Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[CH3:33][N:34]([CH:36](C)C(O)=O)[CH3:35]>>[NH2:8][C:9]1[C:14]([C:15](=[O:16])[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([C:3](=[O:5])[CH2:2][CH2:33][N:34]([CH3:36])[CH3:35])[CH2:31][CH2:32]2)[N:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C(=O)O)N(C)C
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(C(=O)CCN(C)C)CC2)nc1N

Procedure:
The same procedure as described in Example 81 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and dimethylaminopropionic acid (TCI-US) to give 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-3-dimethylamino-propan-1-one. MS (M+H)+: 445.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:24]=[C:23]([CH:25]=O)[CH:22]=[CH:21][C:11]=2[O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].[CH3:27][NH2:28].[BH4-].[Na+].O>C1COCC1.CO>[C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:24]=[C:23]([CH2:25][NH:28][CH3:27])[CH:22]=[CH:21][C:11]=2[O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2]
Reactant: CN
Reactant: CC(C)(C)OC(=O)COc1ccc(C=O)cc1-c1cc(F)cc(C#N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CNCc1ccc(OCC(=O)OC(C)(C)C)c(-c2cc(F)cc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of t-butyl 2-(2-(3-cyano-5-fluorophenyl)-4-formylphenoxy)acetate (21) (120 g, 338 mmol) and MeNH2 (203 mL of a 2M solution in THF, 405 mmol) in methanol (300 mL) was stirred at room temperature for 2 h. Sodium borohydride (12 g, 316 mmol) was added, and the resulting mixture was stirred at room temperature for additional 2 h. Water (30 mL) was added and the MeOH was removed in vacuo. The resulting solution was extracted with EA (3×), and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product t-butyl 2-(2-(3-cyano-5-fluorophenyl)-4-((methylamino)methyl)phenoxy)acetate (22) was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[Cu]C#N.[CH3:9][C@:10]12[CH2:26][CH2:25][C:24]3[C@@H:15]([CH2:16][CH2:17][C:18]4[C:23]=3[CH2:22][CH2:21][C:20](=[O:27])[CH:19]=4)[C@@H:14]1[CH:13]=[CH:12][C:11]2=[O:28]>CCCCCC.O1CCCC1.N>[CH2:1]([C@H:13]1[C@H:14]2[C@H:15]3[C:24]([CH2:25][CH2:26][C@:10]2([CH3:9])[C:11](=[O:28])[CH2:12]1)=[C:23]1[C:18](=[CH:19][C:20](=[O:27])[CH2:21][CH2:22]1)[CH2:17][CH2:16]3)[CH2:2][CH2:3][CH3:4]
Reactant: C[C@]12CCC3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1C=CC2=O
Reactant: [Li]CCCC
Agent: N#C[Cu]
Agent: N
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[C@@H]1CC(=O)[C@@]2(C)CCC3=C4CCC(=O)C=C4CC[C@H]3[C@H]12
Reaction time: 1.5 h

Procedure:
6.25 ml of a 15% solution of n-butyllithium in hexane are added to a suspension of 500 mg of copper(I) cyanide in 10 ml of absolute tetrahydrofuran drop by drop at -78° C. After addition, it is stirred for 15 minutes more at -78° C., before a solution of 1.2 g of 4,9,15-estratriene-3,17-dione in 20 ml of absolute tetrahydrofuran is added drop by drop. Then it is stirred for 90 minutes, during which the temperature of the reaction solution is allowed gradually to rise to -20° C. For finishing, it is poured in concentrated aqueous ammonia solution and extracted with ethyl acetate. After recrystallization of the crude product from ethyl acetate/diisopropyl ether, 940 mg of 15β-n-butyl-4,9-estradiene-3,17-dione with a melting point of 159° to 161° C. are obtained.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([SH:18])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([O:21][C:22](=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br)[CH3:20].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:19]([O:21][C:22](=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:18][C:9]1[NH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)[CH3:20]
Reactant: CCOC(=O)CCCCCCCBr
Reactant: Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Yield: 73.3 %

Procedure:
To a solution of 7.57 g (0.03 mole) 4,5-diphenyl-2-imidazolethiol in 75 ml dimethylformamide was added, dropwise, 7.23 g (0.03 mole) ethyl-8-bromooctanoate in 25 ml dimethylformamide. The reaction mixture was stirred at reflux under nitrogen overnight. The cooled solution was poured into 5% sodium bicarbonate and ice and then extracted with ethyl acetate. The organic layer was backwashed with 5% sodium bicarbonate, water, and saturated sodium chloride solution, then dried over magnesium sulfate and the solvent was removed under vacuum. The residue was chromatographed using hexane:ethyl acetate (7:3). The resulting solid was recrystallized from ethanol and triturated with hexane to give 9.12 g (0.022 mole) of the title compound as a white solid, mp=77°-79° C. H1NMR(DMSO-d6): δ12.6(s,1H), 7.7-7.1(m,10H), 4.0(q,2H,J=8Hz), 3.1(t,2H,J=7Hz), 2.3(t,2H,J=17Hz), 1.8-1.1(m,13H).
Reaction SMILES: C[O-].[Na+].[C:4](#[N:7])[CH:5]=[CH2:6].Cl.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[C:19]([F:25])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO.CCOC(C)=O>[NH2:7][C:4]1[NH:24][N:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:18][C:19]=2[F:25])[CH2:6][CH:5]=1
Reactant: C=CC#N
Reactant: NNc1ccc(OCc2ccccc2)cc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC1=CCN(c2ccc(OCc3ccccc3)cc2F)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaOMe (25 wt. % solution in MeOH, 7.75 mL) and acrylonitrile (2.1 mL) were added to a solution of 4-benzyloxy-2-fluorophenylhydrazine hydrochloride (4.15 g) in MeOH (40 mL) at room temperature. The mixture was stirred at room temperature for 30 minutes and refluxed overnight. Additional NaOMe (25 wt. % solution in MeOH, 3.9 mL) and acrylonitrile (1.05 ml) were added to the reaction mixture and refluxed for 7.5 hours. The mixture was diluted with EtOAc and washed with sat. NaHCO3 and brine. The organic layer was dried over anhydrous MgSO4 and concentrated. The residue was crystallized from CHCl3/hexane to yield 3.86 g of the title compound. NaOMe and MeOH means sodium methoxide and methanol, respectively.
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[F:22][C:23]([F:27])([F:26])[CH2:24][NH2:25]>>[CH2:17]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:25][CH2:24][C:23]([F:27])([F:26])[F:22])=[O:21])=[CH:5][N:6]=2)=[CH:16][O:15][N:14]=1)[CH2:18][CH2:19][CH3:20]
Reactant: NCC(F)(F)F
Reactant: CCCCc1nocc1COc1ccc(C(=O)OC)cn1
Product: CCCCc1nocc1COc1ccc(C(=O)NCC(F)(F)F)cn1
Yield: 69 %

Procedure:
As described for example 25e, 6-(3-butyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (200 mg, 0.69 mmol) was converted, using 2,2,2,-trifluoroethylamine instead of isopropylamine, to the title compound (170 mg, 69%) which was obtained as a white solid after purification by chromatography (silica, 30 to 50% ethyl acetate in heptane). MS: m/e=358.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:13](=[O:29])[N:12]([CH3:30])[C:11]=2[N:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][C:40]=1[C:46]([F:49])([F:48])[F:47]>CN(C=O)C.O>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:13](=[O:29])[N:12]([CH3:30])[C:11]=2[N:10]=[C:9]1[O:45][C:42]1[CH:43]=[CH:44][C:39]([F:38])=[C:40]([C:46]([F:49])([F:47])[F:48])[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Br)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Oc1ccc(F)c(C(F)(F)F)c1)n2Cc1ccccc1
Temperature: 90 °C
Yield: 90.4 %

Procedure:
Step 1 7-Benzyl-8-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.50 g, 0.985 mmol, intermediate 83), potassium carbonate (0.272 g, 1.97 mmol) and 4-fluoro-3-(trifluoromethyl)phenol (0.19 g, 1.03 mmol) were combined in DMF (5 mL). The reaction was heated at 90° C. After 6 h the reaction was cooled, diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to yield a white solid. This solid was purified using a 25 g silica column eluted with 20% ethyl acetate/hexanes to give 7-benzyl-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-8-(4-fluoro-3-(trifluoromethyl)phenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.54 g, 90% yield) as a white solid. LCMS retention time=5.342 min and 97% purity, LCMS MH+=607.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1(Br)[CH:14]=[C:13]([O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:24][CH3:25])[CH:11]=2)[NH:6]1)=[O:4].[CH3:27][N:28]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:12]2[C:7](=[C:8]([N:31]3[CH2:32][CH2:33][CH2:34][N:28]([CH3:27])[CH2:29][CH2:30]3)[CH:9]=[C:10]([O:24][CH3:25])[CH:11]=2)[N:6]=1)=[O:4]
Reactant: CN1CCCNCC1
Reactant: COC(=O)C1(Br)C=C(OCOCC[Si](C)(C)C)c2cc(OC)ccc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(OCOCC[Si](C)(C)C)c2cc(OC)cc(N3CCCN(C)CC3)c2n1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a clear, light brown solution of 2-bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carboxylic acid methyl ester (1.01 g, 2.28 mmol), N-methylhomopiperazine (0.32 mL, 2.57 mmol), and 4 Å sieves in 30 mL anhydrous toluene was added Pd2 (dba)2 (43.8 mg, 0.048 mmol) and BINAP (169.8 mg, 0.27 mmol). The resulting wine colored solution was treated with cesium carbonate (1.124 g, 3.45 mmol). The reaction mixture was heated at reflux under nitrogen for 21 hours. The pea green reaction mixture was cooled to room temperature and concentrated. The crude mixture was purified by flash chromatography on silica gel using a gradient of 95:5 to 40:60 methylene chloride:methanol to afford the desired product as a yellow foam (1.004 g, 92%). 1H NMR (300 MHz, DMSO, d6) δ 7.67 (s, 1 H, ArH3), 6.94 (d, 1 H, Jm=2.4 Hz, ArH5), 6.66 (d, 1 H, Jm=2.4 Hz, ArH7), 5.60 (s, 2 H, OCH2O), 3.94 (s, 3 H, CO2CH3), 3.88 (s, 3 H, OCH3), 3.82 (t, 2 H, J=8.0 Hz, OCH2CH2Si), 3.75 (bs, 4 H, ArNCH2CH2CH2NCH3 & ArNCH2CH2N—CH3), 3.45 (bs, 2 H, ArNCH2CH2NCH3), 3.31 (bs, 2 H, ArNCH2CH2CH2NCH3), 2.83 (s, 3 H, NCH3), 2.28 (bs, 2 H ArNCH2CH2 CH2NCH3), 0.92 (t, 2 H, J=8.0 Hz, OCH2CH2Si), −0.04 (s, 9 H, Si(CH3)3; Mass Spec.: calc. for [C24H37N3O5Si+H]+ Theor. m/z=476; Obs. 476.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[C:9](=[CH:11][C:12]3[N:13]=[C:14]([NH2:18])[S:15][C:16]=3[CH:17]=2)[N:10]=1)=[O:4].[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>O1CCOCC1>[CH2:19]([N:21]([N:5]([C:3](=[O:4])[CH3:2])[C:6]1[S:7][C:8]2[C:9](=[CH:11][C:12]3[N:13]=[C:14]([NH2:18])[S:15][C:16]=3[CH:17]=2)[N:10]=1)[CH2:22][CH3:23])[CH3:20]
Reactant: Nc1nc2cc3nc(NC(=O)CCl)sc3cc2s1
Reactant: CCNCC
Solvent: C1COCCO1
Product: CCN(CC)N(C(C)=O)c1nc2cc3nc(N)sc3cc2s1

Procedure:
A mixture of 0.5 gm of 2-(chloroacetyl-amino)-6-amino-benzo[1,2-d:5,4-d']bisthiazole, 0.7 gm of diethylamine and 3 ml of dioxane was refluxed for 2 hours. Then, the solvent was evaporated in vacuo, the residue was dissolved in ethyl acetate, and the solution was washed with water and dried over sodium sulfate. After evaporation of the solvent, 0.3 gm (60% of theory) of the title compound, M.P. 203°-205° C. (from ethanol/dimethylformamide) were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[NH2:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: CO
Reactant: Nc1cccc(C(=O)O)c1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(N)c1Cl
Yield: 92 %

Procedure:
A mixture of 3-amino-2-chlorobenzoic acid (500 mg, 2.91 mmol), conc. sulfuric acid (6 mL), and methanol (150 mL) was heated under reflux for 24 hours, and placed under reduced pressure to distill the solvent off. The residue was neutralized by addition of aqueous saturated sodium hydrogen carbonate. The neutralized mixture was extracted with toluene, dried over anhydrous magnesium sulfate, and placed under reduced pressure to distill the solvent off. There was obtained 497 mg (yield 92%) of the desired compound in the form of pale brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](Cl)=[O:7])[CH3:2].[NH4+].[N:11]#[C:12][S-:13].[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23]>CC#N>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([NH:11][C:12]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([F:14])=[C:16]([C:22]([F:25])([F:23])[F:24])[CH:17]=1)=[S:13])=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC#N
Product: CCOC(=O)CC(=O)NC(=S)Nc1ccc(F)c(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
3-Chloro-3-oxo-propanoic acid ethyl ester (5 g; 33.2 mmol) was slowly added to a stirred solution of thiocyanic acid, ammonium salt (1:1) (2.781 g; 36.5 mmol) in CH3CN (110 ml) at room temperature. After 2 hours, 4-fluoro-3-(trifluoromethyl)benzenamine (4.27 ml; 33.2 mmol) was added. The solvent was removed under reduced pressure. The resulting residue partitioned between H2O/DCM and the phases separated. The aqueous phase was extracted with DCM (×2) and the combined organic extracts were washed with brine, dried and filtered. Yield: 3.656 g of intermediate D15.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]2[O:11][CH2:10][CH2:9][O:8]2)=[CH:4][CH:3]=1.B(O)(O)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[O:22])[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].[BH4-].[Na+]>O1CCOCC1.O.CO>[O:8]1[CH2:9][CH2:10][O:11][CH:7]1[CH2:6][C:5]1[CH:12]=[CH:13][C:2]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=2)=[CH:3][CH:4]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Brc1ccc(CC2OCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: OCc1cccc(-c2ccc(CC3OCCO3)cc2)c1
Temperature: 125 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
A mixture of 2-(4-bromobenzyl)-1,3-dioxolane (2.0 g, 8.2 mmol), 3-formylboronic acid (2.45 g, 16.4 mmol), tetrakis-(triphenylphosphine)palladium (0) (0.763 g, 0.66 mmol), and sodium carbonate (1.74 g, 16.4 mmol) in dioxan/water (15 mL/3 mL) in a microwave vessel was degassed in a stream of nitrogen for 10 minutes. The vessel was sealed and heated in the microwave at 125° C. for 30 minutes. The solvent was decanted off, and the solid residues washed with ethyl acetate. The organic phases were combined, and the solvent evaporated at reduced pressure. The crude material was purified by silica gel chromatography eluting with 100% iso-hexane to 50% ethyl acetate in iso-hexane to afford an oil. The oil was dissolved in methanol (25 mL) and cooled to 0° C. Sodium borohydride (0.393 g, 10.4 mmol) was added portion-wise, and the reaction mixture was stirred at 0° C. for 30 minutes followed by 1 hour at ambient temperature. The reaction mixture was quenched with water and extracted twice with ethyl acetate. The combined organic extracts were dried with anhydrous magnesium sulfate, and the solvent evaporated at reduced pressure. The crude material was purified by silica gel chromatography eluting with 100% iso-hexane to 100% ethyl acetate in iso-hexane to afford the title compound (1.16 g, 52%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:18]2([O:24][CH3:25])[CH2:22][CH2:21][O:20][CH:19]2[CH3:23])[CH:5]=[C:6]([CH:17]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH3:15])=[CH:10][CH:9]=1.Cl.[NH2:27][OH:28]>>[F:1][C:2]1[CH:3]=[C:4]([C:18]2([O:24][CH3:25])[CH2:22][CH2:21][O:20][CH:19]2[CH3:23])[CH:5]=[C:6]([CH:17]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11](/[C:14](=[N:27]/[OH:28])/[CH3:15])=[CH:10][CH:9]=1
Reactant: COC1(c2cc(F)cc(Oc3ccc(C(C)=O)cc3)c2)CCOC1C
Reactant: NO
Agent: Cl
Product: COC1(c2cc(F)cc(Oc3ccc(/C(C)=N/O)cc3)c2)CCOC1C
Yield: 42 %

Procedure:
Using an analogous procedure to that described in Example 66, 4'-{5-fluoro-3-[(2RS,3SR)-3-methoxy-2-methyltetrahydrofuran-3-yl]phenoxy}acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-{5-fluoro-3-[(2RS,3SR)-3-methoxy-2-methyltetrahydrofuran-3-yl]phenoxy}acetophenone oxime in 42% yield, m.p. 126°-127° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:11]=[O:12])=[C:9](Cl)[N:8]([CH:14]([CH3:16])[CH3:15])[N:7]=1)=[O:5])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([SH:25])[CH:21]=[C:22]([Cl:24])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:11]=[O:12])=[C:9]([S:25][C:20]2[CH:21]=[C:22]([Cl:24])[CH:23]=[C:18]([Cl:17])[CH:19]=2)[N:8]([CH:14]([CH3:16])[CH3:15])[N:7]=1)=[O:5])[CH3:2]
Reactant: Sc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)c1nn(C(C)C)c(Cl)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1C=O
Temperature: 60 °C
Yield: 89.8 %

Procedure:
A solution containing 6 g of 5-chloro-4-formyl-1-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester in 10 ml of anhydrous dimethyl formamide was treated at room temperature with 5.28 g of 3,5-dichlorothiophenol and 4.07 g of potassium carbonate. The mixture was then heated at 60° C. for 1 h before being left to cool to room temperature. The solvent removed under reduced pressure and the residue partitioned between dichloromethane and water. The organic extract was washed with brine then dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using diethyl ether/petoleum ether (1:4 to 1:3) for the elution to give 8.53 g of 5-(3,5-dichlorophenylthio)-4-formyl-1-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester as a yellow oil. Mass spectrum (ESI) m/z [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:11][C:12]1[CH:16]=[CH:15][NH:14][N:13]=1.[F:17][C:18]([F:28])([F:27])[C:19](=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([C:18]([F:17])([F:27])[F:28])[NH:11][C:12]2=[N:13][NH:14][CH:15]=[C:16]12
Reactant: Nc1cc[nH]n1
Reactant: COc1ccccc1C=O
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Product: CCOC(=O)C1=C(C(F)(F)F)Nc2n[nH]cc2C1c1ccccc1OC

Procedure:
The title compound was prepared from 2-methoxybenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:18])[C:4]1[C:12]([I:13])=[C:11]([C:14]#[N:15])[C:10]([I:16])=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[I:17].C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:26][CH:27]([OH:30])[CH2:28][OH:29]>CN(C)C=O>[OH:30][CH:27]([CH2:28][OH:29])[CH2:26][O:8][C:7](=[O:9])[C:6]1[C:10]([I:16])=[C:11]([C:14]#[N:15])[C:12]([I:13])=[C:4]([C:3](=[O:18])[NH:2][CH3:1])[C:5]=1[I:17]
Reactant: OCC(O)CCl
Reactant: CNC(=O)c1c(I)c(C#N)c(I)c(C(=O)O)c1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(I)c(C#N)c(I)c(C(=O)OCC(O)CO)c1I
Yield: 71.7 %

Procedure:
60 g 5-cyano-2,4,6-triiodoisophthalic acid monomethylamide is heated in 150 ml of dimethylformamide with 22 g of sodium carbonate (anhydrous) and 28 g of 1-chloro-2,3-propanediol for 4 hours to 90° C. The mixture is then cooled, vacuum-filtered from the precipitated sodium chloride, and concentrated to dryness under vacuum. The residue is dissolved in 250 ml of ethyl acetate, the solution is filtered over active carbon, and the filtrate is concentrated to half its volume. The product is cooled in an ice bath and gently combined with such an amount of diisopropyl ether that crystallization sets in. After stirring for several, hours in an ice bath, the crystallized product is vacuum-filtered, washed with diisopropyl ether, and dried at 50° C., thus obtaining 48.5 g (=74% of theory) of 5-cyano-3-methylcarbamoyl-2,4,6-triiodobenzoic acid (2,3-dihydroxypropyl)ester as a white powder, mp 117-120° C.
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH:6]=[CH:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH:2]12.[H][H].C1(=O)CCCCCCCCCCC1>>[CH:2]1([OH:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: C1=CCCC2OC2CCC=CCC1
Agent: O=C1CCCCCCCCCCC1
Product: OC1CCCCCCCCCCC1
Temperature: 70 °C

Procedure:
In an SUS-made autoclave having an inner volume of 100 ml and equipped with a stirrer, 20 g (0.112 mol) of 1,2-epoxy-5,9-cyclododecadiene and 0.08 g of a 5 mass % Pt/C catalyst (50% hydrous product, produced by N.E. Chemcat Corporation; 0.0102 mmol as platinum atom) were added and after pressurizing to 5 MPa with hydrogen at room temperature, heated to a temperature of 70° C. Under the same pressure, the contents were heated with stirring until the hydrogen absorption did not occur. After the completion of reaction, the reaction solution was cooled to room temperature, the catalyst was removed by filtration and the resulting reaction solution was analyzed. The analysis of the reaction solution was performed by gas chromatography. As a result, 1,2-epoxy-5,9-cyclododecadiene was 100% consumed and epoxycyclododecane (hereinafter referred to as “ECD”) was produced in a yield of 99.6 mol %. Also, as by-products, cyclododecanone (hereinafter referred to as “CDON”) was produced in 0.04 mol %, cyclododecanol (hereinafter referred to as “CDOL”) was produced in 0.20 mol % and cyclododecane (hereinafter referred to as “CDAN”) was produced in 0.04 mol %.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]2[C:17](=O)NC(=O)NC2=O)=[CH:6][CH:5]=1)[CH3:2].Cl.ClC1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.[OH-].[Na+].Cl>O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:17]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(CCC2C(=O)NC(=O)NC2=O)cc1
Reactant: Clc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1ccc(CCCc2ccncc2)cc1
Reaction time: 0.29 h

Procedure:
A mixture of 6.5 g (0.0235 m) of 5-[2-(4-ethoxyphenyl)ethyl]barbituric acid and 7 g (0.047 m) of 4-chloropyridine hydrochloride was mixed with a mortar and pestle and heated in an oil bath until the reagents formed a melt (185° C.). The mixture was kept at 180°-185° for 15-20 minutes, when the mixture began to noticeably darken. When heat was removed, the mixture quickly formed a hard glass. To this product, 6.5 g of NaOH pellets and 40 mL of water was added, and the mixture was refluxed for 5-6 hours. After cooling, the mixture was acidified with concentrated HCl and refluxed for 11/2 hours. The mixture was then diluted over ice, and the pH was adjusted to neutral using dilute NaOH. The product was then extracted into CH2Cl2. The CH2Cl2 layer was separated, dried, adsorbed onto silica gel, and chromatographed using CH2Cl2 >50% EtOAc/CH2Cl2. The product was an oil which crystallized. Yield 0.5 g. MP 79°-81° C.