Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([F:13])([F:12])[CH:9]([F:11])[O:10][C:5]=2[CH:4]=1.C1N2CN3CN(C2)CN1C3.Cl.[OH2:27]>>[CH:2]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([F:13])([F:12])[CH:9]([F:11])[O:10][C:5]=2[CH:4]=1)=[O:27]
Reactant: FC1Oc2cc(CBr)ccc2OC1(F)F
Reactant: O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: O=Cc1ccc2c(c1)OC(F)C(F)(F)O2

Procedure:
318 g of 6-bromomethyl-2,2,3-trifluoro-1,4-benzodioxane are added to 318 g of urotropin in 630 ml of water, the reaction mixture is heated under reflux for 2 hours, 318 ml of hydrochloric acid and 470 ml of water are then added and the mixture is heated for a further 3 hours. The product is driven over with steam and is separated off and, after drying, distilled. 158 g of distillate are obtained (boiling point: 112-115° C. (under 18 mbar)) and partly crystallize on standing. The crystal sludge is filtered off with suction and the crystals are washed with cold petroleum ether.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4](OS(C(F)(F)F)(=O)=O)[CH2:3][CH2:2]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][C:18]=1[N+:32]([O-:34])=[O:33].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:4]2[CH2:3][CH2:2][O:1][CH2:6][CH:5]=2)=[CH:19][C:18]=1[N+:32]([O-:34])=[O:33]
Reactant: O=S(=O)(OC1=CCOCC1)C(F)(F)F
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C2=CCOCC2)cc1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 65.7 %

Procedure:
2.0 g Trifluoro-methanesulfonic acid 3,6-dihydro-2H-pyran-4-yl ester (8.6 mmol) and 2.89 g 2-(4-methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (10.3 mmol) were dissolved in a mixture of toluene (20 ml) and ethanol (50 ml) 0.35 g of dichloro (1,1′bis-(diphenylphosphine)ferrocene)palladium(II)dichloromethane (0.43 mmol) was added and heated to 85° C. Then aqueous sodium carbonate (2M) (10 ml) was added and the reaction kept at 85° C. for 45 min. After cooling to ambient temperature the reaction was extracted with ethyl acetate/water, the organic phase was dried over sodium sulfate and concentrated. Column chromatography on silica gel (n-heptane/ethyl acetate 4:1) yielded 1.33 g of 4-(4-methoxy-3-nitro-phenyl)-3,6-dihydro-2H-pyran (66%) as a yellow solid; M.p.: 117–120° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:32]3[CH:37]=[CH:36][N+:35]([O-])=[CH:34][CH:33]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.O.[PH2]([O-])=O.[Na+].[PH2]([O-])=O.[Na+]>[Pd].C(O)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(-c3cc[n+]([O-])cc3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: [Pd]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(-c2nn(-c3ccncc3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 24 h
Yield: 10.3 %

Procedure:
A suspension of 4-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-2-indolyl)carbonyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyridiniumolate (0.200 g, 0.00039 mol) and 10% palladium on carbon (0.042 g, 0.00004 mol) in acetic acid (3 mL) was reacted with sodium hypophosphite monohydrate (0.063 g, 0.00059 mol) at 60° C. for 2 hours. Additional 10% palladium on carbon (0.042 g, 0.00004 mol) and sodium hypophosphite (0.045 g, 0.00042 mol) was added and the mixture was stirred for 24 hours. The solvent was removed in vacuo and the residue was slurried in methanol for 4 hours. The mixture was filtered through Celite® 521, washing with methanol. The solvent was removed in vacuo and the residue was purified by preparative RP-HPLC (Rainin C18, 8 mm, 300 A, 25 cm; 50% isocratic for five minutes, then 50%-100% acetonitrile—0.1M ammonium acetate over 25 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give N2-{4-[4-amino-1-(4-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide (0.020 g, 0.00004 mol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 9.48 (s, 1H) 8.72 (d, 2H), 8.47 (s, 1H), 8.42 (d, 2H), 8.20 (d, 1H), 7.72 (d, 1H), 7.60 (d, 1H), 7.48 (s, 1H), 7.42 (d, 1H), 7.36 (s, 1H) 7.34 (t, 1H), 7.16 (t, 1H), 4.05 (s, 3H), 3.99 (s, 1H); RP-HPLC (Delta Pak C18, 5 μm, 300A, 15 cm; 5%-85% acetonitrile—0.1M ammonium acetate over 20 min, 1 mL/min) Rt 19.50 min.;
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([F:13])=[C:11]([F:14])[C:10]([Br:15])=[C:9]([F:16])[C:8]=1[F:17].[C:18](=[O:20])=[O:19].Cl>O1CCCC1.O>[Br:15][C:10]1[C:11]([F:14])=[C:12]([F:13])[C:7]([C:18]([OH:20])=[O:19])=[C:8]([F:17])[C:9]=1[F:16]
Reactant: O=C=O
Reactant: Fc1c(F)c(Br)c(F)c(F)c1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1c(F)c(F)c(Br)c(F)c1F
Temperature: -70 °C
Yield: 81.5 %

Procedure:
n-Butyllithium (42 ml, 2.4M in hexane) was slowly added to a solution of 30.78 g ,1,4-dibromo-2,3,-5,6-tetrafluorobenzene in 200 ml tetrahydrofuran cooled to -70° C. under nitrogen. Solid carbon dioxide (about 12 g) was then added to the stirred mixture which was then allowed gradually to warm to 0° C. at which point 16 ml 6M hydrochloric acid and 16 ml water were added. The reaction mixture was concentrated and the residue extracted with methylene dichloride. The extract was washed with concentrated sodium chloride solution, dried (magnesium sulfate) and concentrated to dryness to give 22.23 g (81.5%) 4-bromo-2,3,5,6-tetrafluorobenzoic acid, m.p. 128°-135° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[CH3:16][O:17][CH2:18][CH2:19]Br.C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][O:13][CH2:19][CH2:18][O:17][CH3:16])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COCCBr
Reactant: CCOC(=O)C1(CO)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(COCCOC)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
1-Hydroxymethyl-cyclohexanecarboxylic acid ethyl ester (2.0 g, 10.9 mmol) is added to a solution of 60% sodium hydride (0.86 g, 21.7 mmol) in 5.0 mL of DMF at 0° C. and the reaction mixture is stirred for 30 minutes; 2-bromoethyl methyl ether (3.0 g, 21.7 mmol) is added over a period of 10 minutes and then the reaction mixture is stirred at room temperature for 14 h. Ice water and 20% ethyl acetate in petroleum ether are added. The two phases are separated and the organic layer is washed with water and brine and dried over Na2SO4. After filtration the solvent is removed under reduced pressure to provide 2.0 g of the title compound as a yellow liquid that is used in the next step without further purification. m/z 245 [M+H].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1.C(N(CC)CC)C.[C]=O.[CH3:21][OH:22].[CH2:23]([OH:25])[CH3:24]>CS(C)=O.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:11]=[C:9]1[NH:8][C:5]2=[N:6][CH:7]=[C:2]([C:21]([O:25][CH2:23][CH3:24])=[O:22])[CH:3]=[C:4]2[CH2:10]1
Reactant: CO
Reactant: O=C1Cc2cc(Br)cnc2N1
Reactant: CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCOC(=O)c1cnc2c(c1)CC(=O)N2
Temperature: 95 °C
Yield: 26 %

Procedure:
To a mixture of 5-bromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (213 mg, 1 mmol) in dimethylsulfoxide (1 ml) and ethanol (5 ml) in Parr bomb were added triethylamine (0.31 ml, 2.25 mmol), palladium acetate (33.7 mg, 0.15 mmol), and 1,4-(bisdiphenylphosphino)propane (61.9 mg, 0.15 mmol). Carbon monoxide gas (40 atm) was applied and the reaction mixture was heated at 95° C. for 18 hours with vigorous stirring. The reaction mixture was diluted with diethyl ether (50 ml) and washed with water (10 ml). The aqueous layer was thoroughly extracted with diethyl ether. The combined organic layers were dried over anhydrous MgSO4, filtered and evaporated under vacuum to give crude product. Trituration of the crude product with methanol provided the title compound as a tan solid (53 mg, 26%). 1H NMR (d6-DMSO): δ 11.39 (s, 1H), 8.62 (s, 1H), 7.95 (s, 1H), 4.27 (q, 2H, J=7 Hz), 3.59 (s, 2H), 1.28 (t, 3H, J=7 Hz). MS (−ve APCI): 205 (4, M−H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:3]=1.C1CCN2C(=NCCC2)CC1.[CH2:35]([NH:37][S:38](Cl)(=[O:40])=[O:39])[CH3:36]>C1COCC1.C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:17][C:6]1[N:5]=[C:4]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[N:3]=[C:2]([NH:1][S:38](=[O:40])(=[O:39])[NH:37][CH2:35][CH3:36])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: COc1ccccc1Oc1c(N)nc(-c2ccncc2)nc1Cl
Reactant: CCNS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCNS(=O)(=O)Nc1nc(-c2ccncc2)nc(Cl)c1Oc1ccccc1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-Amino-6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (100 mg) was dissolved in THF (5 ml) and DCM (5 ml). DBU (46 mg) and DMAP (37 mg) were added followed by the addition of ethyl-sulfamoylchloride (prepared from ethylamine hydrochloride and sulfuryl chloride). The mixture was stirred for 12 h at r.t. The solvent was evaporated. Water and a 10% solution of citric acid were added followed by extraction with EtOAc and DCM. The combined organic layers were dried over sodium sulfate and the solvent was evaporated under reduced pressure. After purification of the residue by chromatography over silicagel with EtOAc/methanol/ammonia=4:1:0.5, ethyl sulfamic acid-[6-chloro-5-(o-methoxy-phenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (10 mg) was obtained. tR=4.31 min, (LC); [M+H]+=436.14 (ES+).
Reaction SMILES: O[NH:2][C:3]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22](=[NH:25])[NH:23]O)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=[NH:4].[C:26]([O:29]C(=O)C)(=[O:28])[CH3:27]>C(O)(=O)C.[Pd]>[C:26]([OH:29])(=[O:28])[CH3:27].[C:22]([C:19]1[CH:18]=[CH:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:7]3[O:6][C:5]([C:3]([NH2:4])=[NH:2])=[CH:9][CH:8]=3)=[CH:11][CH:12]=2)=[CH:21][CH:20]=1)(=[NH:23])[NH2:25]
Reactant: N=C(NO)c1ccc(-c2ccc(-c3ccc(C(=N)NO)o3)cc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CC(=O)O
Product: N=C(N)c1ccc(-c2ccc(-c3ccc(C(=N)N)o3)cc2)cc1
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of 3 (1 mmol) in glacial acetic acid (10 mL) was slowly added acetic anhydride (0.35 mL). After stirring for overnight TLC indicated complete acylation of the starting material, then was added 10% palladium on carbon (80 mg). The mixture was placed on Parr hydrogenation apparatus at 50 psi for 4 h at room temperature. The mixture was filtered through hyflo and the filter pad washed with water. The filtrate was evaporated under reduced pressure and the precipitate was collected and washed with ether to give 5 in 71% yield, mp 236-238° C. 1H NMR (D2O/DMSO-d6); δ 1.78 (s, 2×CH3), 7.31 (d, J=3.6 Hz, 1H), 7.61 (d, J=3.6 Hz, 1H), 7.85-8.11 (m, 8H). EIMS m/e (rel. int.); 304 (M+, 20), 287 (100), 270 (50), 216 (30), 190 (10). High resolution Calc. for C18H16N4O ms 304.13241. Observed 304.13201. Anal. Calc. for C16H14N4O2-2.0AcOH-1.75H2O-0.25EtOH: C %, 57.81; H %, 6.25; N %, 11.98. Found C %, 58.18; H %, 5.90; N %, 11.56.
Reaction SMILES: Cl[C:2]1[C:3](=[O:23])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C([O-])=O.[NH4+].C(OCC)(=O)C>[Pd].CO>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:4]2[C:3](=[O:23])[CH:2]=[C:7]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[CH:6]=[N:5]2)=[CH:20][CH:19]=1
Reactant: COc1ccc(Cn2ncc(N3CCOCC3)c(Cl)c2=O)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(Cn2ncc(N3CCOCC3)cc2=O)cc1

Procedure:
To a mixture of 4-chloro-2-(4-methoxybenzyl)-5-(morpholin-4-yl)pyridazin-3(2H)-one (8.56 g, 25.50 mmol) and 10% Pd/C catalyst (1.45 g) in methanol (105 ml) was added ammonium formate (3.70 g, 58.7 mmol), and the mixture was refluxed under argon with TLC monitoring (ethyl acetate). Further portions of ammonium formate were added until the starting material was completely consumed. The catalyst was filtered off and washed with methanol, then the solvent was evaporated under reduced pressure. The residue was taken up in water (30 ml) and extracted with dichloromethane (4×40 ml). The combined extracts were washed with water, dried (Na2SO4) and evaporated. The crude product was purified by crystallization from ethanol (95%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[CH:22]=[CH:21][C:20](S(N)(=O)=O)=[CH:19][C:18]=1[N+]([O-])=O>>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:11](=[O:12])[CH2:10][C:22]12[CH2:21][CH:20]3[CH2:1][CH:2]([CH2:7][CH:18]([CH2:19]3)[CH2:17]1)[CH2:3]2)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:15]
Reactant: CCOC(=O)CCNCc1ccccc1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Product: CCOC(=O)CCN(Cc1ccccc1)C(=O)CC12CC3CC(CC(C3)C1)C2

Procedure:
The title compound was prepared by substituting 1-adamantaneacetic acid for EXAMPLE 1A and ethyl 3-(benzylamino)propanoate for 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1B.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Ni+2]>[C:1]1([C:21]2[C:16]([C:11]3[CH:10]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Ic1ccccc1-c1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Product: c1ccc(-c2ccccc2-c2ccccc2)cc1
Yield: 78 %

Procedure:
Nickel(II) acetylacetonate has affected other cross-coupling reactions, however. Mitchell and Yan, Can. J. Chem., 58, 2584 (1980), reported yields of 35-60%, 3,3"-dichloro-2,2"-dimethyl-o-terphenyl in the cross-coupling of 3-chloro-2-methylphenylmagnesium chloride with o-dibromobenzene in tetrahydrofuran using equivalent amounts of the reactants and 6 mole percent nickel(II) acetylacetonate based on the Grignard reagent. Ibuki, et al., Bull. Chem. Soc. Japan, 53, 821 (1980), reported cross-coupling two-fold excess phenylmagnesium bromide with 2-iodobiphenyl in the presence of 1.0% nickel(II) acetylacetonate based on the limiting reagent, obtaining a 78-80% yield of o-terphenyl. Clough, et al., J. Org. Chem., 41, 2256 (1976), reported cross-coupling an eight-fold excess of phenylmagnesium iodide with 1,8-diiodonaphthalene using 0.9 mole percent nickel(II) acetylacetonate based on the limiting reagent, producing 1,8-diphenylnaphthalene in 70% yield, while Corriu and Masse, J. Chem. Soc. Chem. Comm., 144 (1972), reported yields of 40 to more than 80% in cross-coupling reactions utilizing 0.1-1 percent nickel(II) acetylacetonate with respect to Grignard reagent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:4]=1C(C1C2C3=C4C(=CC=2)C=CC=C4C=CC3=CC=1)=O.CCCCC(COC(CC(S([O-])(=O)=O)C(OC[CH:46]([CH2:49][CH2:50][CH2:51][CH3:52])[CH2:47][CH3:48])=O)=O)CC.[CH:57]1[CH:62]=[C:61](O)[C:60]2[C:64]([C:66]3[C:73](O)=[CH:72][CH:71]=[CH:70][C:67]=3[C:68](=[O:69])[C:59]=2[CH:58]=1)=O.[Na+]>ClC1C=CC=CC=1>[CH3:28][O:27][C:25]1[CH:26]=[C:3]([O:2][CH3:1])[CH:4]=[CH:23][C:24]=1[C:68]([C:59]1[CH:58]=[CH:57][C:62]2[C:49]3[CH:50]=[CH:51][CH:52]=[C:47]4[C:46]=3[C:71]([C:70]3[C:61]=2[C:60]=1[CH:64]=[CH:66][CH:67]=3)=[CH:72][CH:73]=[CH:48]4)=[O:69]
Reactant: COc1ccc(C(=O)c2ccc3ccc4cccc5ccc2c3c45)c(OC)c1
Reactant: CCCCC(CC)COC(=O)CC(C(=O)OCC(CC)CCCC)S(=O)(=O)[O-]
Reactant: O=C1c2cccc(O)c2C(=O)c2c(O)cccc21
Agent: [Na+]
Solvent: Clc1ccccc1
Product: COc1ccc(C(=O)c2ccc3c4cccc5cccc(c6cccc2c63)c54)c(OC)c1
Yield: 53 %

Procedure:
The synthesis was carried out essentially as described for 2a, but chlorobenzene was used as a solven instead of methylene chloride. Yield: 53%. Found: C, 83.84; H, 4.69; C29H20O3 (MW 416.47) requires C, 83.63; H, 4.84%. Mass-spectrum, MALDI-TOF: 416.92 (100), 252.65 (60). Calculated exact mass for C29H20O3:416.14125; found 416.14125.
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[N:13]([CH3:15])[CH:12]=[C:11]2[CH2:16][C@H:17]([N:19]1[CH2:23][C@@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[O:21]C1=O)[CH3:18])=[O:5])[CH3:2].[OH-].[K+]>O.C(O)C.C(Cl)(Cl)Cl>[NH3:3].[CH2:32]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[N:13]([CH3:15])[CH:12]=[C:11]2[CH2:16][C@H:17]([NH:19][CH2:23][C@@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)[OH:21])[CH3:18])=[O:5])[CH3:33]
Reactant: CCN(CC)C(=O)c1cccc2c(C[C@@H](C)N3C[C@@H](c4cccc(Cl)c4)OC3=O)cn(C)c12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)c1cccc2c(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)cn(C)c12
Product: N
Yield: 141.4 %

Procedure:
A solution of 3-{(2 R)-2-[(5R)-5-(3-chlorophenyl)-2-oxooxazolidin-3-yl]propyl}-1H-indole-7-carboxylic acid diethylamide (10 mg, 0.022 mmol), methyl iodide (21 μL, 0.33 mmol), potassium carbonate (90 mg, 0.66 mmol) in acetone (2 mL) is refluxed for 24 hours. After cooling, the insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by preparative TLC (silica gel, 0.5 mm, 20×20 cm, methanol/chloroform=1/30) to give 3-{(2R)-2-[(5R)-5-(3-chlorophenyl)-2-oxooxazolidin-3-yl]-propyl}-1-methyl-1H-indole-7-carboxylic acid diethylamide (3 mg). A solution of 3-{(2R)-2-[(5R)-5-(3-chlorophenyl)-2-oxooxazolidin-3-yl]-propyl}-1-methyl-1H-indole-7-carboxylic acid diethylamide (3 mg, 0.0064 mmol) and potassium hydroxide (0.6 g) in water (1 mL) and ethanol (1 mL) is stirred at 70° C. for 7 hours. After cooling, ethanol is removed by distillation, and water is added thereto. The mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (60, 2 g, a saturated ammonia solution in chloroform) to give 3-{(2R)-2-[2-(3-chlorophenyl)-(2R)-2-hydroxyethyl-amino]propyl}-1-methyl-1H-indole-7-carboxylic acid diethylamide (2 mg, yield: 71%).
Reaction SMILES: [CH3:1][O:2][C:3]([F:11])([F:10])[C:4]([F:9])([F:8])[C:5](Cl)=[O:6].[CH2:12]([OH:17])[C:13]([F:16])([F:15])[F:14].N1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]([F:11])([F:10])[C:4]([F:9])([F:8])[C:5]([O:17][CH2:12][C:13]([F:16])([F:15])[F:14])=[O:6]
Reactant: OCC(F)(F)F
Reactant: COC(F)(F)C(F)(F)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(F)(F)C(F)(F)C(=O)OCC(F)(F)F
Reaction time: 8 h

Procedure:
Trifluoroethyl 3-methoxytetrafluoropropionate was prepared by reaction of 97.3 g (0.50 mol) of 3-methoxytetrafluoropropionyl chloride, 55.0 g (0.55 mol) of trifluoroethanol, and 39.5 g (0.50 mol) of pyridine in 100 mL methylene chloride. Reaction was extremely slow until the pyridine was added. After having stirred overnight, the reaction mixture was filtered, solids were rinsed with methylene chloride, and filtrates were distilled to give 119.4 g of ester, bp 44°-49° (20 mm, 2.7 kPa). The cloudy product was treated with 2 g of P2O5 and filtered to afford 109.3 g (93%) of the desired ester, pure by GC. IR (CCl4): 2855, 2975, and 3010 (sat'd CH), 1790 (C=O), and 1300-1100 cm-1 (CF, C--O).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.S(Cl)([Cl:12])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]([Cl:12])=[O:9])[S:5][CH:6]=1
Reactant: O=C(O)c1cc(Cl)cs1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(Cl)cs1

Procedure:
1.63 g (10.0 mmoles) of 4-chloro-2-thiophenecarboxylic acid (prepared according to Iriarte, J., et al., J. Het. Chem. 13:393 (1976)) was dissolved in 10 ml of thionyl chloride and heated to reflux. After refluxing for 1.5 hours excess thionyl chloride was evaporated, leaving 1.88 g of crude 4-chloro-2-thiophenecarbonyl chloride as a dark brown oil. This acid chloride was dissolved in 10 ml of N,N-dimethylformamide and slowly added to a cooled (ice-water) 40 ml N,N-dimethylformamide solution of 1.75 g (8.33 mmoles) 5-chloro-2-oxindole-1-carboxamide and 3.05 g (25.0 mmoles) of 4-(N,N-dimethylamino)pyridine. The reaction was complete in 1 hour. The mixture was poured into 100 ml of 1N hydrochloric acid causing a precipitate to form. The crude solid was filtered, dried and recrystallized to give 1.89 g (5.3 mmoles, 64% yield) of title compound as yellow needles, m.p. 212-214° C. (2-butanone).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH3:10].[I:11]Cl>CO.[OH-].[Na+]>[NH2:1][C:2]1[N:7]=[C:6]([NH2:10])[C:5]([I:11])=[C:4]([CH3:9])[N:3]=1
Reactant: N
Reactant: ClI
Reactant: Cc1cc(Cl)nc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(N)nc(N)c1I
Temperature: 0 °C
Reaction time: 14 h
Yield: 80 %

Procedure:
To a 100 mL steel pressure vessel was added 2-amino-4-chloro-6-methylpyrimidine (4.00 g, 28.00 mmol). A saturated solution of NH3 in MeOH (40 mL) was added and the vessel sealed. The pressure vessel was placed into a 160° C. oil bath and heated for 15 h. The vessel was cooled to 0° C. and opened and the solvent removed to give the crude diaminopyrimidine (4.4 g) as the HCl salt. The crude salt was dissolved in MeOH (82.5 mL), and ICl (82.5 mL) was added dropwise over 50 min. The reaction was stirred at 25° C. for 14 h and the solvent removed. The viscous oil was stirred in Et2O (300 mL) for 30 min. The resulting solid was filtered and washed with Et2O (3×20 mL) to give the crude iodinated pyrimidine as a yellow solid (10.1 g). The solids were suspended in 1.0 N NaOH (300 mL) and stirred at 25° C. for 2 h. The solids were filtered, washed with water (2×20 mL), and allowed to dry to afford 2,4-Diamino-5-iodo-6-methylpyrimidine as a white powder (5.6 g, 80%). An analytical sample was prepared by recrystallization from MeCN to give 2,4-Diamino-5-iodo-6-methylpyrimidine as colorless crystals: Rf=0.25 (9:1, CHCl3:MeOH); mp=154-156° C.; 1H NMR (DMSO-d6) δ 6.38 (s, 2H), 6.09 (s, 2H), 2.24 (s, 3H); 13C NMR (DMSO-d6) δ 166.7, 163.0, 162.3, 63.8, 28.4; HREI[M+] 249.9715 (calculated C5H71N4: 249.9715); Anal. (C5H7IN4) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[C:11]([C:19]([OH:21])=[O:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1.O.[CH2:23](O)[CH2:24][OH:25]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[C:11]([C:19]([O:21][CH2:23][CH2:24][OH:25])=[O:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: O=C(O)c1cccc2c1N=C(c1ccccc1Cl)CC2=O
Reactant: OCCO
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1CC(c2ccccc2Cl)=Nc2c1cccc2C(=O)OCCO

Procedure:
2-(2-Chlorophenyl)-4-quinolone-8-carboxylic acid (10 grams) was stirred overnight at 95° to 98° C. in a mixture of 10 ml of concentrated sulfuric acid and 100 ml of ethylene glycol. The reaction solution was poured over into water and separated crystals were collected by filtration and then washed with water. After dried, the crystals were re-crystallized from acetone to give 8.2 grams of the title compounds, pale yellow prisms, melting point 170° to 171° C.