Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.C([O-])([O-])=O.[K+].[K+].[CH2:34]([O:36][C:37](=[O:40])[CH2:38]Br)[CH3:35]>CC(C)=O>[CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:40])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: COc1ccc2c(Oc3ccc(O)cc3)c(-c3ccccc3)c(C)cc2c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
A round-bottomed flask was charged with 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}phenol (233) (0.150 g, 0.421 mmol), K2CO3 (0.116 g, 0.842 mol), acetone, and ethylbromoacetate (0.105 g, 0.632 mmol) under N2. The reaction mixture was refluxed for 5 h and cooled at room temperature. Reaction mixture was filtered and concentrated under reduced pressure to afford the crude product. The product was purified by SiO2 column chromatography using hexanes:EtOAc (19:1 to 9:1) as an eluent to give 0.177 g (95%) of the title compound (234) as a white foam. 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J=9.2 Hz, 1H), 7.54 (s, 1H), 7.29-7.22 (m, 3H), 7.13-7.11 (m, 3H), 7.05 and 7.03 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 6.63 (d, J1=9.2 Hz, 2H), 6.50 (d, J1=9.2 m, 2H), 4.48 (s, 2H), 4.24 (q, J=3.8 Hz, 2H), 3.93 (s, 3H), 2.23 (s, 3H), 1.27 (t, J=3.00 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[CH3:10].CC1(C)C(C)(C)OB([C:33]2[CH:34]=[CH:35][C:36]([C:39]([NH:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[O:40])=[N:37][CH:38]=2)O1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([CH:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH3:10])=[C:2]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([NH:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[O:40])=[N:37][CH:38]=2)[CH:7]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(Nc1ccc(-c2ccc(F)cc2)cc1)c1ccc(Cl)cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C(C)Nc2ccc(-c3ccc(F)cc3)cc2)cn1
Temperature: 25 °C

Procedure:
N-(1-(2-bromo-4-chlorophenyl)ethyl)-4′-fluoro-[1,1′-biphenyl]-4-amine (138 mg, 0.34 mmol), ethyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamido)propanoate (142 mg, 0.41 mmol), Pd(dppf)Cl2 (37 mg, 0.05 mmol), and K2CO3 (108 g, 0.78 mmol) were dissolved in wet DMF (3 mL) and water (4 mL) and heated to 90° C. After 16 h the resulting mixture was cooled to room temperature, filtered through CELITE and the filtrate was diluted with EtOAc, washed with water and sat. aqueous NaHCO3. The organic layer was dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl[C:28]1[N:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1.CCN(CC)CC>C(Cl)Cl.CO>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][N:22]([C:28]4[CH:29]=[CH:30][C:31]([C:34]#[N:35])=[CH:32][N:33]=4)[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CCC4(CCNCC4)CC3)n2)cn1
Reactant: N#Cc1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cn1cc(Nc2ncc(Cl)c(NC3CCC4(CC3)CCN(c3ccc(C#N)cn3)CC4)n2)cn1
Yield: 39.7 %

Procedure:
To a suspension of 5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(3-azaspiro[5.5]undecan-9-yl) pyrimidine-2,4-diamine (0.11 g, 0.29 mmol) in a mixture of DCM and MeOH (5.0 mL/5.0 mL) were added 6-chloropyridine-3-carbonitrile (0.086 g, 0.62 mmol) and Et3N (0.10 mL, 0.72 mmol). The mixture was heated to reflux overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to afford the product as a light yellow solid (55 mg, 39%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5](=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[NH2:6].C(N(CC)CC)C.[C:22]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=1[NH:6][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([C:22]([CH3:24])([CH3:23])[CH3:25])=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1N
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc([N+](=O)[O-])cc1NC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of 4-nitro-anthranilic acid methyl ester (1.500 g, 7.4 mmol) in CH2Cl2 (200 mL) was added triethylamine (8 mL) and 4-tert-butyl benzoyl chloride and the reaction was stirred overnight at rt. It was then poured into brine, extracted with ethyl acetate, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (20/80) to afford 2-(4-tert-butyl-benzoylamino)-4-nitro-benzoic acid methyl ester (1.841 g, 60%) as a yellow solid. mp=146.0-148.4° C.; mass spectrum (−ES, M−H) in/z 355. 1H NMR (400 MHz, DMSO-d6); δ 11.60 (bs, 1H), 9.35 (d, 1H), 8.20 (d, 1H), 8.02 (dd, 1H), 7.90 (d, 2H), 7.64 (d, 2H), 3.95 (s, 3H), 1.36 (s, 9H). Elemental analysis: Calcd. for C19H20N2O5: C, 64.04; H, 5.66; N, 7.86, Found: C, 64.04; H, 5.79; N, 7.76.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[CH:10]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:12]=2)=[CH:4][CH:3]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27].C([O-])([O-])=O.[K+].[K+]>COCCOC>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:9]1[CH:10]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:12]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:34]=2)=[CH:3][CH:4]=1
Reactant: CC(C)(O)c1cn(Cc2ccccc2Cl)c(-c2ccc(Br)cc2)n1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)(O)c1cn(Cc2ccccc2Cl)c(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)n1
Yield: 76.7 %

Procedure:
A mixture of 2-[2-(4-bromophenyl)-1-(2-chlorobenzyl)-1H-imidazol-4-yl]-propan-2-ol (130 mg, 0.32 mmol), 3-methanesulfonyl-phenylboronic acid (80 mg, 0.40 mmol), Cl2Pd(dppf)DCM (13 mg, 5 mol %) and a 2.8M aqueous solution of K2CO3 (0.35 mL, 0.98 mmol) in DME (2 mL) was heated in a microwave unit (Biotage Initiator™) at 120° C. for 4 min. The reaction mixture was concentrated and purified by chromatography (silica, EtOAc/Hex, 45:55 to 90:10) to give the title compound (118 mg, 77%) as a white solid. 1H-NMR. (DCM-d2): δ 8.08 (m, 1H), 7.84 (dd, 2H), 7.55-7.64 (m, 5H), 736 (m, 1H), 7.17-7.26 (m, 2H), 6.85 (d, 1H), 6.77 (s, 1H), 5.24 (s, 2H), 3.00 (s, 3H), 2.86 (br s, 1H), 1.49 (s, 6H); MS (ES): 481 [M+H]+.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2.[Br:23]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:23][C:21]1[CH:20]=[CH:19][C:3]2[N:4]([CH:7]3[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]3)[CH2:5][CH2:6][S:1][C:2]=2[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCSc3ccccc32)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CCSc3cc(Br)ccc32)C1
Reaction time: 1 h
Yield: 120.5 %

Procedure:
A solution of tert-butyl 3-(2H-benzo[b][1,4]thiazin-4(3H)-yl)pyrrolidine-1-carboxylate (0.41 g, 1.302 mmol) in DMF (5 mL), was cooled to 0° C. and treated dropwise with N-bromosuccinimide (0.17 g, 0.977 mmol) in DMF (5 mL) for 15 minutes. The reaction was kept at 0° C. and was stirred for 1 hour at this temperature. At this time, N-bromosuccinimide (0.023 g, 0.130 mmol) in DMF (1 mL) was added dropwise to the reaction, which was then stirred for 1 hour at 0° C. The solution was treated again with N-bromosuccinimide (0.023 g, 0.130 mmol) in DMF (1 mL) and was stirred for 1 hour at 0° C. The solution was diluted in water (100 mL) and extracted with EtOAc (2×100 mL). The aqueous phase was washed once with EtOAc (50 mL). The organic solutions were combined, washed with water (100 mL) and brine (50 mL), and dried (Na2SO4). The crude material was filtered through a silica pad (20% EtOAc/hexanes) and concentrated to give clear oil (0.47 g, 90%). 1H NMR (CDCl3) δ 7.18 (d, J=2.4 Hz, 1H), 7.07 (d, J=8.7 Hz, 1H), 6.62 (d, J=8.7 Hz, 1H), 4.34-4.28 (m, 1H), 3.71-3.23 (m, 6H), 3.03-3.04 (m, 2H), 2.19-1.95 (m, 2H), 1.47 (s, 9H); ESI-MS (m/z, %): 423, 421 (M+Na, 8), 401, 399 (MH+, 2), 343, 345 (100).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:9]([OH:11])=O)[S:7][CH:8]=1)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34]([NH2:36])=[O:35])[C:29](=[O:37])[CH2:28]2.Cl>CN(C)C=O.CN(C1C=CN=CC=1)C>[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34]([NH2:36])=[O:35])[C:29](=[O:37])[CH:28]2[C:9](=[O:11])[C:6]1[S:7][CH:8]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1
Reactant: CC(=O)c1csc(C(=O)O)c1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(=O)c1csc(C(=O)C2C(=O)N(C(N)=O)c3ccc(Cl)cc32)c1
Temperature: 25 °C
Yield: 22 %

Procedure:
A 0.78 g (4.59 nmuoles) sample of 4-acetyl-2-thio-phenecarboxylic acid (prepared according to Satonaka, H., Bull. Chem. Soc. Japan 56:2463 (1983)) was combined with 0.95 g (5.85 mmoles) of 1,1'-carbonyldiimidazole in 10 ml of N,N-dimethylformamide and stirred at room temperature under argon atmosphere. After two hours the reaction contents were transferred to an addition funnel and slowly added to a slurry of 0.88 g (4.18 mmoles) of 5-chloro-2-oxindole-1-carboxamide and 1.38 g (11.28 mmoles) of 4-(N,N-dimethylamino)pyridine in 30 ml of N,N-dimethylformamide stirring at 5° C. (ice bath) under an inert atmosphere. The reaction contents were stirred for fifteen minutes at 5° C. after complete addition followed by twenty-four hours at room temperature. Pouring the reaction mixture into 110 ml of 0.3N hydrochloric acid cause the precipitation of a greenish-yellow solid. Filtration followed by sequential washing with 3N hydrochloric acid and water, provided the crude product which was recrystallized twice from acetic acid to give 0.34 g (0.94 mmoles, 22% yield) of pure 5-chloro-3-(4-acetyl-2-thenoyl)-2-oxindole-1-carboxamide as a greenish-yellow solvated complex with 0.2 equivalents of acetic acid, m.p. 230-233° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][C:8](Cl)=[N:7][CH:6]=1)[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][C:8]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)cc1Oc1ccccc1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(N2CCOCC2)cc1Oc1ccccc1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
A solution of 130 mg (0.468 mmol) 6-chloro-4-phenoxy-nicotinic acid ethyl ester, 0.040 ml (0.47 mmol) morpholine and 0.065 ml (0.47 mmol) triethylamine in 7 ml tetrahydrofuran was stirred at reflux for 40 h. After cooling to room temperature the reaction mixture was filtered, diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried with sodium sulfate and concentrated. Flash column chromatography afforded 66 mg (43%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([C:22]4[N:26]=[CH:25][N:24](C5CCCCO5)[N:23]=4)([OH:21])[CH3:20])[CH:15]=3)[C:10]([CH3:33])=[N:9]2)[CH:5]=[CH:4][N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([C:22]4[N:26]=[CH:25][NH:24][N:23]=4)([OH:21])[CH3:20])[CH:15]=3)[C:10]([CH3:33])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3ncn(C4CCCCO4)n3)ccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: Cc1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3nc[nH]n3)ccc12
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[1-(2-aminopyrimidin-4-yl)-3-methylindazol-6-yl]-2-[1-(oxan-2-yl)-1,2,4-triazol-3-yl]but-3-yn-2-ol (60 mg, 0.13 mmol) in methanol (3 mL) was added p-toluenesulfonic acid (25.38 mg, 0.15 mmol). The reaction mixture was stirred at 55° C. for 1 hr, and then concentrated in vacuo. The crude residue was partitioned between saturated NaHCO3 solution (2 ml) and DCM (2×5 ml). The combined organic extracts were washed with brine (2 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Isolute column, 2-10% methanol gradient in DCM) to give the title compound: 1H NMR (500 MHz, DMSO) delta 1.92 (3H, s), 2.58 (3H, s), 6.96 (2H, s), 7.05 (1H, d, J=5.5 Hz), 7.46-7.28 (1H, m), 7.85 (1H, d, J=8.2 Hz), 8.26 (1H, d, J=5.5 Hz), 8.86 (1H, s), 14.01 (1H, s); LC-MS: m/z=+361.05 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([O:26][CH3:27])[CH:25]=1)[NH2:22]>>[CH3:27][O:26][C:24]1[CH:23]=[C:21]([NH:22][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[C:5]([F:16])=[CH:4][N:3]=2)[CH:20]=[C:19]([O:18][CH3:17])[CH:25]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: COc1cc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)cc(OC)c1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 3,5-dimethoxyaniline gave N2-(3,5-dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. LCMS: ret. time: 19.61 min.; purity: 97%; MS (m/e): 357 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:21]=C)=[C:4]([CH:9]=[C:10]([CH2:13][C:14]2[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].CC(C)=[O:25].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[CH:21]([C:3]1[C:2]([CH3:1])=[C:11]([CH3:12])[C:10]([CH2:13][C:14]2[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=[O:25]
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(C)nc2)c(C)c1C
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cc2ccc(C)nc2)c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3,4-dimethyl-5-((6-methylpyridin-3-yl)methyl)-2-vinylbenzoate (0.44 g) in a mixed solvent of acetone (5.40 mL)-acetonitrile (5.40 mL)-water (5.40 mL) were added osmium oxide (fixed catalyst I) (0.19 g) and sodium periodate (1.59 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.44 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@@H:11]([OH:24])[CH2:12]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:25]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:3]([CH2:10][C@@H:11]([OH:24])[CH2:12][N:28]2[CH2:27][CH2:26][N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)Cn2cc([N+](=O)[O-])nc2Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C[C@H](O)Cn2cc([N+](=O)[O-])nc2Cl)CC1
Yield: 66.4 %

Procedure:
(R)-2-Chloro-1-[2-hydroxy-3-(4-methylbenzene-sulfonyloxy)propyl]-4-nitroimidazole prepared in Example 8 (16.86 g, 44.86 mmol) and tert-butyl piperazine-1-carboxylate (8.36 g, 44.89 mmol) were dissolved in acetonitrile (100 ml). To the solution, triethylamine (6.3 ml, 45.2 mmol) was added followed by stirring under reflux for 6 hours. The reaction mixture was allowed to return to room temperature, and concentrated under reduced pressure. To the residue, water (100 ml) was added and extracted with ethyl acetate (100 ml) twice. The organic phases were combined, washed with water (100 ml) and a saturated saline solution (100 ml) in this order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=40/1) and then recrystallized from ethyl acetate/n-hexane to afford tert-butyl (S)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxypropyl]piperazine-1-carboxylate (11.61 g, yield 66%) as a light yellow powder.
Reaction SMILES: FC1C2(O)CC3CC(O)(CC1(O)C3)C2.OC12CC3(O)CC(O)(CC(O)(C3)C1)C2.[C:29]([O:33][C:34]12[C:54](F)(F)[C:38]3([O:57][C:58](=[O:61])[CH:59]=[CH2:60])[C:39](F)(F)[C:40]([O:47][C:48](=[O:51])[CH:49]=[CH2:50])([C:44](F)(F)[C:36]([O:64][C:65](=[O:68])[CH:66]=[CH2:67])([C:37]3(F)F)[C:35]1(F)F)[C:41]2(F)[F:42])(=[O:32])[CH:30]=[CH2:31]>>[C:48]([O:47][C:40]12[CH2:44][C:36]3([O:64][C:65](=[O:68])[CH:66]=[CH2:67])[CH2:37][C:38]([O:57][C:58](=[O:61])[CH:59]=[CH2:60])([CH2:54][C:34]([O:33][C:29](=[O:32])[CH:30]=[CH2:31])([CH2:35]3)[CH:41]1[F:42])[CH2:39]2)(=[O:51])[CH:49]=[CH2:50]
Reactant: C=CC(=O)OC12C(F)(F)C3(OC(=O)C=C)C(F)(F)C(OC(=O)C=C)(C1(F)F)C(F)(F)C(OC(=O)C=C)(C2(F)F)C3(F)F
Agent: OC12CC3(O)CC(O)(C1)CC(O)(C2)C3
Agent: OC12CC3CC(O)(C1)C(F)C(O)(C3)C2
Product: C=CC(=O)OC12CC3(OC(=O)C=C)CC(OC(=O)C=C)(C1)C(F)C(OC(=O)C=C)(C2)C3

Procedure:
The same reactions as in Examples 1-1 to 1-4 are carried out except that 1,3,5-trihydroxyadamantane used in Example 1-1 is changed to 1,3,5,7-tetrahydroxyadamantane, whereupon formation of 1,3,5,7-tetrakisacryloyloxy(perfluoroadamantane) is confirmed. Further, formation of 2-hydro-1,3,5,7-tetrakisacryloyloxy(perfluoroadamantane) is confirmed.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].I([O-])(=O)(=O)=[O:26].[Na+]>C(Cl)(Cl)Cl.O.O.[Ru](=O)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C:14](=[O:26])[CH2:13]2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)C(=O)C2)c1
Temperature: 25 °C
Reaction time: 264 h
Yield: 29.5 %

Procedure:
To a stirred solution of tert-butyl 4-[3-(ethoxycarbonyl)phenyl]piperidine-1-carboxylate (48 g, 220 mmol) in chloroform (900 mL) was added ruthenium (IV) oxide hydrate (6.0 g, 45 mmol) followed by a solution of sodium periodate (150 g, 700 mmol) in water (900 mL). The resulting heterogenous reaction mixture was stirred at room temperature for 11 days before being filtered through a short column of celite. The organic layer was removed and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with a 10% solution of sodium thiosulfate in water twice, and once with brine. This solution was dried over MgSO4, filtered, and concentrated under reduced pressure. The product was purified by flash chromatography (silica gel, 20% EA/hexanes) to give 22.5 g (64.8 mmol) of tert-butyl 4-[3-(ethoxycarbonyl)phenyl]-2-oxopiperidine-1-carboxylate (29%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4](Cl)[C:3]=1C(OCC)=O.[BrH:25]>C(O)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([Br:25])[CH:3]=1
Reactant: Br
Reactant: CCOC(=O)c1c(Cl)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Solvent: CC(=O)O
Product: Nc1cc(Br)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
A mixture of 5-amino-4-carboethoxy-3-chloro-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (3.3 g), hydrobromic acid (45%; 30 ml) and acetic acid (50 ml) was boiled under reflux for 18 h. The mixture was evaporated to low bulk and basified with sodium hydroxide solution (2M), and the product was filtered off, dried (2.9 g) and recrystallized from a mixture of ethanol and water to give 5-amino-3-bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole (2.5 g), m.p. 132.5-134° C. in the form of a colorless solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClCCl.[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH2:15][C:14]([CH3:18])([CH3:17])[C:13]=2[CH:19]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCCCCC.C(OCC)(=O)C>[C:20]([C:11]1[C:12]2[O:16][CH2:15][C:14]([CH3:17])([CH3:18])[C:13]=2[CH:19]=[C:9]([Br:8])[CH:10]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1(C)COc2ccc(Br)cc21
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CC1(C)COc2c(C(=O)c3ccccc3)cc(Br)cc21

Procedure:
Following General Procedure I and using aluminum chloride (1.76 g, 13.2 mmol), 20 mL of anhydrous dichloromethane, 5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (Intermediate 2, 1.5 g, 6.61 mmol) and benzoyl chloride (1.53 mL, 13.2 mmol) followed by flash column chromatography on silica gel (230-1400 mesh) using 7% ethyl acetate in hexane as the eluent, the title compound was obtained (2.15 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13](=[O:25])[NH:14][C:15]2[CH2:19][CH2:18][CH2:17][C:16]=2[C:20](OCC)=[O:21])=[C:4]([F:26])[CH:3]=1.C[O-].[Na+].Cl>CO>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:20](=[O:21])[C:16]3[CH2:17][CH2:18][CH2:19][C:15]=3[NH:14][C:13]2=[O:25])=[C:4]([F:26])[CH:3]=1
Reactant: CCOC(=O)C1=C(NC(=O)Nc2cc(OC(C)C)c(Cl)cc2F)CCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)Oc1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)c(F)cc1Cl
Reaction time: 2 h

Procedure:
A suspension of 6.0 g of ethyl 2-[3-(4-chloro-2-fluoro-5-isopropoxyphenyl)ureido]-1-cyclopentenecarboxylate in 100 ml of absolute methanol is treated while stirring at room temperature with 7.8 ml of 2N sodium methylate solution and the reaction mixture is stirred for 2 hours. The solution is treated with 7.8 ml of 2N hydrochloric acid and evaporated to dryness. The residue is dissolved in 200 ml of ethyl acetate and the solution is washed with water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is recrystallized from methylene chloride/diethyl ether. There is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-1,5,6,7-tetrahydro-2H-cyclopenta[d]pyrimidine-2,4(3H)-dione, m.p. 215°-217° C.