Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:11]1[CH2:18][C@H:17]([C:19]([OH:21])=[O:20])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O>CO.[Pd]>[C:19]([C@H:17]1[CH2:18][NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:16]1)([OH:21])=[O:20]
Reactant: O=C(O)[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@H]1CN[C@H](C(=O)O)C1
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
N-CBZ-trans-4-carboxy-L-proline (0.458 g, 1.56 mmol) was dissolved in methanol (50 mL) and transferred into a Parr shaker bottle. After adding 10% Pd-C (0.080 g), the mixture was shaken under an atmosphere of hydrogen at 48-50 psi for 0.5 h on the Parr apparatus. The catalyst was removed by filtration through Celite and the filter cake was washed with water. The combined filtrate and washings were concentrated in vacuo to yield a white solid, which was recrystallized from H2O-EtOH-acetone to yield 0.187 g (75%) of 7 as colorless prisms: mp 219°-220° C. (lit. 18 mp 223°-225° C.); [α]25D -54° (c 1.04, H2O) [lit. 18 [α]20D -46.0° (c 1.0, H2O)]; 1H NMR (300 MHz, D2O) δ 4.28 (dd, J=8.6, 7.3 Hz, 1 H, H-2), 3.68-3.57 (m, 2 H, H-5), 3.38-3.29 (m, 1 H, H-4), 2.59 (ddd, J=13.7, 8.6, 6.0 Hz, 1 H, H-3), 2.42 (ddd, J=13.7, 8.1, 7.3 Hz, 1 H, H-3); 13C NMR (75.5 MHz, D2O) δ 178.99, 176.30, 63.67, 50.32, 45.24, 35.18; IR (KBr) 3600-2200 (broad), 1720, 1610, 1515, 1360, 1335, 1285, 1220, 1185 cm -1 ; LRMS (EI, 70 eV) m/e 159 (M+, 19), 114 (100), 87 (53), 68 (92). Anal. Calcd for C6H9NO4 : C, 45.28; H, 5.70; N, 8.80. Found: C, 45.21; H, 5.64; N, 8.68.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[OH-].[NH4+:14]>O>[NH2:1][CH:2]([CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH2:9])=[NH:8])[C:10]([O-:12])=[O:11].[NH4+:14]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: N=C(N)NCCCC(N)C(=O)[O-]

Procedure:
Separately, in a single-necked, round bottomed flask, equipped with a magnetic stirrer, 10.45 g (60 mmol) of Arginine is dissolved in 300 ml of water. To this is added 78 ml of 1M ammonium hydroxide with vigorous stirring, until heat production ceases. At this point the water is removed by evaporation to yield the carboxylate salt, ammonium 2-amino-5-guanidinopentanoate, shown below.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[K+].C1OCCOCCOCCOCCOCCOC1.C1(C=CC(O)=CC=1)O.Cl[CH2:35][Ge:36]([CH3:39])([CH3:38])[CH3:37].CCCCCC.C(OC)(=O)C>C(#N)C>[C:1]([O:6][CH2:35][Ge:36]([CH3:39])([CH3:38])[CH3:37])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C[Ge](C)(C)CCl
Reactant: C=C(C)C(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Oc1ccc(O)cc1
Agent: [K+]
Solvent: CCCCCC
Solvent: CC#N
Solvent: COC(C)=O
Product: C=C(C)C(=O)OC[Ge](C)(C)C
Temperature: 80 °C

Procedure:
Approximately 225 ml of acetonitrile, 48 grams of potassium methacrylate, 2 grams of 18-crown-6 ether and 1 gram of hydroquinone was placed in a round bottom flask fitted with a condenser, stirrer, and septum inlet. The reaction mixture was heated to 80° C., using a heating mantle, and through the septum inlet approximately 45 grams of chloromethyltrimethyl germanium was added by syringe, in one aliquot. The reaction mixture was maintained for 65 hours at 80° C. with stirring. The reaction mixture was then cooled and filtered by vacuum suction through a fritted glass filter. The filtered solids were then washed with approximately 125 ml of acetonitrile and the wash filtrate combined with the first filtrate. The acetonitrile in the combined filtrate was removed by heating to 35° C. under vacuum. A 10:1 by volume mixture of n-hexane and methyl acetate was prepared. Approximately 50 ml of this mixture was added to the remaining reaction product. This combined mixture was then passed through a glass column containing 45 grams of silica adsorbent immersed in the n-hexane/methyl acetate mixture. The column was then washed with the n-hexane/methyl acetate mixture until IR analysis of the eluent showed no further trimethylgermylmethyl methacrylate. The n-hexane and methyl acetate present in the eluent were then removed under vacuum at 35° C. The remaining liquid was vacuum distilled at 4 mm Hg to yield pure trimethylgermylmethyl methacrylate (boiling point 58° C. at 4 mm Hg pressure).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:27])[C:10]=1[C:11]([N:13]1[C:21]2[CH:20]=[CH:19][N:18]=[C:17]([C:22]([CH:24]3[CH2:26][CH2:25]3)=[O:23])[C:16]=2[CH:15]=[CH:14]1)=[O:12])[C:5](O)=[O:6].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:49][N:50]([CH3:54])[CH2:51][CH2:52][NH2:53].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:27])[C:10]=1[C:11]([N:13]1[C:21]2[CH:20]=[CH:19][N:18]=[C:17]([C:22]([CH:24]3[CH2:25][CH2:26]3)=[O:23])[C:16]=2[CH:15]=[CH:14]1)=[O:12])[C:5]([NH:53][CH2:52][CH2:51][N:50]([CH3:54])[CH3:49])=[O:6]
Reactant: O=C(O)c1cc(Cl)c(C(=O)n2ccc3c(C(=O)C4CC4)nccc32)c(Cl)c1
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1cc(Cl)c(C(=O)n2ccc3c(C(=O)C4CC4)nccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.5 %

Procedure:
To a stirred solution of 3,5-dichloro-4-{[4-(cyclopropylcarbonyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]carbonyl}benzoic acid (40 mg, 0.095 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (22 mg, 0.115 mmol) and 15 mg 1-hydroxybenzotriazole (15 mg, 0.115 mmol) in dimethylformamide, was added N,N-dimethylethane-1,2-diamine (8.4 mg, 0.095 mmol). The resulting reaction mixture was stirred at room temperature for about 16 hours. The reaction mixture was poured drop wise into ie-cooled saturated aquoeus sodium bicarbonate solution. The precipitated solid was filtered, washed with water and dried under vacuum. The solid thus obtained was triturated with diethyl ether, filtered and dried to get 3,5-dichloro-4-{[4-(cyclopropylcarbonyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]carbonyl}-N-[2-(dimethylamino)ethyl]benzamide (11 mg, 25%).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14](=[CH:20][C:21]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([OH:29])=O)[C:22]=3[CH3:30])[C:15](=[O:19])[NH:16]2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([N:33]([CH2:37][CH3:38])[CH2:34][CH2:35][NH2:36])[CH3:32].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:31]([N:33]([CH2:37][CH3:38])[CH2:34][CH2:35][NH:36][C:27]([C:23]1[C:22]([CH3:30])=[C:21]([CH:20]=[C:14]2[C:13]3[C:17](=[CH:18][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:11][CH:12]=3)[NH:16][C:15]2=[O:19])[NH:25][C:24]=1[CH3:26])=[O:29])[CH3:32]
Reactant: Cc1[nH]c(C=C2C(=O)Nc3cc(NC(=O)c4ccccc4)ccc32)c(C)c1C(=O)O
Reactant: CCN(CC)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cc(NC(=O)c4ccccc4)ccc32)c1C
Reaction time: 2 h

Procedure:
To a solution of N-(2-oxo-2,3-dihydro-1H-indol-6-yl)-benzamide (80 mg, 0.32 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (53 mg, 0.32 mmol) in ethanol (8 ml) is added 4 drops of piperidine. It is stirred at 80° C. for 20 hours and then cooled to room temperature. The precipitate is collected by vacuum filtration, washed with a small amount of cold ethanol to give crude 5-(6-benzoylamino-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid. This carboxylic acid (20 mg, 0.050 mmol) is then dissolved in DMF (1 ml). To this reaction is also added N, N-diethylethylenediamine (17 mg, 0.15 mmol), N,N-diisopropylethylamine (19 mg, 0.15 mmol) and HATU (23 mg, 0.061 mmol). It is stirred for 2 hours and concentrated. The desired compound is obtained after HPLC purification: 1H NMR (DMSO-d6) δ 1.24 (t, 6H, J=7.2 Hz), 2.43 (s, 3H), 2.47 (s, 3H), 3.20-3.24 (m, 6H), 3.57 (q, 2H, J=5.4 Hz), 7.38 (d, 1H, J=6.6 Hz), 7.53 (t, 2H, J=7.2 Hz), 7.56 (s, 1H), 7.58-7.61 (m, 2H), 7.73-7.77 (m, 2H), 7.96 (d, 2H, J=7.8 Hz), 9.32 (s, 1H), 10.27 (s, 1H), 10.97 (s, 1H), 13.60 (s, 1H); LC-MS: 500.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]2[N:6]([CH2:14][C:15](=O)[CH2:16][CH3:17])[C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Cl.[NH2:23][OH:24].N1C=CC=CC=1.O>C(O)C>[Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]2[N:6]([CH2:14][C:15](=[N:23][OH:24])[CH2:16][CH3:17])[C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1
Reactant: NO
Reactant: CCC(=O)Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: CCC(Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21)=NO

Procedure:
1-[5,6-Dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-butan-2-one (339 mg, 1 mmol), hydroxylamine hydrochloride (227.5 mg, 3.25 mmol) and pyridine (3 mL) in ethanol (3 mL) were heated to 70° C. for 5 hours. The reaction mixture was then poured into water and extracted with EtOAc. The organic layer was washed with 15% NaCl, brine, then dried over anhydrous MgSO4. The solvent was distilled out under reduced pressure. Column chromatography (silica gel, EtOAc/hexanes (0% to 60%) yielded the title compound as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:4]=1[O:5][CH2:6][CH:7]=[O:8])=O>C(O)(=O)C>[CH:7]([C:6]1[O:5][C:4]2[C:9]([O:13][CH3:14])=[CH:10][CH:11]=[CH:12][C:3]=2[CH:1]=1)=[O:8]
Reactant: COc1cccc(C=O)c1OCC=O
Solvent: CC(=O)O
Product: COc1cccc2cc(C=O)oc12

Procedure:
2-(2-Formyl-6-methoxyphenoxy)acetaldehyde, dimethyl acetal (31 g) was heated to reflux in glacial acetic acid (120 ml) overnight. The mixture was then cooled and the solvent removed in vacuo to give a red oil. Purification by Kugelrohr distillation gave the title compound (17 g) as a pale yellow oil which solidified on standing.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([C:15]([F:18])([F:17])[F:16])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>CO.[OH-].[OH-].[Pd+2]>[NH2:12][C:11]1[C:2]([CH3:1])=[C:3]([CH:8]=[C:9]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cc(C(F)(F)F)cc(N)c1C
Reaction time: 3 h
Yield: 57.6 %

Procedure:
To a stirred solution of methyl 2-methyl-3-nitro-5-(trifluoromethyl)benzoate (20.0 g, 76.0 mmol) in MeOH (400 ml) was added Pd(OH)2 (2.00 g). The reaction mixture was stirred for 3 hours under hydrogen atmosphere. After purging with nitrogen, the mixture was filtered and the filtrate was concentrated in vacuo to give the titled compound as an orange solid (10.2 g, 58% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.47 (brs, 1H), 7.01 (d, J=2.0 Hz, 1H), 3.92 (m, 2H), 3.91 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:28])=[O:27])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=S(=O)(Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1)c1ccccc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and benzenesulfonyl chloride. 1H NMR (DMSO-d6) δ: 7.57-7.76 (m, 9H), 7.92 (d, 1H), 8.01 (d, 1H), 8.15 (s, 1H), 8.77 (s, 1H), 10.59 (s, 1H); MS (ES): 411.99 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10]C)=[O:9])[C:4]([O:12][CH2:13][C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[S:25][C:26]=3[CH3:27])=[CH:18][CH:19]=2)=[N:3]1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4]([O:12][CH2:13][C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[S:25][C:26]=3[CH3:27])=[CH:18][CH:19]=2)=[N:3]1
Reactant: COC(=O)Cc1cn(C)nc1OCc1ccc(OCc2nc(-c3ccccc3)sc2C)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(COc2nn(C)cc2CC(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
A mixture of methyl [1-methyl-3-[6-(5-methyl-2-phenyl-4-thiazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]acetate (497 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (2 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [1-methyl-3-[6-(5-methyl-2-phenyl-4-thiazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]acetic acid (411 mg, yield 85%), which was then recrystallized from ethanol-hexane. melting point: 140–141° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][C:11](=[O:19])[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)[CH2:4][CH2:3]1.CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH:11]([OH:19])[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)[CH2:4][CH2:3]1
Reactant: CN1CCC(=C2c3ccccc3CC(=O)c3ccccc32)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CN1CCC(=C2c3ccccc3CC(O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3.0 g. (0.01 mole) of 1-methyl-4-(10,11-dihydro-10-oxo-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (0.01 mole) in 200 ml. of dry ether is added dropwise in a dry inert atmosphere to a stirred suspension of 3.8 g. (0.1 mole) of lithium aluminum hydride. The reaction is then stirred overnight (20 hours) at room temperature under a dry inert atmosphere. Then there is added dropwise carefully with stirring 3 ml. of water followed by 3 ml. of 20% NaOH solution in water followed by 15 ml. of water. The ether solution of the product is decanted and the remaining salts washed with ether and decanted. The combined ether solutions of the product are dried over anhydrous MgSO4, filtered, and the ether evaporated on a rotary evaporator. This gives after one recrystallization from ethanol 1-methyl-4-(10,11-dihydro-10-hydroxy-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, m.p. 205°-206°C.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]([O-])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[N:8][CH:7]=1.ONC(=O)CCC(N)=O>CN(C)C=O>[OH:2][CH2:1][CH2:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[N:8][CH:7]=1
Reactant: O=C([O-])c1cccnc1
Reactant: NCCO
Agent: NC(=O)CCC(=O)NO
Solvent: CN(C)C=O
Product: O=C(NCCO)c1cccnc1
Yield: 73 %

Procedure:
The ethanolamine was dissolved in dried N,N-di-methyl formamide (DMF) and chilled in an ice bath. The nicotinate derivative, also dissolved in DMF, was added to the DMF-amine mixture, dropwise under a nitrogen atmosphere. As the nicotinate derivative was added, the mixture turned milky and was slurried for at least one half hour. The milky substance was the N-hydroxy-succinamide precipitating, which was filtered off. The DMF-mixture was washed with ether to remove any precipitant. The solvent mixture was removed under high vaccum. The oily residue was triturated with ether, yielding a precipitant, N-(2-hydroxyethyl)-nicotinamide, which was recrystallized from ethyl acetate/petroleum ether. This compound had a melting point of 86°-87° C.; and Rf value of 0.30 (TLC: silica: chloroform/methanol (10:1)); and a yield of 73%.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C@@H:22]([CH3:33])[CH2:23][O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27](SC)[N:26]=3)[CH2:17][CH2:16]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].OO.C(=O)(O)[O-:37].[Na+]>C(O)(=O)C>[C:1]([C:5]1[N:6]=[C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C@@H:22]([CH3:33])[CH2:23][O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([OH:37])[N:26]=3)[CH2:17][CH2:16]2)[CH:8]=[C:9]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: CSc1nccc(OC[C@H](C)CN2CCN(c3cc(C4CCC4)nc(C(C)(C)C)n3)CC2)n1
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@@H](COc1ccnc(O)n1)CN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1.3 g of (R)-2-tert-butyl-4-cyclobutyl-6-{4-[2-methyl-3-(2-methylsulfanyl-pyrimidin-4-yloxy)-propyl]-piperazin-1-yl}-pyrimidine (2.76 mmol) were dissolved in 15 ml of acetic acid. 2.5 g of aqueous hydrogen peroxide (22.1 mmol, 30% in water) were added at 0° C. The reaction mixture was stirred for 15 h at room temperature, poured onto water and the aqueous phase was adjusted to alkaline pH with saturated sodium bicarbonate solution. After extraction with ethyl acetate, the organic phase was dried over magnesium sulfate, filtered, and the solvent evaporated. The crude product was purified by chromatography on silica gel using dichloromethane-methanol (2%), fractions containing the product were combined, the solvent was evaporated, and the residue treated with acetonitril, filtered and dried to yield 0.13 g of the title compound as a white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](B(O)O)=[CH:3][N:2]=1.[N:14]1([CH2:19][C:20]2[CH:21]=[CH:22][C:23](Br)=[N:24][CH:25]=2)[CH:18]=[CH:17][N:16]=[CH:15]1>>[N:14]1([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=[N:2][CH:3]=3)=[N:24][CH:25]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: OB(O)c1cncc2ccccc12
Product: c1ccc2c(-c3ccc(Cn4ccnc4)cn3)cncc2c1

Procedure:
Synthesized using 4-isoquinolinylboronic acid (218 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 97 mg, 0.34 mmol, 54%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.26 (s, 2H), 7.00 (t, J=1.3 Hz, 1H), 7.16 (brs, 1H), 7.58-7.66 (m, 4H), 7.70-7.73 (m, 1H), 8.04 (d, J=8.2 Hz, 1H), 8.17 (dd, J=8.5, 0.6 Hz, 1H), 8.62 (s, 1H), 8.71 (d, J=1.6 Hz, 1H), 9.30 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.1, 119.1, 124.5, 125.0, 127.4, 128.0, 128.5, 130.0, 130.4, 130.8, 131.1, 133.6, 135.7, 137.4, 143.5, 148.5, 153.4, 156.6; MS (ESI): m/z=287.10 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[Br:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C)c1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc(CBr)c1Br
Yield: 47.4 %

Procedure:
A procedure similar to that described in Bull. Chem. Soc. Japan, 59, 3285–3286 (1986), fully incorporated herein by reference, was used. In a two liter round bottom flask equipped with an overhead stirrer and heating mantle was placed 2-bromo-meta-xylene (60.08 g, 0.325 mol) and carbon tetrachloride (650 ml). To this were added N-bromosuccinimide (57.78 g, 0.325 mol) and an additional 550 ml carbon tetrachloride. After stirring fifteen minutes benzoyl peroxide (0.72 g, 2.9 mmol, 0.9 mole %) was added, and the mixture was heated to reflux. After four hours the reaction was cooled, and the carbon tetrachloride was removed. The residue was taken up in 10% methylene chloride in n-hexane (600 ml) and filtered through silica (250 g). The filter cake was washed with an additional 400 ml of the in 10% methylene chloride in n-hexane. The filtrate was evaporated to give a clear liquid (74.22 g, 51% conversion by NMR). Vacuum distillation produced a fraction distilling at 72° C.–80° C. at 0.1 Torr as a water white liquid (40.62 g, 47% yield). NMR (CD2Cl2). 7.2 (m, 3H), 4.62 (s, 2H), 2.4 (s, 3H). Elemental analysis: C, 36.18%; H, 3.12%; Br, 61.14%; (theory: C, 36.40%; H, 3.06%; Br, 60.54%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([F:35])([F:34])[CH:31]1[O:33][CH2:32]1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.O.C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:27])([F:28])[CH:24]([F:25])[F:26])[CH:17]=2)[CH2:32][CH:31]([OH:33])[C:30]([F:35])([F:34])[F:29])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)C(F)(F)Oc1cccc(CNc2cccc(Oc3ccccc3)c2)c1
Reactant: FC(F)(F)C1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Temperature: 50 °C
Yield: 62.9 %

Procedure:
To a mixture of the amine product (15.0 g, 0.038 mol) from EX-1B and 1,1,1-tri-fluoro-2,3-epoxypropane (8.58 g, 0.077 mol, TCI) was added a suspension of ytterbium (III) trifluoromethanesulfonate (2.37 g, 0.0031 mol) in 15 mL of acetonitrile. The resulting mixture was heated at 50° C. in a sealed glass vial for 1.5 h. The reaction mixture was cooled to room temperature then diluted with water and ethyl acetate and extracted. The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:4 ethyl acetate in hexane to afford 12.03 g (62%) of the desired (2RS)-3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy) phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil. Anal. calcd. for C24H20F7NO3: C, 57.26; H, 4.00; N, 2.78. Found: C, 56.96; H, 4.35; N, 2.69. HRMS calcd. 504.1410 [M+H]+. found: 504.1431. 1H NMR (CDCl3) δ 7.28 (m, 4H), 7.14 (t, 1H), 7.07, (m, 3H), 7.00 (s, 1H), 6.94 (d, 2H), 6.46 (dd, 1H), 6.38 (dd, 1H), 6.35 (t, 1H), 5.84 (t, 1H), 4.60 (t, 2H), 4.36 (m, 1H), 3.82 (d, 1H), 3.48 (m, 1H), 2.51 (s, 1H). 19F NMR (CDCl3) δ −79.0 (s, 3F), −88.21 (d, 2F), −137.05 (dd, 2F).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)=[O:4].[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1.C(N(C(C)C)CC)(C)C>O1CCCC1>[N:15]1([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=2)=[O:4])[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: CCCOc1ccc(C(=O)CBr)cc1
Reactant: c1nc[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCOc1ccc(C(=O)Cn2cncn2)cc1
Yield: 30.4 %

Procedure:
By substantially following the procedure of Example 608a using 29 g of 2-bromo-4'-propoxyacetophenone (Example 585b), 10 g of 1,2,4-triazole, 15 g (116 mmole) of diisopropylethylamine, and 100 ml of tetrahydrofuran, 8.4 g of the desired compound, mp 97°-99° C., was obtained.