Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH:5]=[CH:4][CH:3]=1.[C:7]([C:11]1[CH:16]=[C:15](N(C)C)[CH:14]=[C:13]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]=1[OH:24])([CH3:10])([CH3:9])[CH3:8].O1CCC[CH2:26]1.[Na]>O>[CH3:1][C:2]1[CH:6]=[CH:5][CH2:4][C:3]=1[CH2:26][C:15]1[CH:16]=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:12]([OH:24])=[C:13]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=1
Reactant: CN(C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C1CCOC1
Reactant: CC1=CC=CC1
Agent: [Na]
Solvent: O
Product: CC1=C(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CC=C1
Temperature: 70 °C
Yield: 90 %

Procedure:
To a stirred mixture of 40 g (0.5 m) methylcyclopentadiene, 39.5 g (0.15 m) 2,6-di-t-butyl-4-dimethylaminophenol and 100 ml of tetrahydrofuran was slowly added 6.0 g (0.26 m) of sodium. The temperature was raised to 70° C. and the mixture allowed to react for 20 hours. A gas chromatograph showed that all of the 2,6-di-t-butyl-4-dimethylaminophenol had reacted. The mixture was diluted with water, extracted with toluene and rotovaped to remove the toluene and leave 38 g of crude product. A 90% yield, 31.5 g, of pure product methyl-(3,5-di-tert-butyl-4-hydroxybenzyl)cyclopentadiene was obtained by distillation, b.p. 155° to 160° C. at 1.5 mm as a viscous yellow oil. After standing at room temperature for 2 weeks, the material was analyzed by mass spectral analysis and by gas chromatography. Both showed that the product and its dimer were present. The mass spectrum showed a 3 to 1 ratio of the monomer to dimer, m/e 298 and m/e 596, respectively. The gas chromatograph showed a sharp peak for the monomer followed by the broad peak due to the slow decomposition of the dimer.
Reaction SMILES: [Cl:1][C:2]1=[C:3]([Cl:9])[C:4]([O:6][C:7]1=[O:8])=[O:5].[CH3:10][CH:11]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)[CH2:12][NH2:13].O>C(O)(=O)C>[CH3:10][CH:11]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([CH3:22])([CH3:24])[CH3:23])=[CH:19][CH:20]=1)[CH2:12][N:13]=[C:4]([OH:5])/[C:3](/[Cl:9])=[C:2](/[Cl:1])\[C:7]([OH:6])=[O:8]
Reactant: CC(CN)Cc1ccc(C(C)(C)C)cc1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(CN=C(O)/C(Cl)=C(/Cl)C(=O)O)Cc1ccc(C(C)(C)C)cc1
Yield: 39.2 %

Procedure:
16.7 g (0.1 mol) of dichloromaleic anhydride and 20.5 g (0.1 mol) of 2-methyl-3-(4-tert.-butylphenyl)-propylamine are stirred in 100 ml of glacial acetic acid under reflux for 4 hours. 100 ml of water are added, the oil which has separated out is extracted with methylene chloride, the methylene chloride phase is concentrated and the residue is recrystallized from ethanol. 14.6 g (41.2% of theory) of dichloromaleic acid N-[2-methyl-3-(4-tert.-butylphenyl)-propyl]-imide of melting point 64°-65° C. are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12])#[CH:2].CCN(CC)CC.Cl[C:23]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][N:26]=[C:25]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([CH:40]3[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)[N:24]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CCOC(C)=O.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>[CH3:14][O:13][C:11](=[O:12])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=1[C:1]#[C:2][C:27]1[C:28]([C:29]([F:30])([F:31])[F:32])=[CH:23][N:24]=[C:25]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([CH:40]3[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:44][CH2:45]3)=[CH:36][CH:35]=2)[N:26]=1
Reactant: C#Cc1cc(C)ccc1CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(C)cc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A solution of methyl 2-(2-ethynyl-4-methylphenyl)acetate (A86) (0.196 g, 71% pure) in DMF (3 mL) and Et3N (0.309 mL, 2.22 mmol) was added to a mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (K5) (0.371 g, 0.812 mmol), PdCl2(PPh3)2 (0.078 g, 0.11 mmol), CuI (0.021 g, 0.11 mmol) and PPh3 (0.019 g, 0.074 mmol) in DMF (3 mL). The resulting mixture was heated under microwave irradiation at 120° C. for 15 minutes then diluted with EtOAc and passed through a plug of Celite, washing with EtOAc (50 mL). The filtrate was concentrated in vacuo and the residue purified by silica gel column chromatography (Biotage Isolera, 40 g cartridge, 0-35% EtOAc in petroleum benzine 40-60° C.) to give the title compound A87 as a yellow oil (133 mg, 30%); 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 7.74 (s, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.44 (s, 1H), 7.24-7.16 (m, 4H), 4.43-4.14 (m, 2H), 3.90 (s, 2H), 3.69 (s, 3H), 2.80 (t, J=11.7 Hz, 2H), 2.63 (tt, J=12.0, 3.3 Hz, 1H), 2.34 (s, 3H), 1.81 (d, J=12.7 Hz, 2H), 1.69-1.54 (m, 2H), 1.49 (s, 9H). LCMS-A: rt 7.057 min; m/z 609.3 [M+H]+.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5]([NH:7][C:8]1[CH:12]=[CH:11][O:10][N:9]=1)=O.OC[C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1.C(P(CCCC)CCCC)CCC.C1CCN(C(/N=N/C(N2CCCCC2)=O)=O)CC1>O1CCCC1>[O:10]1[CH:11]=[CH:12][C:8]([NH:7][CH2:5][C@@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[C:25]([F:35])[CH:24]=3)[CH2:18]2)=[N:9]1
Reactant: O=C(Nc1ccon1)OCC(Cl)(Cl)Cl
Reactant: O=C1O[C@@H](CO)CN1c1ccc(N2CCOCC2)c(F)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: O=C1O[C@@H](CNc2ccon2)CN1c1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 331.2 %

Procedure:
To a stirred solution of 3-(2,2,2-trichloroethyloxycarbonylamino)isoxazole (260 mg, 1.0 mmol), 5(R)-hydroxymethyl-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one (see WO 95/07271; 293 mg, 1 mmol) and tributylphosphine (303 mg, 1.5 mmol) in dry tetrahydrofuran (10 ml) at 0° C. under a nitrogen atmosphere, was added 1,1-(azodicarbonyl)dipiperidine (378.5 mg, 1.5 mmol) in dry tetrahydrofuran (3 ml). The reaction allowed to warm to room temperature and was stirred for 4 days by which time a white suspension had formed. The reaction mixture was filtered and the residue washed with tetrahydrofuran. The filtrate was concentrated by rotary evaporation to give a yellow oil (1.2 g) which was purified by MPLC (30% ethyl acetate/hexane, ICN Alumina N 32–63) and further MPLC (100% CH2Cl2, ICN Alumina N 32–63). Concentration of the fractions by rotary evaporation gave the title compound as a crisp white foam (296 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[C:12](I)=[CH:11][CH:10]=[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].[CH:18]([Sn](CCCC)(CCCC)CCCC)=[CH2:19]>C1(C)C=CC=CC=1.CCOCC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[Cl:1][C:2]1[C:12]([CH:18]=[CH2:19])=[CH:11][CH:10]=[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5]
Reactant: CCNC(=O)c1c([Si](C)(C)C)ccc(I)c1Cl
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=Cc1ccc([Si](C)(C)C)c(C(=O)NCC)c1Cl
Reaction time: 24 h
Yield: 21.3 %

Procedure:
To a solution of the compound of Example 239 (0.382 g, 1.0 mmol), tetrakis(triphenylphosphine)-palladium(O) (23 mg, 0.02 mmol) and 2.6-di-t-butyl-4-methylphenol (1.5 mg) in toluene (10 mL) was added vinyltributyltin (0.349 g, 1.1 mmol). The light yellow solution was heated at reflux for 24 h, additional tetrakis(triphenylphosphine)palladium(O) (15 mg) was added, and reflux was continued for 24 h. The cool mixture was diluted with ether, filtered through Celite, concentrated and purified by RC (ethyl acetate/hexanes). The product was further purified by recrystallization from pentane to afford the title compound as white needles (0.060 g, 21%). m.p. 127-128° C.
Reaction SMILES: C#C.[CH3:3][C:4](C)([O-])C.[K+].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)=[CH:12][CH:11]=1.[Cl-:34].[NH4+]>O1CCCC1>[ClH:34].[C:3]([C:23]1([OH:26])[CH2:22][CH2:21][N:20]([CH2:19][CH2:18][CH2:17][CH:16]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)[CH2:25][CH2:24]1)#[CH:4]
Reactant: O=C1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: [Cl-]
Reactant: CC(C)(C)[O-]
Agent: C#C
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC1(O)CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Product: Cl
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Acetylene is introduced into a solution containing 38.4 g of potassium tert-butoxide in 250 ml of tetrahydrofuran at a temperature between 0° C. and -5° C. under stirring for 30 minutes, then 78.0 g of 1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidone dissolved in 200 ml of tetrahydrofuran are dropwise added and acetylene is introduced for an additional one hour. Thereafter the reaction mixture is cooled to -10° C. and saturated aqueous ammonium chloride solution is added under nitrogen. After evaporating tetrahydrofuran under reduced pressure, the residue is extracted with benzene. The benzene solution is washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. After taking up the residue in acetone, the hydrochloride is precipitated by adding hydrogen chloride in diisopropyl ether solution. The title hydrochloride is obtained in 91.0% yield, m.p.: 166°-168° C.
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([OH:24])(=[S:23])[CH3:22]>C(Cl)(Cl)(Cl)Cl>[C:21]([S:23][CH:10]([CH2:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])(=[O:24])[CH3:22]
Reactant: CC(O)=S
Reactant: O=C(C=CC(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)SC(CC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
A mixture of 2.57 g. of 1-(3-benzoylacryloyl)-L-proline, 1.42 ml. of thioacetic acid and 30 ml. of carbon tetrachloride is stirred for one hour and then concentrated in vacuo to an amber gum. This gum is dissolved in dichloromethane and the solvent removed in vacuo several times giving the desired product as an off-white glass.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][C:10]1([C:41]1[CH:46]=[C:45]([CH:47]2OCC[O:48]2)[C:44]([CH3:52])=[CH:43][C:42]=1[O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][C:10]1([C:41]1[CH:46]=[C:45]([CH:47]=[O:48])[C:44]([CH3:52])=[CH:43][C:42]=1[O:53][CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(OCc2ccccc2)c(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C1OCCO1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccccc2)c(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 102.6 %

Procedure:
To a tetrahydrofuran solution (80 mL) of 2,3,4,6-tetra-O-benzyl-1-C-[2-(benzyloxy)-5-(1,3-dioxolan-2-yl)-4-methylphenyl]-D-glucopyranose (10.6 g, 13.0 mmol) cooled in ice was added 6 M hydrochloric acid (80 mL), and the mixture was stirred for 14 hours at room temperature. To the reaction solution was added ice water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (10.2 g, quant.) as a yellow oily compound.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([NH:12][C:13]([C:15]1[C:20]([NH2:21])=[N:19][C:18]([NH2:22])=[C:17]([Cl:23])[N:16]=1)=[O:14])=[NH:11])[CH2:2]2.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35])[CH2:29]Cl>CN(C=O)C>[Cl-:23].[NH2:21][C:20]1[C:15]([C:13]([N:12]=[C:10]([NH2:11])[NH:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N+:1]([CH2:29][C:28]4[CH:31]=[C:32]([O:36][CH3:37])[C:33]([O:34][CH3:35])=[C:26]([O:25][CH3:24])[CH:27]=4)([CH2:6][CH2:5]3)[CH2:2]2)=[O:14])=[N:16][C:17]([Cl:23])=[C:18]([NH2:22])[N:19]=1
Reactant: N=C(NC(=O)c1nc(Cl)c(N)nc1N)NC1CN2CCC1CC2
Reactant: COc1cc(CCl)cc(OC)c1OC
Solvent: CN(C)C=O
Product: COc1cc(C[N+]23CCC(CC2)C(NC(N)=NC(=O)c2nc(Cl)c(N)nc2N)C3)cc(OC)c1OC
Product: [Cl-]
Yield: 42 %

Procedure:
N-(1-Aza-bicyclo[2.2.2]oct-3-yl)-N′-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-guanidine (Intermediate 4, 152 mg, content ca. 66%, 0.30 mmol) and 3,4,5-trimethoxybenzyl chloride (Aldrich, 77 mg, 0.36 mmol) is stirred in DMF (1 mL) at r.t. for ca. 18 h. The crude mixture is purified by preparative HPLC (5 mM ammonium formate in H2O: CH3CN gradient). The product thus obtained is triturated with a mixture of diethyl ether (4 mL) and methanol (1.5 mL), collected by filtration and dried under vacuum at 70° C. Further trituration with water (0.3 mL), filtration and drying under vacuum at 70° C. yields the title compound (35 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[C:8]2[C:3]1=[C:4]([OH:17])[C:5]([CH3:16])=[CH:6][C:7]=2[CH3:15].C(=O)([O-])[O-].[K+].[K+].CC(C)=O.Cl[CH2:29][CH2:30][CH2:31][C:32](Cl)=[O:33]>O>[OH:17][C:4]1[C:5]([CH3:16])=[CH:6][C:7]([CH3:15])=[C:8]2[C:3]=1[CH:2]([N:1]1[CH2:29][CH2:30][CH2:31][C:32]1=[O:33])[CH:14]1[CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(Cl)CCCCl
Reactant: Cc1cc(C)c2c(c1O)C(N)C1CCCCC21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C)c2c(c1O)C(N1CCCC1=O)C1CCCCC21

Procedure:
4.0 Grams of 9-amino-8-hydroxy-5,7-dimethyl-1,2,3,4,4a,9a-hexahydrofluorene and 2.5 g of potassium carbonate were added to a mixture of 50 ml of acetone and 20 ml of water and thereto was added dropwise 2.5 ml of γ-chlorobutyryl chloride under ice-cooling and stirring. After stirring for 2 hours, the reaction mixture was concentrated and to the residue was added water and extraction was effected with chloroform. The choroform layer was dried with magnesium sulfate and concentrated. Then, the residue was dissolved in 30 ml of DMF and to the solution was added 2.0 g of sodium hydride (60% oiliness), followed by stirring to generate a gas with generation of heat. Then, the reaction mixture was stirred at room temperature overnight and thereafter concentrated. To the residue was added water and extraction was effected with chloroform. The chloroform layer was dried with magnesium sulfate and concentrated. To the residue was added ethyl acetate and the produced precipitate was collected by filtration and recrystallized from hydrous ethanol to obtain 2.0 g of 8-hydroxy-5,7-dimethyl-9-(2-oxo-1-pyrrolidinyl)-1,2,3,4,4a,9a-hexahydrofluorene having a melting point of 240°-213° C. (decomposed) and of light brown powdery crystal.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH:9]1[C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25]O.B(F)(F)F>>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([C:14]([O:16][CH3:25])=[O:15])[CH:9]1[C:17]1[C:18]([Cl:24])=[CH:19][CH:20]=[CH:21][C:22]=1[Cl:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)C1CC(=O)N(Cc2ccccc2)C1c1c(Cl)cccc1Cl
Agent: FB(F)F
Product: COC(=O)C1CC(=O)N(Cc2ccccc2)C1c1c(Cl)cccc1Cl

Procedure:
A solution of 25 g of 1-benzyl-2-(2,6-dichlorophenyl)-5-oxopyrrolidin-3-carboxylic acid in 247 ml of boron trifluoride methanol was refluxed for 7 hours and then concentrated in vacuo to a solid. The solid was dissolved in chloroform and the chloroform washed with a saturated sodium carbonate solution and then with a saturated sodium bicarbonate solution. Drying (Na2SO4), filtration, and concentration in vacuo provided 18 g of off-white crystals, m.p. 97°-102°.
Reaction SMILES: O.O.[Sn](Cl)Cl.Cl.[F:7][C:8]1[CH:24]=[CH:23][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1>COCCOC.CCO>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:12](=[O:13])[C:11]2[CH:23]=[CH:24][C:8]([F:7])=[CH:9][CH:10]=2)=[CH:15][CH:16]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: Nc1ccc(C(=O)c2ccc(F)cc2)cc1
Yield: 83.6 %

Procedure:
A solution of tin (II) chloride dihydrate (1.05 g, 4.7 mmol) in cone hydrochloric acid (4.2 mL) was added to 4-fluoro-4′-nitrobenzophenone (0.37 g, 1.5 mmol) in a mixture of DME (4 mL) and EtOH (5 mL) at such a rate that the internal temperature remained under 35° C. After 5 h the reaction mixture was quenched by addition to ice-water (40 mL). The mixture was diluted with DCM (25 mL), made basic (pH=11) by addition of 10% NaOH, and then extracted with DCM (2×25 mL). The combined extracts were washed with water and brine, dried (anhyd Na2SO4) and concentrated under reduced pressure. The crude material was chromatographed (silica, EtOAc/Hex, 0:100 to 40:60) to afford 4′-amino-4-fluorobenzophenone (0.27 g, 83%) as a white solid. 1H-NMR (DMSO-d6) δ 7.68 (2H, dd, J=5.6, 8.8), 7.51 (2H, d, J=8.8), 7.32 (2H, app t, J=8.8), 6.61 (2H, d, J=8.8), 6.18 (2H, br s). A solution of tin (II) chloride dihydrate (1.05 g, 4.7 mmol) in conc hydrochloric acid (4.2 mL) was added to 4-fluoro-4′-nitrobenzophenone (0.37 g, 1.5 mmol) in a mixture of DME (4
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[CH2:17]([NH:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C(Cl)Cl>[CH2:17]([NH:33][C:34]1[CH:35]=[CH:36][C:37]([C:38]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:39])=[CH:41][CH:42]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 6.4 g. (50 m moles) 4-chlorophenol and 7.6 g. (75 m moles) triethylamine in 500 ml. methylene chloride is added 10.4 g. (25 m moles) 4-(hexadecylamino)benzoyl chloride hydrochloride in 250 ml. methylene chloride. After four hours at reflux, the solution is cooled, washed with water and dilute phosphoric acid, and dried. After passing the solution through a column of alumina, the solvent is evaporated and the residue is crystallized from diisopropyl ether.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]1([OH:18])[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1>>[N+:8]([C:7]1[C:2]([O:17][CH:14]2[CH2:15][CH2:16][CH:11]([OH:18])[CH2:12][CH2:13]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: OC1CCC(O)CC1
Reactant: O=[N+]([O-])c1cccnc1F
Product: O=[N+]([O-])c1cccnc1OC1CCC(O)CC1

Procedure:
Prepared analogously to III.1 from 3.6 g 2-fluoro-3-nitropyridine and 2.9 g 1,4-cyclohexanediol
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C)C=O.ClCCl>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([CH:27]=[O:28])=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 41 %

Procedure:
Oxalyl chloride (1.72 ml) and dry dimethylformamide (2 drops) were added to a stirred suspension of 4'-benzyloxy-4-biphenylcarboxylic acid (3.04 g) in dry dichloromethane (100 ml). The reaction mixture was stirred for 12 hours at ambient temperature. The mixture was evaporated to dryness. Triphenylphosphine (5.2 g) and bis(triphenylphosphine) copper [I] tetrahydroborate (6.0 g) was added to a solution of the crude product in acetone (150 ml). The mixture was stirred at ambient temperature for 2 hours. The mixture was filtered and the filtrate evaporated. The residue was purified by medium pressure chromatography on silica gel using a mixture of 20% dichloromethane/hexane to remove less polar impurities, followed by ethyl acetate as eluant to give 4'-benzyloxy-4-biphenylcarboxaldehyde as a colourless solid (41% yield), m.p. 122°-123° C., NMR (CDCl3): 5.1 (2H, s), 7.1 (2H, d), 7.4-7.6 (7H, m), 7.7-7.9 (4H, d of d), and 10.0 (1H, s); m/z 289 (M+H).
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=[O:12])[CH:2]=[CH2:3].[CH2:16]([CH2:18][NH2:19])[OH:17]>>[OH:17][CH2:16][CH2:18][N:19]=[C:14]([CH:5]1[CH:6]([C:11]([OH:13])=[O:12])[CH:7]2[CH2:10][C:4]1([CH2:1][CH:2]=[CH2:3])[CH:9]=[CH:8]2)[OH:15]
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Reactant: NCCO
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=NCCO

Procedure:
760 g of allylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride (isomeric mixture) are placed into the reaction vessel, and 227.55 g of monoethanolamine are added dropwise with stirring. The mixture is refluxed for 2 hours, and water and some excess monoethanolamine are distilled off until a temperature of 175° C. is reached. The pressure is then decreased to 2670 Pa. The temperature is lowered to 100° C. and the product is rectified at 4.9 Pa. At between 170° and 174° C., there distil over 712.4 g (77.3% of theory) of a pale yellow oil having the following characteristic values:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[C:9]([C:18]#[N:19])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:20]([O:22]CC)=[O:21].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[C:9]([C:18]#[N:19])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)c1cnn(-c2ccc(OCC(C)C)c(C#N)c2)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)COc1ccc(-n2ncc(C(=O)O)c2N)cc1C#N
Yield: 43.7 %

Procedure:
To a solution (10 ml) of ethyl 5-amino-1-(3-cyano-4-isobutoxyphenyl)-pyrazole-4-carboxylate (1 g) in ethanol was added 5 N aqueous sodium hydroxide solution (1 ml) with string, and the mixture was refluxed under heating for 2 hours. After the completion of the reaction, the reaction mixture was poured into water, and the mixture was neutralized with acetic acid. The precipitated crystals were recrystallized from a mixed solvent of dioxane and water to give 0.4 g of 5-amino-1-(3-cyano-4-isobutoxyphenyl)pyrazole-4-carboxylic acid, melting point 204° C. (decomposition).