[BrH:18]>C(O)(=O)C>[BrH:18].[N+:15]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[CH2:14][NH:6][CH2:7]2)([O-:17])=[O:16]
Reactant: CCOC(=O)N1Cc2cccc([N+](=O)[O-])c2C1
Agent: Br
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc2c1CNC2
Temperature: 100 °C
Reaction time: 20 h

Procedure:
2.36 g of 2-ethoxycarbonyl-4-nitroisoindoline was added to 70 ml of 25% hydrobromic acid in acetic acid. The mixture was stirred for 20 hours at 100° C., concentrated under reduced pressure, and recrystallized from ethanol to give 2.11 g of 4-nitroisoindoline hydrobromide.
Reaction SMILES: [NH2:1][N:2]1[CH2:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)[C:3]1=[S:17].[CH3:18][C:19]1[CH:20]=[C:21]([N:26]2[C:30]([OH:31])=[C:29]([CH:32]=O)[C:28]([CH3:34])=[N:27]2)[CH:22]=[CH:23][C:24]=1[CH3:25].C(O)C>CO>[C:14]([C:11]1[CH:10]=[CH:9][C:8]([N:4]2[C:5](=[O:7])[CH2:6][N:2]([N:1]=[CH:32][C:29]3[C:28]([CH3:34])=[N:27][N:26]([C:21]4[CH:22]=[CH:23][C:24]([CH3:25])=[C:19]([CH3:18])[CH:20]=4)[C:30]=3[OH:31])[C:3]2=[S:17])=[CH:13][CH:12]=1)([OH:16])=[O:15]
Reactant: NN1CC(=O)N(c2ccc(C(=O)O)cc2)C1=S
Reactant: Cc1ccc(-n2nc(C)c(C=O)c2O)cc1C
Solvent: CCO
Solvent: CO
Product: Cc1ccc(-n2nc(C)c(C=NN3CC(=O)N(c4ccc(C(=O)O)cc4)C3=S)c2O)cc1C
Yield: 93.8 %

Procedure:
50 mg (0.2 mmol) of the 1-amino-3-(4-carboxyphenyl)-2-thioxoimidazolidin-4-one synthesized above in 1) and 55 mg (0.22 mmol) of the 1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazole-4-carbaldehyde synthesized in 1) of Reference Synthetic Example 1 were stirred in a liquid mixture of 10 ml of ethanol and 5 ml of methanol at room temperature for 96 hours. The resulting insoluble was collected by filtration to obtain 87 mg of the desired product as a yellow solid (yield 85%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:29]=O)=[N:21]1.N1CCCCC1>CO>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](/[CH:29]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[N:21]1
Reactant: CN1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: CN1CCN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 37.4 %

Procedure:
A solution of 6-hydroxy-7-[(4-methylpiperazin-1-yl)methyl]benzofuran-3(2H)-one (0.131 g, 0.500 mmol) in methanol (2 mL) was added with 1H-indazole-3-carbaldehyde (0.0731 g, 0.500 mmol), and piperidine (0.00426 g, 0.0500 mmol) at room temperature, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, then added with methanol (2 mL), and suspended in methanol and thereby washed to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-hydroxy-7-[(4-methylpiperazin-1-yl)methyl]benzofuran-3(2H)-one (0.0731 g, 37%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:4]([CH3:14])[CH2:3]1.[C:15](O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[C:15]([O:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:4]([CH3:14])[CH2:3]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@H]1C[C@H](OC(=O)c2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
To a solution of the alcohol of step A (0.81 g, 4.0 mmol), benzoic acid (0.74 g, 6.0 mmol) and triphenylphosphine (2.11 g, 8.0 mmol) in toluene (20 mL) was added DIAD (1.67 mL, 8.0 mmol). After being stirred at room temperature for 4 hours, the solution was concentrated. The residue was purified by flash chromatography eluting with 0%, 5% and 20% EtOAc/hexanes provided 1.0 g of the title compound. MS calculated (M+H)+308. Found 308.1.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[O:18][C:19]([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)=[C:20]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[C:27](=[O:31])[CH2:26][CH2:25]4)[CH:21]=2)[CH2:12]1)=O)C1C=CC=CC=1>C(O)C.C1CCCCC=1.[Pd]>[NH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[O:18][C:19]([C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)=[C:20]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[C:27](=[O:31])[CH2:26][CH2:25]4)[CH:21]=2)[CH2:12]1
Reactant: O=C1CCc2cc(-c3cc(C4CCCN(C(=O)OCc5ccccc5)C4)oc3-c3ccncc3)ccc21
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: O=C1CCc2cc(-c3cc(C4CCCNC4)oc3-c3ccncc3)ccc21
Temperature: 90 °C
Yield: 87.8 %

Procedure:
A solution of the product of Step 5 (2.3 g, 4.67 mmol) in ethanol (100 ml) and cyclohexene (60 ml) was treated with 10% palladium on charcoal (0.8 g) and heated at 90° C. for 1.5 hours. After cooling to room temperature, the reaction mixture was filtered through celite and washed several times with ethanol. The filtrate was evaporated in vacuo and the residue purified by silica gel chromatography eluting with chloroform/ethanol/0.880 ammonia solution (95:4.5:0.5) followed by (90:9:1) to yield the title compound (1.47 g, 88%); MS(ES+) m/e 359 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:36])[CH2:34][C:8]2[C:9]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:30]([O:32]C)=[O:31])[CH:25]=4)[CH:19]=3)=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:11][C:7]=2[C:6](=[O:35])[CH2:5]1.Cl>CCO.O>[CH3:3][C:4]1([CH3:36])[CH2:34][C:8]2[C:9]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([C:30]([OH:32])=[O:31])[CH:25]=4)[CH:19]=3)=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:11][C:7]=2[C:6](=[O:35])[CH2:5]1
Reactant: COC(=O)c1cc(-c2cc(-c3c(N4CCOCC4)sc4c3CC(C)(C)CC4=O)ccn2)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(=O)c2sc(N3CCOCC3)c(-c3ccnc(-c4ccnc(C(=O)O)c4)c3)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
Sodium hydroxide (11 mg, 0.27 mmol) was added to a mixture of Example 215 (65 mg, 0.14 mmol) in EtOH (5 mL) and water (1 mL) and the reaction mixture was stirred at room temperature for 2 h. Water (5 mL) was added; the reaction mixture was adjusted to pH 6 with 1N aqueous hydrochloric acid and then extracted with EtOAc (2×15 mL). The combined organic layers were dried (magnesium sulfate) and the solvent was removed in vacuo to give the title compound (60 mg, 92%) as a yellow solid. δH (CDCl3) 8.91-8.78 (3H, m), 8.37 (1H, d, J 4.3 Hz), 8.04 (1H, s), 7.43 (1H, d, J 4.9 Hz), 3.74-3.62 (4H, m), 3.09-2.97 (4H, m), 2.54 (2H, s), 2.48 (2H, s), 1.06 (6H, s). LCMS (ES+) 464.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]1([CH3:36])[CH:14]([C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16])[N:13]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:12]2[S:11][CH2:10]1>C(Cl)Cl.[B-](F)(F)(F)F.[Ag+]>[NH:1]([C:9]1([CH3:36])[CH:14]([C:15]([O:17][CH2:18][C:19]([Cl:20])([Cl:21])[Cl:22])=[O:16])[N:13]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:12]2[S:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CC1(Br)CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC1(Nc2ccccc2)CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl

Procedure:
Aniline (0.28 g) was added to a solution of 2,2,2-trichloroethyl 3-bromo-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate (1.10 g) in methylene chloride (15 ml). To the solution was added silver fluoborate 0.45 g under ice-cooling under stirring and stirred at the same temperature for 4 hours. After the reaction, the mixture was filtered and the filtrate was washed with dilute phosphoric acid aqueous solution and water in turn. The solution was dried over magnesium sulphate and concentrated. The residue was subjected to column chromatography on silica gel (25 g) using chloroform. The 12th to 13th fractions of fractions, each of which was separated into 20 cc, were concentrated to give oily 2,2,2-trichloroethyl 3-anilino-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](\[CH3:17])/[CH2:5][CH2:6]/[CH:7]=[C:8](/[CH3:16])\[CH2:9][CH2:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13].N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([O:1][CH2:2]/[CH:3]=[C:4](\[CH3:17])/[CH2:5][CH2:6]/[CH:7]=[C:8](/[CH3:16])\[CH2:9][CH2:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])(=[O:26])[CH3:25]
Reactant: C=C(C)C(=O)CC/C(C)=C\CC/C(C)=C/CO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)CC/C(C)=C\CC/C(C)=C/COC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 0.5 g (0.0021 mol) of (6Z,10E)-12-hydroxy-2,6,10-trimethyl-1,6,10-dodecatrien-3-one dissolved in 5 ml of methylene chloride and 1.3 ml of pyridine is treated with 1 ml of acetic anhydride. The solution is stirred at room temperature for 18 hours under argon. After removing the solvent the residue is taken up three times in toluene and freed from solvent on a rotary evaporator. The residue is chromatographed on silica gel with ether-hexane 1:5. There is obtained (2E,6Z)-3,7,11-trimethyl-10-oxo-2,6,11-dodecatrienyl acetate which has the following bands in the IR spectrum: 1739 cm-1, 1675 cm-1, 1629 cm-1, 1449 cm-1, 1370 cm-1, 948 cm-1.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:28]O)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[C:15]([F:27])[CH:14]=2)[O:10][N:9]=1)[CH3:2].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:55]1[CH2:58][CH:57]([C:59]([O:61][CH3:62])=[O:60])[CH2:56]1.C(N(CC)C(C)C)(C)C>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:28][N:55]2[CH2:58][CH:57]([C:59]([O:61][CH3:62])=[O:60])[CH2:56]2)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[C:15]([F:27])[CH:14]=2)[O:10][N:9]=1)[CH3:2]
Reactant: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3cccc(F)c3)c(F)c2)n1
Reactant: COC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3cccc(F)c3)c(F)c2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using (4-ethyl-5-{5-[3-fluoro-4-(3-fluorophenoxy)phenyl]-1,2,4-oxadiazol-3-yl}-2-thienyl)methanol (0.18 g, 0.43 mmol) that was obtained in Example 20 (20b), carbon tetrabromide (0.22 g, 0.65 mmol), triphenylphosphine (0.17 g, 0.65 mmol), methyl 3-azetidinecarboxylate hydrochloride (99 mg, 0.65 mmol), N,N-diisopropylethylamine (0.22 mL, 1.3 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:3 to 1:2) as the eluent to afford the title compound (0.14 g) in a yield of 64% as a pale yellow oily product.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21].CCN(CC)CC.OP([O-])(O)=O.[K+]>C(Cl)Cl.CO>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]3[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][C:23]([NH:22][CH2:20][CH3:21])=[O:24])[C:11]=3[CH:10]=[N:9][CH:8]=2)=[CH:19][CH:18]=1)#[N:17]
Reactant: CCN=C=O
Reactant: N#Cc1ccc(-c2cncc3c2CCCC3N)cc1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CCNC(=O)NC1CCCc2c(-c3ccc(C#N)cc3)cncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
A cooled (0° C.) solution of (rac)-4-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)benzonitrile (example 1) (62.3 mg, 250 μmol) in CH2Cl2 (5 mL) was treated with ethyl isocyanate (51.6 μL, 625 μmol) in CH2Cl2 (0.6 mL) and Et3N (69.7 μL, 500 μmol). After ½ h the solution was stirred at room temperature for 1 h and treated with MeOH (0.2 mL). The reaction mixture was poured on aq. 10% KH2PO4 solution followed by extraction with AcOEt (3×). The organic phases were washed once with aq. sat. NaCl solution. The combined organic phases were dried (Na2SO4), filtered and purified by flash chromatography (50 g SiO2, Telos-cartridge, CH2Cl2/MeOH (1 to 3%)). Precipitation from CH2Cl2 with n-pentane gave the title compound (64 mg, 80%) as off-white powder. MS: 321.2 (M+H+).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:11](O)[CH2:12][CH3:13].C1C=CC=CC=1.S(=O)(=O)(O)O>O>[SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:11][CH2:12][CH3:13])=[O:5]
Reactant: CCCO
Reactant: O=C(O)c1ccccc1S
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: CCCOC(=O)c1ccccc1S
Temperature: 25 °C
Yield: 62 %

Procedure:
A mixture of 50 g (0.32 mole) of 2-mercaptobenzoic acid, 30 g (0.5 mole) of n-propanol, 200 ml of benzene and 1.0 g of sulfuric acid (93%) was stirred at reflux in a flask equipped with a condenser and Dean-Stark water separator. After 24 hours at reflux, 6.0 ml of water was collected in the water separator. The mixture was cooled to ambient temperature, washed with 150 ml of 10% sodium carbonate solution, washed with three 150 ml water washes, dried over sodium sulfate, filtered and concentrated using a rotary evaporator. The residual oil was distilled to give n-propyl 2-mercaptobenzoate: 41.5 g (62% yield); bp 103°C/0.5 mm; mol wt 196: