Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([OH:24])[CH:6]=1)(=[O:3])[CH3:2].N1C=CC=CC=1.FC(F)(F)S([O-])(=O)=O.[F:39][C:40]([I+]C1C=CC=CC=1)([F:48])[C:41]([F:47])([F:46])[C:42]([F:45])([F:44])[F:43]>ClCCl>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:19])([F:20])[F:21])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:40]([F:48])([F:39])[C:41]([F:47])([F:46])[C:42]([F:45])([F:44])[F:43])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(O)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reactant: FC(F)(F)C(F)(F)C(F)(F)[I+]c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(OC(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.3 %

Procedure:
2.1 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole was dissolved in 60 mL of dichloromethane, and 0.51 g of pyridine was added. To the obtained solution, 3.0 g of (perfluoro-n-propyl)phenyliodonium trifluoromethanesulfonate was slowly added, followed by stirring at room temperature for 1 hour. The solvent was distilled off under reduced pressure, a saturated salt solution was added, extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 0.10 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,2,3,3,3-heptafluoropropoxy)pyrazole.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)C1C=CC=CC=1.[CH:15]1[C:28]2[C:19](=[N:20][CH:21]=[C:22]3[C:27]=2[CH:26]=[CH:25][CH:24]=[CH:23]3)[CH:18]=[CH:17][CH:16]=1>O>[Cl:3][C:25]1[CH:24]=[CH:23][C:22]2[C:27]([CH:26]=1)=[C:28]1[C:19]([CH:18]=[CH:17][CH:16]=[CH:15]1)=[N:20][CH:21]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: c1ccc2c(c1)cnc1ccccc12
Solvent: O
Solvent: CN(C)c1ccccc1
Product: Clc1ccc2cnc3ccccc3c2c1
Yield: 96 %

Procedure:
Phosphorus oxychloride (15 ml) and dimethylaniline (0.63 ml) were added to phenanthridine (2.0 g), followed by refluxing for 3 hours. The solution was poured into H2O to generate a solid, and the obtained solid was extracted with chloroform, followed by drying with sodium sulfate. After filtration, the filtrate was evaporated to dryness under reduced pressure. The obtained solid was purified by column chromatography (eluent: chloroform) (amount: 2.1 g, yield: 96%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([F:11])[F:10].[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH:13]=[CH2:14]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([CH:9]([F:11])[F:10])=[C:2](/[CH:14]=[CH:13]/[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:7]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: FC(F)c1ccc(Cl)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1cc(Cl)ccc1C(F)F
Temperature: 90 °C
Reaction time: 5 h
Yield: 22.1 %

Procedure:
To a solution of Intermediate 14A (0.88 g, 3.64 mmol) in DMF (10 mL) was added tert-butyl acrylate (1.401 g, 10.93 mmol), TEA (1.270 mL, 9.11 mmol) and Pd(OAc)2 (0.082 g, 0.364 mmol). The reaction was warmed to 90° C. After 5 h, the reaction was cooled to rt and then filtered to remove the solid. The filtrate was diluted with EtOAc, washed with 1M HCl, saturated NaHCO3, and brine. The organic phase was dried over MgSO4, filtered and concentrated. Purification by normal phase chromatography gave Intermediate 14B (232 mg, 22% yield) as a tan oil. MS (ESI) m/z: 233.1 (M-tBu)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](Cl)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.Cl.[NH2:23][C@H:24]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15]([NH:23][C@@H:24]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)N[C@@H](Cc3ccccc3)C(=O)OC(C)(C)C)c2nc1OC
Reaction time: 24 h

Procedure:
Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 200 mg (0.64 mmol) and L-phenylalanine, tert-butyl ester hydrochloride 173 mg (0.67 mmol). Reaction was continued for 24 hours, and the crude product was eluted through a flash column (4:1 hexanes:ethyl acetate), 180 mg (57%), mp 86-88° C.; 1H NMR (CDCl3): δ 8.32 (s, 1H), 7.22 (m, 5H), 6.39 (d, 1H, J=6.6 Hz), 4.88 (q, 1H, J=6.1, J=6.8 Hz), 4.07 (s, 3H), 4.00 (s, 3H), 3.23 (d, 2H, J=5.9 Hz), 2.56 (s, 3H), 1.37 (s, 9H); MS (APCI): m/z 497 (M+H). Anal. Calcd. for C25H28N4O7: C, 60.48; H, 5.68; N, 11.28. Found: C, 59.73; H, 5.53; N, 11.28.
Reaction SMILES: Cl.[F:2][CH:3]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH3:22][O:23][C:24]1[CH:31]=[C:30]([CH2:32][CH:33]=O)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27].C([BH3-])#N.[Na+].CO>CC(O)=O>[F:2][CH:3]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:33][CH2:32][C:30]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([O:23][CH3:22])[CH:31]=2)[CH2:7][CH2:6]1
Reactant: COc1cc(CC=O)ccc1C#N
Reactant: Cc1c(C(F)CN2CCNCC2)ccc2c1COC2=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(CCN2CCN(CC(F)c3ccc4c(c3C)COC4=O)CC2)ccc1C#N
Reaction time: 12 h

Procedure:
5-(1-Fluoro-2-piperazin-1-ylethyl)-4-methyl-2-benzofuran-1(3H)-one hydrochloride (30 mg, 0.11 mmol), 2-(methyloxy)-4-(2-oxoethyl)benzonitrile (37 mg, 0.22 mmol), sodium cyanoborohydride (67 mg, 1.078 mmol) were added to a 25 mL flask containing a stir bar; to the flask was added MeOH (3 mL) and few drops of AcOH. The reaction mixture was subsequently stirred for 12 hr; LC indicated that reaction had gone to completion. The solution was concentrated to dryness, redissolved in EtOAc (15 mL) and washed with aq. NaHCO3 and aq. NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to dryness. It was then re-dissolved in MeOH (3.5 mL) again, filtered and shot into mass-directed HPLC for separation to give the desired product. LC-MS (IE, m/z): 450 [M+1]+.
Reaction SMILES: C([NH2:4])(=O)C.[C:5]([C:9]1[CH:49]=[CH:48][C:12]([C:13]([NH:15][C@H:16]([C:44]([O:46][CH3:47])=[O:45])[CH2:17][C:18]2[CH:43]=[CH:42][C:21]([C:22]([O:24][CH2:25][C:26]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=3)=O)=O)=[CH:20][CH:19]=2)=[O:14])=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6]>CC(=O)OCC>[C:5]([C:9]1[CH:49]=[CH:48][C:12]([C:13]([NH:15][C@@H:16]([CH2:17][C:18]2[CH:43]=[CH:42][C:21]([C:22]3[O:24][CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=4)[N:4]=3)=[CH:20][CH:19]=2)[C:44]([O:46][CH3:47])=[O:45])=[O:14])=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(N)=O
Reactant: CCCCCCCOc1ccc(C(=O)COC(=O)c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC)cc2)cc1
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(-c2coc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)OC)cc3)n2)cc1
Temperature: 140 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
To borontrifluoride diethyl etherate (33.3 μl, 0.27 mmol) was added a mixture of acetamide (763 mg, 12.9 mmol) and (S)-2-(4-(heptyloxy)phenyl)-2-oxoethyl 4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate (159 mg, 0.26 mmol). The reaction mixture was stirred at 140° C. for 1 h. The reaction mixture was allowed to cool to RT, diluted with EA (15 mL) and extracted with NaHCO3 (3×15 mL) and brine (15 mL). The combined organics were dried over MgSO4, filtered and concentrated. The residue was recrystallised from Et2O (5 mL), filtered and rinsed with Et2O. The filtrate was concentrated to afford 55 mg (16%) of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)oxazol-2-yl)phenyl)propanoate as an orange oil. LCMS-ESI (m/z) calculated for C37H44N2O5: 596.8; found 597.0 [M+H]+, tR=3.11 min. (Method 4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[CH2:11][O:10][C:9]2=[O:20])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH:14]=3)[CH2:11][O:10][C:9]2=[O:20])=[CH:6][CH:7]=1
Reactant: O=C1OC[C@H](c2cccc(O)c2)N1c1ccc(Cl)cc1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1OC[C@H](c2cccc(Oc3ncccn3)c2)N1c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To (S)-3-(4-chlorophenyl)-4-(3-hydroxyphenyl)oxazolidin-2-one (0.05 mmol) is added Cs2CO3 (0.1 mmol) and 2-chloropyrimidine (0.06 mmol) in DMF (1 mL). The mixture is stirred at 80° C. for 3 h then cooled to room temperature and filtered through Whatman 0.42 μM filter and purified by preparative HPLC (C-18, 10-90% ACN/water (0.05% TFA)). HPLC-MS calculated for C19H14ClN3O3 (M+H+): 368.0, found 368.0.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[O:27])[CH2:11][CH2:10]2)=[C:4]([N+:28]([O-])=O)[CH:3]=1.[H][H]>[Pd].CO>[NH2:28][C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=1[NH:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[NH:20][C:19]2=[O:27])[CH2:13][CH2:14]1
Reactant: [H][H]
Reactant: O=c1[nH]c2ccccc2n1CCCN1CCC(Nc2ccc(Cl)cc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1NC1CCN(CCCn2c(=O)[nH]c3ccccc32)CC1
Yield: 100 %

Procedure:
A mixture of 21.5 parts of 1-[3-{4-[(4-chloro-2-nitrophenyl)amino]-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one and 240 parts of methanol is hydrogenated at normal pressure and at room temperature with 10 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 18.5 parts (100%) of 1-[3-{4-[(2-aminophenyl)amino]-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one as a residue.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(N(CC)CC)C.Br[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[NH:20][C:19]=2[CH:25]=1>CN(C)C=O>[CH2:1]([NH:4][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[NH:20][C:19]=2[CH:25]=1)[CH2:2][CH3:3]
Reactant: CCCN
Reactant: O=C1COc2ccc(CCBr)cc2N1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCNCCc1ccc2c(c1)NC(=O)CO2

Procedure:
In a round-bottomed flask equipped with a mechanical stirrer and a calcium chloride guard tube, 0.01 mol of n-propylamine and 0.015 mol of triethylamine are added to a solution of 6-(2-bromoethyl)-3-oxo-2,3-dihydro-1,4-benzoxazine in 40 cm3 of dimethylformamide. The mixture is heated to reflux for 15 hours and the precipitate formed is drained in the heated state. The residue is evaporated under vacuum and the product is recrystallized.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH2:13][CH2:14][CH3:15])[CH:7]=[CH:8][CH:9]=2)[C:4]=1[O:16]COC.Cl.O.[C:22](OCC)(=[O:24])C>CC(C)=O>[OH:16][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:13][CH2:14][CH3:15])[C:11]([CH:22]=[O:24])=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: CCCc1cccc2ccc(OC)c(OCOC)c12
Reactant: CCOC(C)=O
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CCCc1cccc2c(C=O)cc(OC)c(O)c12
Temperature: 0 °C
Reaction time: 5 h

Procedure:
206 g of 2-methoxy-1-methoxymethoxy-8-propylnaphthalene was dissolved in 1160 ml of acetone and cooled to 0° C. Diluted hydrochloric acid (concentrated hydrochloric acid 84 ml/water 206 ml) was added to the solution in 15 minutes, which was returned to room temperature at which the reaction was effected at 20° C. for 5 hours, followed by addition of water and extraction with ethyl acetate. The resultant organic phase was washed with a saturated saline solution to neutrality, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. 173 g of the resultant brown oily substance was dissolved in 1350 g of dichloromethane without purification and cooled down to 0° C. 176.3 ml of titanium tetrachloride was dropped in the solution at 5° C. or below, to which 114.3 ml of dichloromethyl methyl ether was added at 5° C. or below at which the reaction was carried out for 10 minutes. The reaction solution was slowly added to iced water and extracted with ethyl acetate. The resultant organic phase was washed with a saturated sodium hydrogencarbonate aqueous solution and a saturated saline solution in this order and dried with anhydrous magnesium sulfate, and was concentrated under reduced pressure. The resultant crystals were washed with a 30% isopropyl ether/hexane solution to obtain 103 g of the captioned compound as yellowish brown crystals.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([CH2:11]Br)=[CH:7][C:6]=2[C:5]([F:13])=[C:4]([F:14])[CH:3]=1.[CH3:15][OH:16].C[O-].[Na+]>CO>[Br:1][C:2]1[C:10]2[O:9][C:8]([CH2:11][O:16][CH3:15])=[CH:7][C:6]=2[C:5]([F:13])=[C:4]([F:14])[CH:3]=1
Reactant: CO
Reactant: Fc1cc(Br)c2oc(CBr)cc2c1F
Agent: C[O-]
Agent: [Na+]
Product: COCc1cc2c(F)c(F)cc(Br)c2o1
Yield: 80 %

Procedure:
The compound (489 mg, 1.50 mmol) of Step 1 of Example 54 was dissolved in methanol (7 mL), and a 25% sodium methoxide methanol solution (1.5 mL) were added thereto, and heated under reflux for 3 hours. The resultant was returned to room temperature, and the solvent was distilled away under reduced pressure. The resulting residue was diluted with ethyl acetate, washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane/ethyl acetate) to thus obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[Al](C)C.[CH3:13][N:14]1[C:19](=[O:20])[CH:18]=[C:17]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:16]=[C:15]1[CH2:27][C:28](OCC)=[O:29].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:28](=[O:29])[CH2:27][C:15]2[N:14]([CH3:13])[C:19](=[O:20])[CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:16]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)n1C
Agent: C[Al](C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1c(CC(=O)Nc2ccc(F)cc2)nc(N2CCOCC2)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.135 ml of 4-fluoroaniline and 0.670 ml of a 2M solution of trimethylaluminium are added, dropwise, to a solution of 190 mg of ethyl [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate in 10 ml of toluene. After stirring for 30 minutes at ambient temperature, 10 ml of toluene are added. After stirring for 4 hours at ambient temperature, the reaction mixture is poured into water and a 1M solution of potassium phosphate is added. The precipitate is filtered through sintered glass and then rinsed with ethyl acetate. The filtrate is then washed with water and then with a saturated aqueous solution of sodium chloride. The organic phase is extracted and then dried over magnesium sulphate, filtered through sintered glass, and concentrated under reduced pressure. After purification of the residue by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol (95/05, V/V), 20 mg of N-(4-fluorophenyl)-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH:1]#[C:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH2:10]1[CH2:14][O:13][CH2:12][CH2:11]1>>[CH:12]([O:13][CH2:14][CH2:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]2[CH2:4][CH2:3][CH2:2][CH2:1][CH2:1]2)=[CH:4][CH:5]=1)=[CH2:11]
Reactant: C1CCOC1
Reactant: C#Cc1ccc(O)cc1
Product: C=COCCOc1ccc(C2CCCCC2)cc1

Procedure:
In 80 ml of THF were dissolved 20 g of poly(p-hydroxystyrene), VP-8000 (produced by Nippon Soda Co., Ltd.), and 6.5 g of 4-cyclohexylphenoxyethyl vinyl ether. Thereto, 0.01 g of p-toluenesulfonic acid was added. The resulting mixture underwent reaction for 18 hours at room temperature. The reaction solution was dripped into 5L of distilled water with vigorous stirring, and fine solid particles precipitated out were filtered off and dried. Thus, Polymer (B-32) was obtained.
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:28])[C@:7]1([OH:27])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C:21](=[CH:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)(=O)C.[OH-].[K+]>CO.C(Cl)Cl>[OH:27][C@:7]1([C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C:21](=[CH:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)[C:6](=[O:28])[CH2:5][OH:4]
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Temperature: 0 °C
Yield: 89.8 %

Procedure:
At room temperature, 1.5 g of 21-acetoxy-17-hydroxy-4,9(11)-pregnadiene-3,20-dione in 40 ml of methanol is agitated for 2 hours at room temperature with 15 ml of 0.2N methanolic potassium hydroxide solution. The reaction mixture is introduced into ice water. The precipitated product is suctioned off, dissolved in methylene chloride, washed with water, and dried over sodium sulfate, thus obtaining 1.2 g of 17,21-dihydroxy-4,9(11)-pregnadiene-3,20-dione; mp 248.2° C.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[C:9]3[C:14]([CH:15]=[CH:16][C:6]=2[N:5]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])=[CH:19][CH:18]=2)[C:4](=[O:36])[CH2:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.I[CH2:38][CH2:39][OH:40]>>[O:1]=[C:2]1[NH:8][C:7]2[C:9]3[C:14]([CH:15]=[CH:16][C:6]=2[N:5]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH2:38][CH2:39][OH:40])[S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])=[CH:19][CH:18]=2)[C:4](=[O:36])[CH2:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])cc2)c2ccc3ccccc3c2N1
Reactant: OCCI
Product: O=C1CC(=O)N(c2ccc(N(CCO)S(=O)(=O)c3ccccc3[N+](=O)[O-])cc2)c2ccc3ccccc3c2N1

Procedure:
By using N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide obtained in Example 145, and 2-iodoethanol, the title compound was obtained in the same manner as that of Example 152.
Reaction SMILES: [C:1]([C:4]1[N:8]([CH3:9])[N:7]=[C:6]([O:10][CH2:11][C:12]([O:14]CC)=[O:13])[CH:5]=1)(O)=O.CCN=C=NCCCN(C)C.[CH2:28]([N:32]1[C:39]([NH2:40])=[C:38]([NH2:41])[C:36](=[O:37])[N:35]([CH2:42][CH:43]([CH3:45])[CH3:44])[C:33]1=[O:34])[CH:29]([CH3:31])[CH3:30]>CO>[CH2:42]([N:35]1[C:36](=[O:37])[C:38]2[NH:41][C:1]([C:4]3[N:8]([CH3:9])[N:7]=[C:6]([O:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=3)=[N:40][C:39]=2[N:32]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:33]1=[O:34])[CH:43]([CH3:45])[CH3:44]
Reactant: CCOC(=O)COc1cc(C(=O)O)n(C)n1
Reactant: CC(C)Cn1c(N)c(N)c(=O)n(CC(C)C)c1=O
Agent: CCN=C=NCCCN(C)C
Solvent: CO
Product: CC(C)Cn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CC(C)C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (5-carboxy-1-methylpyrazol-3-yl)oxyacetate (0.5 mmol) and EDCI (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-diisobutyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[5-(1,3-diisobutyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]([CH:32]([CH3:34])[CH3:33])=[C:12]([CH2:14][CH2:15][C:16]([C:18]2[CH:30]=[CH:29][C:21]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:20]([CH3:31])[CH:19]=2)=[O:17])[N:13]=1.[H-].[Na+].[CH3:37]I>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]([CH:32]([CH3:33])[CH3:34])=[C:12]([CH2:14][CH:15]([CH3:37])[C:16]([C:18]2[CH:30]=[CH:29][C:21]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:20]([CH3:31])[CH:19]=2)=[O:17])[N:13]=1
Reactant: CI
Reactant: CCOC(=O)COc1ccc(C(=O)CCc2nc(-c3ccc(Cl)cc3Cl)oc2C(C)C)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(C(=O)C(C)Cc2nc(-c3ccc(Cl)cc3Cl)oc2C(C)C)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
Ethyl [4-[3-[2-(2,4-dichlorophenyl)-5-isopropyl-4-oxazolyl]propionyl]-2-methylphenoxy]acetate (450 mg, 0.89 mmol) was dissolved in dry THF (4 mL). Sodium hydride (40 mg, 1.00 mmol) was gradually added to the solution. The mixture was stirred for 30 minutes at room temperature. Methyl iodide (0.07 mL, 1.12 mmol) was dropwise added to the mixture. The resulting mixture was stirred for 27 hours at room temperature. Sodium hydride (10 mg, 0.25 mmol) and methyl iodide (0.02 mL, 0.32 mmol) were further added to the mixture. The resulting mixture was stirred for 19 hours 30 minutes at room temperature. The solvent was removed under reduced pressure. Ethyl acetate (5 mL) was added to the residue. The residue was washed with a saturated saline (2 mL), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel with ethyl acetate/hexane (1/9) to give the desired compound (218 mg) as colorless oil (purity 97%, yield 29%).
Reaction SMILES: [Na].C[Si](C)(C)N[Si](C)(C)C.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=1.[Cl:22][C:23]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:24]=1C(OC)=O.Cl>C1COCC1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([C:30]2[CH:29]=[CH:24][C:23]([Cl:22])=[CH:32][C:31]=2[Cl:33])=[O:21])=[CH:16][CH:17]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: COC(=O)c1ccc(Cl)cc1Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Br)cc1)c1ccc(Cl)cc1Cl
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
436 ml of a 2M solution of the sodium salt of hexamethyldisilazane in THF are cooled to −60° C., under a nitrogen atmosphere, 400 ml of THF are added, followed by dropwise addition of a solution of 75 g of 4-bromophenylacetic acid in 100 ml of THF, and the mixture is stirred for 1 hour 30 minutes at −70° C. 67.9 g of methyl 2,4-dichlorobenzoate are then added dropwise and the mixture is stirred for 30 minutes and then allowed to warm to 5° C. The reaction mixture is poured into a mixture of ice/1 liter of 2N HCl and extracted with ether, the organic phase is washed with saturated NaHCO3 solution and with water, and dried over Na2SO4, the solvent is evaporated off under vacuum to a volume of 200 ml, pentane is added and the crystalline product formed is filtered off by suction. 80 g of the expected compound are obtained.