Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.[C:25]([C:29]1[CH:30]=[C:31](C(O)=O)[N:32]([C:34]2[CH:35]=[N:36][C:37]([CH3:40])=[N:38][CH:39]=2)[N:33]=1)([CH3:28])([CH3:27])[CH3:26].C(C1C=C([NH:54][C:55]([NH:57][C:58]2[C:67]3[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=3)[C:61]([O:68][C:69]3[CH:74]=[CH:73][N:72]=[C:71]([NH:75][CH2:76][CH:77]4[CH2:79][CH2:78]4)[N:70]=3)=[CH:60][CH:59]=2)=[O:56])N(C)N=1)(C)(C)C>C(COC)OC.C1COCC1>[C:25]([C:29]1[CH:30]=[C:31]([NH:54][C:55]([NH:57][C:58]2[C:67]3[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=3)[C:61]([O:68][C:69]3[CH:74]=[CH:73][N:72]=[C:71]([NH:75][CH2:76][CH:77]4[CH2:79][CH2:78]4)[N:70]=3)=[CH:60][CH:59]=2)=[O:56])[N:32]([C:34]2[CH:39]=[N:38][C:37]([CH3:40])=[N:36][CH:35]=2)[N:33]=1)([CH3:26])([CH3:27])[CH3:28]
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(Oc2ccnc(NCC3CC3)n2)c2ccccc12
Reactant: Cc1ncc(-n2nc(C(C)(C)C)cc2C(=O)O)cn1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: Cc1ncc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(NCC4CC4)n3)c3ccccc23)cn1
Temperature: 85 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
Diphenylphosphoryl azide (DPPA) (0.09 mL, 0.423 mmol, 1.1 equiv.) and triethylamine (0.075 mL, 0.54 mmol, 1.4 equiv.) were added to 5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazole-3-carboxylic acid (100 mg, 0.384 mmol, 1.0 equiv.) in 2.0 mL anhydrous dimethoxyethane in a sealed tube. The mixture was heated at 85° C. for 2.5 h, then a solution of the cyclopropylmethylaminopyrimidine-ether intermediate (see Example 4)(118 mg, 0.38 mmol, 1.0 equiv.) in 3.0 mL anhydrous THF was added and the resulting mixture stirred at room temperature overnight. The solvent was removed in vacuo and the crude urea was purified by column chromatography on silica gel using 0–65% EtOAc in hexanes eluent mixtures. The product was purified further by prep-HPLC affording 15 mg of the title compound (7% yield).
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([Cl:11])=[C:5]2[S:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.O1CCOCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.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].C(Cl)Cl>[Cl:11][C:10]1[CH:9]=[CH:8][N:7]=[C:6]2[C:2]([C:16]3[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=3)=[CH:3][S:4][C:5]=12
Reactant: Clc1ccnc2c(Br)csc12
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Fc1ccc(-c2csc3c(Cl)ccnc23)cc1
Temperature: 90 °C
Yield: 84.8 %

Procedure:
A vessel capable of sealing was charged with a mixture of 3-bromo-7-chlorothieno[3,2-b]pyridine (500 mg, 2.012 mmol), 4-fluorophenylboronic acid (310 mg, 2.213 mmol), PdCl2(dppf)-CH2Cl2 adduct (82 mg, 0.101 mmol), dioxane (8 mL), and a 2.0 M aqueous solution of K3PO4 (3 mL, 6.04 mmol) and was purged with nitrogen for 10 min. The vessel was sealed and heated at 90° C. for 1 h. Upon cooling, the reaction mixture was diluted with water and extracted with CH2Cl2. The combined organics were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by BIOTAGE® eluting with 40%-80% EtOAc/CH2Cl2 at 30 mL/min. Concentration of appropriate fractions provided the title compound (450 mg, 49% yield) as a white powder. LC/MS: Example 98A @ 3.62 min (RT) (Condition G). MS (ES): m/z=263.03, [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1>C(O)(C)C.CC(C)=O.C(#N)C.O=[Mn]=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1
Reactant: OCc1ccc(O)cn1
Agent: O=[Mn]=O
Solvent: CC#N
Solvent: CC(C)=O
Solvent: CC(C)O
Product: O=Cc1ccc(O)cn1
Reaction time: 20 h
Yield: 21.8 %

Procedure:
A mixture of 5-hydroxy-2-hydroxymethylpyridine (14 g) and MnO2 (100 g) in isopropylalcohol (600 mL) was stirred under N2 for 20 h. The reaction mixture was filtered and filtrate concentrated under vacuum affording a crude product as a solid (12 g). It was suspended in acetone/acetonitrile (25 mL each) and the solid residue was filtered off. It was washed with cold acetone/acetonitrile 1:1 mixture to give pure 5-hydroxypyridine-2-carboxaldehyde (3 g) as a solid.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:11])=[C:6]([C:18]([F:21])([F:20])[F:19])[CH:5]=1)=[N+]=[N-].[H-].[Li+].[Al+3].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1.O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[OH:11])=[C:6]([C:18]([F:21])([F:19])[F:20])[CH:5]=1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)c2ccccn2)c(C(F)(F)F)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(C(O)c2ccccn2)c(C(F)(F)F)c1
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a suspension of [4-azido-2-(trifluoromethyl)phenyl](2-pyridyl)methanone (2.0 g) in THF (20 ml) was added dropwise a solution of aluminum lithium hydride (520 mg) in. THF (20 ml) at 0° C. under nitrogen atmosphere. After finishing the dropping, the mixture was allowed to be at room temperature, and the mixture was stirred for 1 hour. Water (0.52 ml), 15% aqueous solution of sodium hydroxide (0.52 ml) and water (1.6 ml) were sequentially added to the mixture at 0° C., and the mixture was allowed to be at room temperature and the mixture was stirred overnight. Magnesium sulfate was added to the mixture, and the unnecessary substances were filtered off. The solvent was distilled off under reduced pressure and the obtained residue was recrystallized from hexane-ethyl acetate, to give [4-amino-2-(trifluoromethyl)phenyl](2-pyridyl)methanol (1.51 g) as colorless crystals.
Reaction SMILES: Cl[CH:2]([CH3:5])[C:3]#[N:4].Cl.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH:16]2[CH2:21][CH2:20][N:19]([CH:2]([CH3:5])[C:3]#[N:4])[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CC(Cl)C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C#N)N1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 100 °C

Procedure:
A mixture of 25 parts of 2-chloropropanenitrile, 61 parts of (4-fluorophenyl)(4-piperidinyl)methanone hydrochloride, 63 parts of sodium carbonate and 160 parts of acetonitrile is stirred and refluxed (100° C.) overnight. The reaction mixture is cooled, water is added and the layers are separated. The aqueous phase is extracted with 4-methyl-2-pentanone. The combined organic phases are dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane, hexane and methanol (50:49:1 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is crystallized from 2,2'-oxybispropane. The product is filtered off, and dried yielding 17 parts of 4-(4-fluorobenzoyl)-α-methyl-1-piperidineacetonitrile; mp. 126.7° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH:25]([CH:28]1[NH:32][C:31](=[O:33])[N:30]([CH3:34])[C:29]1=[O:35])([CH3:27])[CH3:26]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:32]4[CH:28]([CH:25]([CH3:26])[CH3:27])[C:29](=[O:35])[N:30]([CH3:34])[C:31]4=[O:33])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC(C)C1NC(=O)N(C)C1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4C(C)C)cc3F)CC2)c(C)c1
Yield: 59.3 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (157 mg) described in Preparation Example 114 and 5-isopropyl-3-methylimidazolidine-2,4-dione (69 mg) described in Preparation Example 216 and by the reaction and treatment in the same manner as in Example 536, the title compound (111 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([C:25]([OH:27])=[O:26])[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38].C(O)(=O)C>CN(C)C=O>[CH3:38][C:37]([CH3:40])([CH3:39])[C:36](=[O:41])[CH2:35][O:26][C:25]([C:11]1([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:22])[Cl:23])=[O:18])[CH2:12]1)=[O:27]
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCCC(C(=O)O)(C(=O)OCc2ccccc2)C1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)COC(=O)C1(C(=O)OCc2ccccc2)CCCN(C(=O)OCC(Cl)(Cl)Cl)C1
Temperature: 60 °C

Procedure:
A mixture of piperidine-1,3,3-tricarboxylic acid 1-(2,2,2-trichloroethyl) 3-benzyl ester (3.9 g 8.8 mmol), potassium carbonate (1.83 g 13 mmol) and bromopinacolone (2.31 g 13 mmol) in N,N-dimethylformamide (55 mL) is heated at 60° C. for 2 h. The mixture is cooled back to room temperature, neutralized with acetic acid (13 mmol) and concentrated under reduced pressure. the residue is dissolved in ethyl acetate, washed with water and concentrated. Cristallization in diethyl oxide gives piperidine-1,3,3-tricarboxylic acid 1-(2,2,2-trichloroethyl) 3-benzyl 3-(3,3-dimethyl-2-oxobutyl)ester melting at 114° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][CH2:11][OH:12].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl.[Cl-].[Na+].O>[CH3:20][S:21]([O:12][CH2:11][CH2:10][CH2:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])(=[O:23])=[O:22]
Reactant: OCCCc1c(Cl)cccc1Cl
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(2,6-dichlorophenyl)-1-propanol (125 mg, 0.61 mmol) and triethylamine (123 mg, 1.22 mmol) in methylene chloride (3 mL), methanesulfonyl chloride (105 mg, 0.915 mmol) was added under ice cooling, followed by stirring at room temperature for 2 hours. Brine was added to the reaction mixture. The organic layer was allowed to separate, was collected, and was then dried over anhydrous sodium sulfate. Subsequent to concentration under reduced pressure, the residue was purified by chromatography on a silica gel column (hexane/ethyl acetate=10/1) to yield the title compound as a pale yellow syrupy substance (yield: quantitative).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14].[F-].[K+]>C1(C)C=CC=CC=1>[CH2:14]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)[CH:13]=[CH2:12]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cccc2ncccc12
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=CCc1cccc2ncccc12
Reaction time: 3 h
Yield: 95.9 %

Procedure:
5-Bromo-quinoline (5.6 g, 27 mmol) was dissolved in 40 mL toluene. BHT (50 mg) was added, along with allyl tributyl stannane (9.3 mL, 30 mmol), and tetrakis(triphenyl)phospine palladium (600 mg, 0.52 mmol). The reaction was refluxed overnight, then cooled. Potassium fluoride solution (1.0 g, in 18 mL H2O) was added. The reaction was stirred for 3 hours, then filtered. The reaction mixture was concentrated in vacuo. It was chromatographed in 3:1 hexane/ethyl acetate to yield 4.38 g (95%) of 5-allyl-quinoline as a yellow oil. MS (APCI) m/z 170.1 (M+1).
Reaction SMILES: [CH:1](=[N:8][C:9]1C=CC=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NCCC[Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21].[SiH4]>C1(C)C(C)=CC=CC=1>[C:2]1([CH:1]=[N:8][CH2:9][CH2:10][CH2:11][Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[Si](CCCN)(OC)OC
Reactant: C(=Nc1ccccc1)c1ccccc1
Agent: [SiH4]
Solvent: Cc1ccccc1C
Product: CO[Si](CCCN=Cc1ccccc1)(OC)OC
Temperature: 90 °C

Procedure:
25 grams (0.138 moles) of N-benzylidene aniline [cas no. 538-51-2, from TCI America] was combined with 24.7 grams (0.138 moles) of gamma-aminopropyltrimethoxysilane [cas no. 13822-56-5, Silquest A-1110 Silane from Crompton Corporation] and 100 grams of xylene. The resulting slurry was warmed to 90° C. for one hour before a vacuum of 20 mm Hg was applied. Distillation of the xylene and aniline resulted in 36 grams (98%) of N-benzylidene aminopropyltrimethoxysilane [cas no. 67674-55-9] by GC analysis.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl[C:14]1[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=1.[N:24]1([CH2:30][C:31]2[CH:32]=[C:33]([NH2:43])[CH:34]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:36]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>O1CCOCC1.C(OCC)(=O)C>[N:24]1([CH2:30][C:31]2[CH:32]=[C:33]([NH:43][C:14]3[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=3)[CH:34]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:36]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: Nc1cc(CN2CCOCC2)cc(-c2ccccc2)c1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)c1ccnc(Nc2cc(CN3CCOCC3)cc(-c3ccccc3)c2)n1
Temperature: 80 °C

Procedure:
p-Toluenesulfonic acid monohydrate (75 mg, 0.395 mmol) was added to a solution of 2-chloro-4-(trifluoromethyl)pyrimidine (36 mg, 0.198 mmol) and 5-(morpholin-4-ylmethyl)biphenyl-3-amine (53 mg, 0.198 mmol) in dioxane (1.98 mL) and heated to 80° C. for 14 hours, then allowed to cool to room temperature. The mixture was diluted with ethyl acetate (30 mL) and washed with saturate aqueous NaHCO3 (30 mL) and 1:1 water: brine (2×30 mL). The organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (thyl acetate/hexanes) provided N-[5-(morpholin-4-ylmethyl)biphenyl-3-yl]-4-(trifluoromethyl)pyrimidin-2-amine. MS ESI calc'd. for C22H22F3N4O [M+H]+ 415, found 415. 1H NMR (400 MHz, CDCl3): δ 8.67 (d, J=4.9 Hz, 1H); 7.90 (s, 1H); 7.66 (d, J=7.7 Hz, 2H); 7.58 (s, 1H); 7.51-7.42 (m, 3H); 7.39 (t, J=7.4 Hz, 1H); 7.33 (s, 1H); 7.06 (d, J=4.9 Hz, 1H); 3.76 (t, J=4.5 Hz, 4H); 3.61 (s, 2H); 2.54 (t, J=4.2 Hz, 4H).
Reaction SMILES: [C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[NH:14][CH2:13][CH:12]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=3)=[O:24])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:39](Cl)(=[O:44])[CH2:40][CH:41]([CH3:43])[CH3:42].N1C=CC=CC=1.O>ClCCCl.C(Cl)Cl>[C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:39](=[O:44])[CH2:40][CH:41]([CH3:43])[CH3:42])[CH2:13][CH:12]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=3)=[O:24])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)CC(=O)Cl
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CNc3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)CC(C)C)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (400 mg) obtained from Step 1 of Example 93 was suspended in 1,2-dichloroethane (10 ml), isovaleryl chloride (104 μl) and pyridine (70 μl) were added, and the mixture was refluxed for 1 hour and 30 minutes. Water and methylene chloride were added to the reaction mixture, separated, and the organic layer was successively washed with 1N hydrochloric acid and saturated aqueous sodium bicarbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 296 mg of the titled compound.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:17]=2)=[C:10]([CH3:33])[CH:9]=1)=[O:6])C.[OH-].[Na+]>CCO>[F:32][C:29]1[CH:28]=[CH:27][C:26]([S:23]([C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=2[OH:22])[O:15][C:11]2[C:12]([CH3:14])=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]([OH:34])=[O:3])=[CH:9][C:10]=2[CH3:33])(=[O:25])=[O:24])=[CH:31][CH:30]=1
Reactant: CCOC(=O)C(=O)Nc1cc(C)c(Oc2ccc(O)c(S(=O)(=O)c3ccc(F)cc3)c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(NC(=O)C(=O)O)cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Reaction time: 1 h

Procedure:
A solution of the title E compound, N-{4-[3-(4-fluorobenzenesulfonyl)-4-hydroxy-phenoxy]-3,5-dimethylphenyl}oxamic acid ethyl ester (773 mg, 1.58 mmol) in 15 mL of EtOH is treated with aqueous 1N sodium hydroxide (NaOH; 4.75 mL, 4.75 mmol) at RT. After 1 h, the reaction is quenched with aqueous 1N HCl (5.5 mL) and the product is taken up in EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated. The product is triturated with Et2O and dried in vacuo to afford N-{4-[3-(4-fluorobenzenesulfonyl)-4-hydroxyphenoxy]-3,5-dimethylphenyl}oxamic acid: NMR (DMSO-d6) 2.06 (s, 6H), 6.88 (d, 1H, J=9), 7.03 (dd, 1H, J=9,3), 7.13 (d, 1H, J=3), 7.43 (appt, 2H, J=9), 7.61 (s, 2H), 7.94 (dd, 2H, J=9,5), (s, 10.5 (s, 1H), 10.69 (s, 1H); IR (KBr) 1240, 1481, 1685, 1764; ESI-MS 458 [M−1]−.
Reaction SMILES: C(O[CH:5]1[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH:7]=[CH:6]1)(=O)C.[N-:22]=[N+:23]=[N-:24].[Na+].O1CCCC1.O>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C(OCC)(=O)C>[C:10]1([C:9]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][CH:7]([N:22]=[N+:23]=[N-:24])[CH:6]=[CH:5]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)OC1C=CCC1(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC1C=CC(c2ccccc2)(c2ccccc2)C1
Reaction time: 14.5 h
Yield: 56.8 %

Procedure:
To a mixture of 5,5-diphenyl-2-cyclopentenyl acetate (0.30 g) and sodium azide (84 mg) in a solution of tetrahydrofuran (3 ml) and water (1.5 ml) was added tetrakis(triphenylphosphine)palladium(O) (62 mg) at room temperature under an argon atmosphere. After being stirred for 14.5 hours, ethyl acetate was added. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of n-hexane and ethyl acetate as an eluent to give 4,4-diphenyl-2-cyclopentenyl azide (0.16 g).
Reaction SMILES: CS(C)=O.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH:13](Br)([CH2:15][CH3:16])[CH3:14].[OH:18][C:19]1[C:28]([OH:29])=[C:27]2[C:22]([C:23](=[O:32])[CH2:24][C:25]([CH3:31])([CH3:30])[O:26]2)=[CH:21][CH:20]=1>COCCOCCOC>[CH:13]([O:18][C:19]1[C:28]([OH:29])=[C:27]2[C:22]([C:23](=[O:32])[CH2:24][C:25]([CH3:30])([CH3:31])[O:26]2)=[CH:21][CH:20]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: CCC(C)Br
Reactant: CC1(C)CC(=O)c2ccc(O)c(O)c2O1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: CS(C)=O
Product: CCC(C)Oc1ccc2c(c1O)OC(C)(C)CC2=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
In 80 ml of dimethyl sulfoxide 4.2 g (20 millimoles) of 7.8-dihydroxy-2,2-dimethyl-4-chromanone are dissolved, whereupon 10 ml of diethylene glycol dimethylether, 4.1 g (30 millimoles) of potassium carbonate, 0.5 g of potassium iodide and 3.3 (2.6 ml, 24 millimoles) of sec. butyl bromide are added. The reaction mixture is heated at 100° C. for 10 hours, poured onto 200 ml of crushed ice and extracted with 100 ml of carbon tetrachloride. To the aqueous phase 20 ml of 10% sodium hydroxide solution are added, the mixture is cooled to 0° C., acidified with concentrated hydrochloric acid and stirred at 0° C. for 2 hours. The product is filtered, washed twice with 20 ml of water, dried and crystallized from 20% ethanol. Thus 4.4. g of the desired compound are obtained, yield 83%, mp.: 108°-110° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]([C@@:18]2([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[CH2:20][O:19]2)[CH3:17])=[C:9](Cl)[N:8]=1>>[N:1]1([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@H:16]([CH3:17])[C@:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])([OH:19])[CH2:20][N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[C:9]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[N:8]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: C[C@@H](n1cnc2c(Cl)nc(Cl)nc21)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Product: C[C@@H](n1cnc2c(-n3cncn3)nc(-n3cncn3)nc21)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 14.6 %

Procedure:
Using 1H-1,2,4-triazole (59 mg) and (2S)-2-[(1R)-1-[2,6-dichloro-9 (9H)-purinyl]ethyl]-2-(2,4-difluorophenyl) oxirane (168 mg), Compound 50 (21 mg) was obtained as a white powder by the same way as in Example 1.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12](=[O:37])[CH2:13][CH2:14][CH2:15][CH2:16][S:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:10].Br[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].[Cl-].[NH4+]>C1COCC1.CCOCC.CN(P(N(C)C)(N(C)C)=O)C>[CH2:9]([O:11][C:12](=[O:37])[CH:13]([CH2:14][CH2:15][CH2:16][S:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH3:10]
Reactant: CCOC(=O)CCCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)CC(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of LDA (2M, 9.1 mL, 18.17 mmol) at −70° C. was added HMPA(10 mL) followed by the drop wise addition of a solution of the compound of example 27 (6.12 g, 15.14 mmol) in anhydrous THF (10 mL). The reaction mixture was allowed to warm up to −40° C. and was stirred for another 30 minutes, after which, a solution of tert-butyl bromoacetate (2.5 mL, 16.65 mmol) in anhydrous THF (10 mL) was added. The reaction mixture was stirred for 1 h at the same temperature and then allowed to warm up to room temperature followed by stirring for 24 h. The reaction mixture was portioned between ether and saturated ammonium chloride. The water phase was extracted several times with ether. The recombined organic layer was washed with brine, dried, filtered and evaporated. Silica gel chromatography using 5% ethyl acetate in hexanes provided the product as a light yellow oil. 1H-NMR(CDCl3, 400 MH: 1.24(t, J=7.1 Hz, 3H); 1.43(s, 9H); 1.40–1.57(m, 4H); 2.15(m, 2H); 2.24(m, 1H); 2.58(m, 2H); 4.12(q, J=7.1 Hz, 2H), 7.19–7.23, 7.26–7.30, 7.41(m, 15H).
Reaction SMILES: C([O:4][CH2:5][CH3:6])(=O)C.[NH2:7][CH2:8][C:9]([NH2:12])([CH3:11])[CH3:10]>>[CH3:10][C:9]([NH2:12])([CH3:11])[CH2:8][NH:7][C:5]([CH3:6])=[O:4]
Reactant: CCOC(C)=O
Reactant: CC(C)(N)CN
Product: CC(=O)NCC(C)(C)N
Temperature: 100 °C
Yield: 57.4 %

Procedure:
A mixture of 26.4 g (0.3 mol) of ethyl acetate and 79.2 g (0.9 mol) of 1,2-diamino-2-methylpropane was heated at 100° C. in a pressure bomb for 36 hours. The reaction mixture was evaporated in vacuo and distilled to give 22.4 g (57.4%) of product; boiling point 100° C./0.1 mmHg. This product was identified by NMR and IR spectroscopy.