Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][NH:6][CH3:7].[C:8]([C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][C:13]([C:21]([OH:23])=O)([CH2:14]3)[CH2:12]1)[CH2:18]2)(O)=[O:9].[CH3:24][N:25](C=O)[CH3:26]>>[CH3:5][N:6]([CH3:7])[C:8]([C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][C:13]([C:21](=[O:23])[N:25]([CH3:26])[CH3:24])([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:9]
Reactant: O=C(O)C12CC3CC(C1)CC(C(=O)O)(C3)C2
Reactant: CN(C)C=O
Reactant: CNC
Solvent: O=S(Cl)Cl
Product: CN(C)C(=O)C12CC3CC(C1)CC(C(=O)N(C)C)(C3)C2
Reaction time: 2 h
Yield: 95 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1,3-dicarboxyadamantane obtained by the method of Example 64 was dissolved in 10 ml of DMF. To the mixture, 30 mmole of thionyl chloride was added dropwise over 30 minutes and the mixture was heated to begin to reflux around the conclusion of addition. After refluxing for 2 hours, the mixture was cooled. To the mixture, 50 mmole of dimethylamine was added dropwise over 30 minutes while retaining the temperature of the mixture at 10° C. or less, and then stirred for more 2 hours. As a result, the conversion of 1,3-dicarboxyadamantane was 99%, and 1,3-bis(N,N-dimethylcarbamoyl)adamantane (yield 95%) was formed.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[CH2:14](I)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][CH3:15])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:11])([F:12])[F:10]
Reactant: Oc1ccc(OC(F)(F)F)c(Br)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(OC(F)(F)F)c(Br)c1
Yield: 125 %

Procedure:
To a solution of the 3-bromo-4-trifluoromethoxyphenol (1.0 g, 2.48 mmol) in acetone (30 ml) was added ethyl iodide (0.795 ml, 9.94 mmol) followed by potassium carbonate (1.37 g, 9.94 mmol) and the reaction was heated to reflux for 12 hrs. The reaction mixture was cooled then filtered and concentrated in vacuo. Dichloromethane (20 ml) and water (20 ml) were added and the solution was filtered through a phase separation cartridge. The organic layer was collected, and evaporated in vacuo to afford crude title compound as a colourless oil (884 mg, 80%). Material was taken on without further purification.
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[S:15][C:14]([NH:16][C:17](=[O:40])[CH:18]([C:28]3[CH:33]=[CH:32][C:31]([S:34]([CH:37]4[CH2:39][CH2:38]4)(=[O:36])=[O:35])=[CH:30][CH:29]=3)[O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])=[N:13][CH:12]=2)=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[CH:37]1([S:34]([C:31]2[CH:30]=[CH:29][C:28]([CH:18]([O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])[C:17]([NH:16][C:14]3[S:15][C:11]([O:10][C:7]4[CH:6]=[CH:5][C:4]([C:3]([OH:41])=[O:2])=[CH:9][CH:8]=4)=[CH:12][N:13]=3)=[O:40])=[CH:33][CH:32]=2)(=[O:35])=[O:36])[CH2:38][CH2:39]1
Reactant: COC(=O)c1ccc(Oc2cnc(NC(=O)C(Oc3ccc(F)cc3F)c3ccc(S(=O)(=O)C4CC4)cc3)s2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Oc2cnc(NC(=O)C(Oc3ccc(F)cc3F)c3ccc(S(=O)(=O)C4CC4)cc3)s2)cc1
Reaction time: 2.5 h
Yield: 85.6 %

Procedure:
4-{2-[2-(4-Cyclopropanesulfonyl-phenyl)-2-(2,4-difluoro-phenoxy)-acetylamino]thiazol-5-yloxy}-benzoic acid methyl ester (1.4 g, 2.33 mmol, obtained in example A74) was taken in THF: MeOH (1:1, 20 mL), to it was added aqueous solution of LiOH (0.34 g, 7.94 mmol in 10 mL water) and stirred for 1-4 h. After completion of the reaction, organic solvent was removed under reduced pressure. The aqueous layer was washed with diisopropyl ether then acidified with 1 N HCl to pH 2. The solid formed was filtered, washed with water, followed by washing with diisopropyl ether & dried under vacuum to get the title compound (1.17 g, 86%).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH3:29][O:30][CH2:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:29][O:30][CH2:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:34][CH2:33]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: COCC1CCNCC1
Product: COCC1CCN(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)CC1

Procedure:
4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 4-(methoxymethyl)piperidine via General Procedure E to give 21.9 mg of 280 following reverse phase purification. MS (Q1) 491.3 (M)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:17]=1.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH2:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([NH:22][CH2:21][CH2:20][N:19]([CH3:23])[CH3:18])=[N:7][C:6]=2[CH:17]=1
Reactant: CN(C)CCN
Reactant: O=C1Nc2cc(Cl)ccc2Nc2ccccc21
Product: CN(C)CCNC1=Nc2cc(Cl)ccc2Nc2ccccc21
Yield: 63.5 %

Procedure:
8-Chloro-5,10-dihydro-dibenzo[b,e][1,4]diazepine-11-one (25 mg, 0.1 mmol) and N,N-dimethylethylenediamine (44 mg, 0.5 mmol) were reacted according to GP4 to give 20 mg of the title compound (160FE16D). MS (ESI) 315 (MH+). Purity for MH+ (UV/MS) 100/100.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[O:14]1>C(O)C.[Pd]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH2:13][C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:15]([OH:22])=[O:14]
Reactant: O=C1OC(c2c(O)c3ccccc3oc2=O)c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1ccccc1Cc1c(O)c2ccccc2oc1=O
Reaction time: 12 h
Yield: 82.8 %

Procedure:
To a solution 4-Hydroxy-3-(3-oxo-1,3-dihydro-isobenzofuran-1-yl)-chromen-2-one (60 mg) in ethanol is added 10% Pd/C (10 mg) then stirred under a hydrogen balloon for 12 hours. The reaction mixture is filtered through a pad of celite and the filtrate concentrated in vacuo to give 2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid as white solid (50 mg). MS: 295[M−H].
Reaction SMILES: [CH:1]1([CH:4]([CH:12]2[CH2:14][CH2:13]2)[NH:5]S(C(C)(C)C)=O)[CH2:3][CH2:2]1.[ClH:15].O1CCOCC1>CO>[Cl-:15].[CH:1]1([CH:4]([CH:12]2[CH2:14][CH2:13]2)[NH3+:5])[CH2:3][CH2:2]1
Reactant: Cl
Reactant: CC(C)(C)S(=O)NC(C1CC1)C1CC1
Solvent: CO
Solvent: C1COCCO1
Product: [Cl-]
Product: [NH3+]C(C1CC1)C1CC1
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-(dicyclopropylmethyl)-2-methylpropane-2-sulfinamide (86 g, 400 mmol) in MeOH (200 mL) was added 4 N HCl in dioxane (200 mL, 800 mmol). The reaction mixture was left to stir for 30 min, concentrated to half the volume, and diluted with Ether. The white precipitate was filtered through a fritted glass, washed with ether, and dried under high-vacuum to give the title compound. 1H NMR (600 MHz, CD3SOCD3) δ 8.17 (br s, 3H); 1.89 (t, 1H); 1.02 (m, 2H); 0.54 (m, 2H); 0.48 (m, 2H); 0.39 (m, 4H).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C(N(CC)CC)C.[Cl:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21](=[O:23])[CH3:22])[CH:16]=[CH:17][C:18]=1Cl>>[C:1]([O:4][CH2:22][C:21](=[O:23])[CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(=O)Cc1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Cc1cccc(Cl)c1
Yield: 46 %

Procedure:
This crude material was reacted with acetic acid (1.42 mL, 1.49 g, 24.8 mmol) and triethylamine (3.46 mL, 2.51 g, 24.8 mmol), as described above for the synthesis of 3-(3,4-dichlorophenyl)propan-2-one. Flash chromatography over silica gel (20% ethyl acetate in hexanes) gave pure product (1.22 g, 46% yield): 1H NMR (400 MHz, CDCl3) δ 2.16 (s, 3H) 3.72 (s, 2H) 4.69-4.71 (m, 2H) 7.08-7.11 (m, 1H) 7.21-7.23 (m, 1H) 7.26-7.29 (m, 2H).
Reaction SMILES: Cl.[CH2:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH2:5][CH2:4][NH:3]1.[C:15](=[O:18])([O-])[O-:16].[K+].[K+].O>C(Cl)(Cl)Cl.CO>[C:6]([O:16][C:15]([N:3]1[CH2:4][CH2:5][C:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:8][C:7]=2[CH2:2]1)=[O:18])([CH3:10])([CH3:7])[CH3:5]
Reactant: c1ccc2c3c(sc2c1)CNCC3
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ccccc23)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A 2.00 g (8.86 mmol) portion of 3,4-dihydro-1H-benzo[4,5]thieno[2,3-c]pyridine hydrochloride was dissolved in a mixed solvent of 70 ml chloroform and 10 ml methanol, and the solution was mixed with 3.67 g (26.58 mmol) of potassium carbonate and cooled to 0° C. This was mixed with 2.24 ml (9.75 mmol) of di-t-butyl bicarbonate and stirred overnight at room temperature. The reaction solution was poured into ice-cooled water and extracted with chloroform. The extract was washed with water and dried (Na2SO4), and then the solvent was removed by evaporation under a reduced pressure and the thus obtained oily material was purified by a silica gel column chromatography (250 cc; elution by ethyl acetate-hexane=1:6) to obtain 2.04 g of the title compound (80% in yield).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1([CH3:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][N:21]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1([CH3:17])[CH2:16][CH2:15][N:14]([C:20]2[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][N:21]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Reactant: N#Cc1ccnc(Cl)c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(NC(=O)OCc2ccccc2)CCN(c2cc(C#N)ccn2)CC1
Yield: 55.9 %

Procedure:
A solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester (310 mg, 1.25 mmol, Example 30B), 2-chloro-4-cyanopyridine (250 mg, 1.8 mmol) and diisopropylethylamine (280 μL) in dioxane (6 mL) was heated in a sealed tube at 90° C. for 3 days. The reaction mixture was cooled, concentrated, and then flash chromatographed using a gradient of 5% ethyl acetate/hexane to 30% ethyl acetate/hexane to provide the titled compound (245 mg) as a colorless foam. MS (CI) m/z 350 (M+H)+; 1H NMR (300 MHz, MeOH-d4) δ 8.22 (d, 1H), 7.34 (m, 1H), 7.29 (m, 5H), 7.00 (s, 1H), 6.77 (d, 1H), 5.04 (s, 2H), 3.95-3.89 (m, 2H), 3.26 (m, 2H), 2.19-2.10 (m, 2H), 1.61-1.50 (m, 2H), 1.27 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[NH:13][C:12]=2[CH:20]=O)[CH2:4][CH2:3]1.[CH2:22]([S:24]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31](=[O:36])[CH2:30]2)(=[O:26])=[O:25])[CH3:23]>>[CH2:22]([S:24]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31](=[O:36])/[C:30]/2=[CH:20]\[C:12]1[NH:13][C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[C:11]=1[CH2:10][CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)(=[O:25])=[O:26])[CH3:23]
Reactant: CCS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CN1CCN(CCCc2c(C=O)[nH]c3c2CCCC3)CC1
Product: CCS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CCN(C)CC1)CCCC3)C(=O)N2

Procedure:
3-[3-(4-Methylpiperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde, prepared as described in Example 2, was condensed with 5-ethylsulfonyloxindole (Example 5) following the procedure described in Example 1 above. The reaction mixture was purified by flash chromatography and eluting with (dichloromethane: methanol 30/1, 20/1, 15/1) to give the desired product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[S:8][CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13]>C(O)C>[N+:12]([C:11]1[CH:10]=[CH:9][S:8][C:7]=1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccsc1Cl
Reactant: c1c[nH]cn1
Solvent: CCO
Product: O=[N+]([O-])c1ccsc1-n1ccnc1
Yield: 45.4 %

Procedure:
Imidazole (860 mg, 12.63 mmol) was added to a solution of 2-chloro-3-nitro-thiophene (1 g, 6.10 mmol) in abs. ethanol (20 mL). The reaction mixture was heated to reflux in a sealed tube for 3 days and then concentrated under reduced pressure. Purification by flash chromatography (silica, 25:75 ethyl/hexane) gave 1-(3-nitrothiophen-2-yl)-1H-imidazole (540 mg, 45%). See Erker, T. J. et al., J. Heterocylic. Chem. 39 (2002) 857-861. Method [3] m/z 195.9 (M+H); retention time=0.615.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([C:13]([OH:15])=O)[CH2:10][NH:9][C:8]=2[CH:16]=1.[Br:19][C:20]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:21]=1[NH2:22].N1C=CC=CC=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CC1CCCO1>[Br:19][C:20]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:21]=1[NH:22][C:13]([CH:11]1[O:12][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:18])[F:17])=[CH:16][C:8]=2[NH:9][CH2:10]1)=[O:15]
Reactant: Cc1ccc(N)c(Br)c1
Reactant: O=C(O)C1CNc2cc(OC(F)(F)F)ccc2O1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CC1CCCO1
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)C2CNc3cc(OC(F)(F)F)ccc3O2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
6-(Trifluoromethoxy)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (600 mg, 2.28 mmol) and 2-bromo-4-methyl-aniline (424 mg, 286 μL, 2.28 mmol) were dissolved in 2-methyltetrahydrofuran (7 mL) and pyridine (461 μL, 5.70 mmol). T3P (2902 mg, 2.7 mL of 50% w/w solution, 4.56 mmol) was added and the reaction was stirred for 30 min at room temperature. Purification by silica gel chromatography (10-100% ethyl acetate/hexanes) provided N-(2-bromo-4-methylphenyl)-6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide (743 mg, 76% yield). LC/MS m/z 432.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[S:29][CH:30]=1)[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[CH2:37]([P:46](=[O:53])([O:50][CH2:51][CH3:52])[O:47][CH2:48][CH3:49])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[S:29][CH:30]=1)[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:37]/[P:46](=[O:53])([O:47][CH2:48][CH3:49])[O:50][CH2:51][CH3:52])=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1csc(N2CCOCC2)n1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2csc(N3CCOCC3)n2)c(OC)c1)OCC
Reaction time: 15 h
Yield: 71.2 %

Procedure:
To a mixture of 3-[(3-methoxy-4-{[2-(morpholin-4-yl)-1,3-thiazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.40 g), tetraethyl methylenediphosphonate (0.25 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.040 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-{3-[(3-methoxy-4-{[2-(morpholin-4-yl)-1,3-thiazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.36 g, yield 71%) from a fraction eluted with ethyl acetate-hexane (4:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 93-94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[CH:12][C:11]=1[C:22]([F:25])([F:24])[F:23]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[CH:12][C:11]=2[C:22]([F:23])([F:25])[F:24])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2ccc(Cl)cc2)c(C(F)(F)F)c1

Procedure:
A mixture of 4-chloroaniline (127.5 g) and 2-chloro-3,5-dinitrobenzotrifluoride (270.5 g.) in toluene (2 l.) was heated under reflux for 16 hours and the hot mixture then filtered. The filtrate was concentrated in vacuo, and the true amounts of toluene removed by co-distillation with industrial methylated spirit, to give a black semi-solid. Extraction of this solid with cyclohexane gave yellow crystals of 2(4-chloroanilino)-3,5-dinitrobenzotrifluoride, melting point 104°-106° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.N1[CH:16]=[CH:15]N=C1.C(Cl)(=O)C.Cl.[NH2:22][CH:23]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:24]1=[O:30].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(#N)C.O>[Br:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[C:15]([CH3:16])[N:22]([CH:23]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:24]1=[O:30])[C:4]2=[O:6]
Reactant: NC1CCC(=O)NC1=O
Reactant: c1c[nH]cn1
Reactant: Nc1c(Br)cccc1C(=O)O
Agent: Cl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CC(=O)Cl
Solvent: CC#N
Solvent: O
Product: Cc1nc2c(Br)cccc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.1 %

Procedure:
To a stirred mixture of 2-amino-3-bromobenzoic acid (1.0 g, 4.6 mmol) and imidazole (0.38 g, 5.5 mmol) in acetonitrile (10 mL), was added acetyl chloride (0.6 mL, 8.3 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (0.76 g, 4.6 mmol), imidazole (0.7 g, 10 mmol) and triphenyl phosphite (1.5 mL, 5.6 mmol) and heated to reflux for 22 hours. To the mixture, was added water (60 mL). The suspension was filtered and washed with water (2×50 mL), ethyl acetate (2×50 mL), and water (50 mL) to give 3-(8-bromo-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (0.34 g, 21% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 25/75 CH3CN/0.1% H3PO4, 9.47 min (99.6%); mp: 307-309° C.; 1H NMR (DMSO-d6) δ 2.16-2.23 (m, 1H, CHH), 2.58-2.67 (m, 2H, 2CHH), 2.68 (s, 3H, CIA), 2.76-2.92 (m, 1H, CHH), 5.31 (dd, J=5, 11 Hz, 1H, NCH), 7.41 (t, J=8 Hz, 1H, Ar), 8.04 (dd, J=2, 8 Hz 1H, Ar), 8.15 (dd, J=1, 8 Hz 1H, Ar), 11.07 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.73, 23.85, 30.57, 56.76, 121.09, 121.82, 125.86, 127.47, 138.08, 144.23, 156.23, 159.97, 169.29, 172.58; LCMS: MH=350, 352; Anal Calcd for C14H12N3O3Br: C, 48.02; H, 3.45; N, 12.00; Br, 22.82. Found: C, 47.74; H, 3.23; N, 11.85; Br, 22.42.
Reaction SMILES: CS([CH2:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][C:11]2[CH:12]=[C:13]([C:19]#[N:20])[C:14](=[CH:17][CH:18]=2)[C:15]#[N:16])=[CH:8][CH:7]=1)(=O)=O.[Li+].[Br-:24]>C1COCC1>[Br:24][CH2:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][C:11]2[CH:12]=[C:13]([C:19]#[N:20])[C:14](=[CH:17][CH:18]=2)[C:15]#[N:16])=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)Cc1ccc(Oc2ccc(C#N)c(C#N)c2)cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(Oc2ccc(CBr)cc2)cc1C#N
Temperature: 25 °C

Procedure:
To a solution of 4-[4-(methansulfonylmethyl)phenoxy]phthalonitrile (1.2 g, 3.3 mmol) prepared according to Example 2, in anhydrous THF (15 ml) kept in an inert atmosphere, LiBr (0.4 g, 4.6 mmol) was added. The solution was refluxed for 1 hour, during which a white precipitate formed, then it was allowed to cool at room temperature. The white precipitate was filtered off and the solvent was evaporated. From the crude mixture the desired product was isolated by filtration on silica gel (eluent: chloroform). (1.0 g, 95%)
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([N:17]1[CH2:22][C@@H:21]([CH3:23])[O:20][C@@H:19]([CH3:24])[CH2:18]1)[N:5]=2.[F-].[Cs+].[OH:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][C@@H:19]1[O:20][C@H:21]([CH3:23])[CH2:22][N:17]([C:6]2[N:5]=[C:4]3[C:9]([N:10]=[C:2]([C:32]4[CH:33]=[C:28]([OH:27])[CH:29]=[CH:30][CH:31]=4)[NH:3]3)=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:7]=2)[CH2:18]1
Reactant: C[C@@H]1CN(c2nc(N3CCOCC3)c3nc(Br)[nH]c3n2)C[C@H](C)O1
Reactant: OB(O)c1cccc(O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CC#N
Product: C[C@@H]1CN(c2nc(N3CCOCC3)c3nc(-c4cccc(O)c4)[nH]c3n2)C[C@H](C)O1
Temperature: 115 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
To a round bottom flask were added, 8-bromo-2-((2S,6R)-2,6-dimethyl-morpholin-4-yl)-6-morpholin-4-yl-9H-purine (38.2 mg, 0.096 mmol), cesium fluoride 58.4 mg, 0.39 mmol), 3-hydroxyphenylboronic acid (39.8 mg, 0.29 mmol) and tetrakis(triphenylphosphine)palladium (8.9 mg, 7.69 mmol) followed by 1 mL of acetonitrile/water solvent mixture (10/1 ratio). Suspension was heated to 115° C. and stirred overnight. Upon completion of the reaction, the suspension was cooled and solids filtered off. Solvent was removed under reduced pressure and the crude was purified directly by preparative HPLC to provide 3-[2-((2S,6R)-2,6-dimethyl-morpholin-4-yl)-6-morpholin-4-yl-9H-purin-8-yl]-phenol (18.5 mg, 47%) as yellow solid. LC/MS analysis method 7, mass (ES+) m/z 411.2, retention time 1.40 min. 1HNMR (CDCl3): 7.34 (1H, d), 7.24 (2H, m), 6.87 (1H, d), 4.35 (2H, d), 4.30 (4H, brs), 3.80 (4H, m), 3.57 (2H, m), 2.53 (2H, t), 1.16 (6H, d).
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:22][CH2:23][CH3:24])(=[O:21])[C:18]#[C:19][CH3:20].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][C:19]([CH3:20])=[C:18]([C:17]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC#CC(=O)OCC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)CN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 26.7 %

Procedure:
Benzyl(methoxymethyl)[(trimethylsilyl)methyl]amine (10.78 mL, 42.12 mmol) and ethyl but-2-ynoate (5.89 mL, 50.54 mmol) were stirred in DCM (500 mL) at 0° C. under nitrogen, then trifluoroacetic acid (161 μL, 2.11 mmol) was added dropwise. The reaction mixture stirred at 0° C. for 20 minutes, then the ice bath was removed and the solution was allowed to warm to room temperature. The solution was stirred at room temperature overnight. The mixture was concentrated and purified by FCC, eluting with 0-70% EtOAc in heptane, to afford the title compound (2.76 g, 27%). δH (500 MHz, DMSO-d6) 7.38-7.32 (m, 4H), 7.30-7.23 (m, 1H), 4.13 (q, J 7.1 Hz, 2H), 3.75 (s, 2H), 3.60-3.51 (m, 4H), 2.05 (s, 3H), 1.22 (t, J 7.1 Hz, 3H).