Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH:13]([CH3:21])[C:14](=O)[CH2:15][C:16]([O:18][CH3:19])=[O:17].C(OC(=O)C)C>CN(C)C=O>[CH3:21][C:13]1[O:10][C:1]([CH:2]=[CH:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[N:11][C:14]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CC(=O)C(C)Br
Reactant: NC(=O)C=Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1nc(C=Cc2ccccc2)oc1C
Temperature: 100 °C
Reaction time: 15 h
Yield: 11.4 %

Procedure:
Cinnamamide (0.5 g) and methyl 4-bromo-3-oxopentanoate (0.71 g) were dissolved in N,N-dimethylformamide (2.5 ml) and the mixture was stirred 100° C. for 15 h. Ethylacetate (50 ml) was added, and the mixture was washed with water (100 ml) and then with saturated brine (100 ml), and dried (Na2SO4). Ethyl acetate was evaporated under reduced pressure and the obtained residue was purified by column chromatography to give the title compound (0.1 g).
Reaction SMILES: [NH2:1]C1C=CC=CC=1.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[N:16][C:11]=2[N:10]=[N:9]1>C(Cl)(Cl)Cl>[NH2:1][N:9]1[N:8]=[C:12]2[CH:13]=[CH:14][CH:15]=[N:16][C:11]2=[N:10]1
Reactant: Nc1ccccc1
Reactant: c1cnc2nn[nH]c2c1
Solvent: ClC(Cl)Cl
Product: Nn1nc2cccnc2n1

Procedure:
Anilines of general formula 9m or the corresponding bromides 3m with an 2-propan-2-ol group in 5-position of the triazolopyridine (see Scheme 18) can be prepared starting from ester 51 by bromination in chloroform followed by cyclization as already described in Scheme 8 to give 2-amino-triazolopyridine 53. The ester 53 can then be treated with methyl magnesium bromide to provide the tertiary alcohol 54. Conversion of the bromide by e.g. Suzuki reaction gives aniline 9m or after Sandmeyer reaction bromide 3m. The starting material 51 is either commercially available or can be synthesized by methods known in the art, e.g for R=Me, 51 can be prepared from the corresponding bromide by reaction with trimethyl boroxine in the presence of a palladium catalyst.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[OH:32][CH:33]([CH:37]([CH3:39])[CH3:38])[C:34](O)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:32][CH:33]([CH:37]([CH3:39])[CH3:38])[C:34]([N:22]1[CH2:23][CH2:24][N:19]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:7]=2)[CH2:20][CH2:21]1)=[O:35]
Reactant: CC(C)C(O)C(=O)O
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCN(C(=O)C(O)C(C)C)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
To a solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (250 mg, 0.78 mmol) in CH2Cl2 (6 mL) was added triethylamine (217 μL, 1.56 mmol) followed by the addition of 2-hydroxy-3-methylbutanoic acid (120 mg, 1.0 mmol) and HATU (380 mg, 1.00 mmol). The reaction mixture was stirred at room temperature for 3 h and then quenched with H2O. The aqueous layer was extracted with CH2Cl2, dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 CH2Cl2:hexanes gave 2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3-methylbutan-1-one (230 mg, 70%). LC/MS: m/z 421.3 (M+H)+ at 2.43 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) d 8.45 (m, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.70 (s, 1H), 7.39 (m, 2H), 6.95 (m, 2H), 4.79 (d, J=7.2 Hz, 1H), 4.11 (dd, J=7.0, 5.9 Hz, 1H), 3.87 (m, 8H), 2.52 (s, 3H), 1.91 (m, 1H), 0.88 (dd, J=22.8, 6.7 Hz, 6H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[I:12]N1C(=O)CCC1=O.O>ClCCl>[I:12][C:11]1[C:4]2[C:3]([O:2][CH3:1])=[N:8][CH:7]=[N:6][C:5]=2[NH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ncnc2[nH]ccc12
Solvent: ClCCl
Solvent: O
Product: COc1ncnc2[nH]cc(I)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To 4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (3, 3.20 g, 21.4 mmol) in 280 mL of dichloromethane, N-iodosuccinimide (5.3 g, 24.0 mmol) suspended in dichloromethane was added. The reaction was stirred at room temperature for 2 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was washed with ethyl acetate and hexane to provide the desired compound (35, 4.80 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:29])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[NH:19][C:20]2[CH:28]=[C:27]3[C:23]([CH:24]=[N:25][NH:26]3)=[CH:22][CH:21]=2)=[CH:7][C:6]=1[N+:30]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>CCO>[NH2:30][C:6]1[CH:7]=[C:8]([NH:11][C:12](=[O:29])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[NH:19][C:20]2[CH:28]=[C:27]3[C:23]([CH:24]=[N:25][NH:26]3)=[CH:22][CH:21]=2)[CH:9]=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Solvent: CCO
Product: CC(C)(C)c1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2)cc1N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The title compound was prepared from N-(4-tert-butyl-3-nitro-phenyl)-2-(1H-indazol-6-ylamino)-nicotinamide by dissolving in EtOH (20 ml) and adding Sn(II)Cl2 (12.58 g) and stirred at RT for 5 h and at 0 C. overnight. The mix was warmed to RT and quenched by pouring onto ice, neutralized with NaHCO3 and basified with 6N NAOH. An emulsion formed upon addition of EtOAc which was filtered through Celite and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with H2O, brine and dried over MgSO4 then purified by flash chromatography (3–5% MeOH to afford the product as a orange-yellow solid.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([C:23]([CH3:40])=[CH:24][C:25]2[CH:26]=[C:27]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[CH:28]=[CH:29][CH:30]=2)[CH:12]=[C:13]([O:15][Si](C(C)(C)C)(C)C)[CH:14]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:38][C:36]([CH3:39])([CH3:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C:27]1[CH:26]=[C:25]([CH:24]=[C:23]([C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[C:13]([OH:15])[CH:12]=2)[CH3:40])[CH:30]=[CH:29][CH:28]=1
Reactant: CC(=Cc1cccc(CCCCCC(C)(C)O)c1)c1cc(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=Cc1cccc(CCCCCC(C)(C)O)c1)c1cc(O)cc(O)c1

Procedure:
In a manner similar to Example 3(i), by reacting 402 mg (0.69 mmol) of 7-(3-{2-[3,5-bis(tert-butyldimethylsilanyloxy)phenyl]propenyl}phenyl)-2-methylheptan-2-ol with 1.4 ml of tetrabutylammonium fluoride 1M/THF, after purification on a silica column (ethyl acetate 40-heptane 60), white crystals (m=176 mg; Y=72%) are obtained. m.p. 113-4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([NH2:24])=[O:23])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[C:22]([C@H:21]([N:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:20][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:15][CH:14]=1)[S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:23])[NH2:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)C[C@H](C(N)=O)N(Cc1ccc(CO)cc1)S(=O)(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](C(N)=O)N(Cc1ccc(COS(C)(=O)=O)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2R)-2-[N-(4-chloro-benzenesulfonyl)-N-(4-hydroxymethyl-benzyl)amino]-4-methyl-pentanoic acid amide (1.5 g, 3.5 mmol) in CH2Cl2 (15 mL) cooled to 0° C. was added Et3N (0.74 mL, 5.3 mmol). A solution of methanesulfonyl chloride (0.29 mL, 3.5 mmol) in 5 mL CH2Cl2 was added dropwise and the reaction was allowed to stir at 0° C. for 1 h. The reaction mixture was diluted with 25 mL CH2Cl2, quickly washed with 1 N HCl, brine, and dried by passing the organic phase through a cotton plug. The solvent was removed in vacuo affording the title compound in quantitative yield. The resulting foam was used as is in subsequent reactions. MS (EST), (M-95)+, 409.15 1H NMR (CDCl3) δ 7.70 (d, 2H, J=8.0), 7.48 (d, 2H, J=8.0), 7.41 (d, 2H, J=8.0), 7.38 (d, 2H, J=8.0), 6.27 (br s, 1H), 5.32 (br s, 1H), 5.24 (s, 2H), 4.64 (d, 1H, Jab=16), 4.43 (d, 1H, Jab=16), 4.33 (t, 1H, J=6), 2.90 (s, 3H), 1.90 (m, 1H), 1.60 (m, 2H), 0.96 (d, 3H, J=7.0), 0.91 (d, 3H, J=7.0)
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19].C(=O)(O)[O-].[Na+]>O>[Br:15][C:16]1[CH:17]=[C:18]([NH:19][C:3]([C:4]2[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=2)=[N:2][OH:1])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: Nc1ccc(F)c(Br)c1
Reactant: COCCNc1nonc1C(Cl)=NO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COCCNc1nonc1C(=NO)Nc1ccc(F)c(Br)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 98.6 %

Procedure:
N-Hydroxy-4-[(2-methoxyethyl)amino]-1,2,5-oxadiazole-3-carboximidoyl chloride (46.0 g, 0.208 mol) was mixed with water (300 mL). The mixture was heated to 60° C. 3-Bromo-4-fluoroaniline [Oakwood products, product #013091] (43.6 g, 0.229 mol) was added and stirred for 10 min. A warm sodium bicarbonate (26.3 g, 0.313 mol) solution (300 mL water) was added over 15 min. The reaction was stirred at 60° C. for 20 min. LCMS indicated reaction completion. The reaction solution was cooled to room temperature and extracted with ethyl acetate (2×300 mL). The combined ethyl acetate solution was dried over sodium sulfate and concentrated to give the desired product (76.7 g, 98%) as a crude brown solid. LCMS for C12H14BrFN5O3 (M+H)+: m/z=374.0, 376.0. 1H NMR (400 MHz, DMSO-d6): δ 11.55 (s, 1H), 8.85 (s, 1H), 7.16 (t, J=8.8 Hz, 1H), 7.08 (dd, J=6.1, 2.7 Hz, 1H), 6.75 (m, 1H), 6.14 (t, J=5.8 Hz, 1H), 3.48 (t, J=5.2 Hz, 2H), 3.35 (dd, J=10.8, 5.6 Hz, 2H), 3.22 (s, 3H).
Reaction SMILES: OC(C1C=CC=CC=1)C([NH:5][CH:6]([CH3:16])[CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=O>Cl>[CH3:16][C@H:6]([NH2:5])[CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(CCCc1cccnc1)NC(=O)C(O)c1ccccc1
Agent: Cl
Product: C[C@H](N)CCCc1cccnc1

Procedure:
As in Example 16, a solution of 16.3 g of [S-(S*,S*)]-alpha-hydroxy-N-[1-methyl-4-(3-pyridinyl)butyl]benzeneacetamide in 160 mL of 6N HCl was heated at reflux for 22 hours. The crude product, obtained by the usual work up was distilled to yield 8.3 g of (S)-alpha-methyl-3-pyridinebutanamine, (bp 85°-87° C./0.1 mm)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8].CC1C=CC(S(O[CH2:23][CH2:24][CH2:25][S:26][C:27]2[CH:32]=[CH:31][C:30](/[C:33](/[C:40]3[NH:41][C:42](=[O:47])[C:43]([CH3:46])=[CH:44][CH:45]=3)=[CH:34]\[CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:29][C:28]=2[Cl:48])(=O)=O)=CC=1.O>C(#N)C>[Cl:48][C:28]1[CH:29]=[C:30](/[C:33](/[C:40]2[NH:41][C:42](=[O:47])[C:43]([CH3:46])=[CH:44][CH:45]=2)=[CH:34]\[CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:31]=[CH:32][C:27]=1[S:26][CH2:25][CH2:24][CH2:23][N:9]([CH2:10][CH3:11])[CH2:7][CH3:8]
Reactant: Cc1ccc(S(=O)(=O)OCCCSc2ccc(/C(=C\C3CCCC3)c3ccc(C)c(=O)[nH]3)cc2Cl)cc1
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCN(CC)CCCSc1ccc(/C(=C\C2CCCC2)c2ccc(C)c(=O)[nH]2)cc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
Potassium carbonate (290 mg) and diethylamine (219 μL) were sequentially added to a solution of 3-({2-chloro-4-[(E)-2-cyclopentyl-1-(5-methyl-6-oxo-1,6-dihydropyridin-2-yl)ethenyl]phenyl}sulfanyl)propyl 4-methylbenzenesulfonate (33 mg) in acetonitrile (3 mL), and the mixture was stirred at 90° C. for two hours. The reaction solution was poured into water, followed by extraction with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:0→9:1) to give the title compound (18 mg, 66%) as a colorless amorphous.
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2].[CH:20]1([CH2:25][C:26](Cl)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([CH2:25][C:26]([NH:13][C:11]2[S:12][C:8]([C:6]3[O:5][N:4]=[C:3]([CH2:1][CH3:2])[N:7]=3)=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:10]=2)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: CCc1noc(-c2sc(N)nc2-c2ccccc2)n1
Product: CCc1noc(-c2sc(NC(=O)CC3CCCC3)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-ethyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and cyclopentyl-acetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[C:9](=[N:13]\[NH:14][C:15]([NH2:17])=[NH:16])/[C:10]([NH2:12])=O>C(O)C>[CH:5]1[CH:6]=[C:7]([Cl:8])[C:2]([Cl:1])=[C:3]([C:9]2[N:13]=[N:14][C:15]([NH2:17])=[N:16][C:10]=2[NH2:12])[CH:4]=1
Reactant: N=C(N)N/N=C(/C(N)=O)c1cccc(Cl)c1Cl
Solvent: CCO
Product: Nc1nnc(-c2cccc(Cl)c2Cl)c(N)n1

Procedure:
(E)-2-(2',3'-dichlorophenyl)-2-(guanidinylimino)acetamide as described in Reference Example 1 (0.3 g) was dissolved in ethanol (10 ml) and was irradiated by exposure to sunlight.
Reaction SMILES: C(O[C:4](=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])C.[CH3:11][C:12]([CH3:14])=[O:13].[Na:15]>C(O)C>[OH:10][C:4](=[CH:11][C:12](=[O:13])[CH3:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Na:15]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(C)=O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(O)=CC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.6 %

Procedure:
To a mixture of diethyloxalate (81 mL, 0.66 mol) and acetone (45 mL, 0.66 mol) was slowly added over 2-3 hours a solution of sodium metal (15.0 g, 0.66 mol) in absolute ethanol (330 mL) and condensation was allowed to occur with stirring at room temperature for 4 hours. The precipitate thus formed was filtered, washed with ethanol and dried to afford the title compound as a bright yellow solid (103.5 g, 87%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH3:16][O:17][C:18]([CH:20]1[CH2:25][NH:24][CH2:23][CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:19]>C(O)(C)(C)C>[CH3:16][O:17][C:18]([CH:20]1[CH2:25][N:24]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=3)[N:5]=[CH:4][N:3]=2)[CH2:23][CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:19]
Reactant: Clc1cc(-c2ccc(Cl)c(Cl)c2)ncn1
Reactant: COC(=O)C1CNCCN1C(=O)OC(C)(C)C
Solvent: CC(C)(C)O
Product: COC(=O)C1CN(c2cc(-c3ccc(Cl)c(Cl)c3)ncn2)CCN1C(=O)OC(C)(C)C
Temperature: 150 °C
Yield: 192.6 %

Procedure:
4-Chloro-6-(3,4-dichloro-phenyl)-pyrimidine (0.11 g, 0.4 mmol) was added in one portion to a suspension of piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.21 g, 0.85 mmol) and in tert-butanol (2 ml) in a microwave reactor tube. The tube was sealed and heated to 150° C. in a microwave for 40 minutes at a pressure of 250 psi. After this time the reaction mixture was cooled to room temperature and the solvent was removed. The resulting residue was purified by flash column chromatography (elution: 20% EtOAc, 80% Heptane) to give the title compound (0.36 g, 75% yield) as a colourless oil. δH (500 MHz, DMSO) 8.59 (s, 1H) 8.43 (d, J=2.05 Hz, 1H) 8.17 (dd, J=8.51, 2.05 Hz, 1H) 7.74-7.81 (m, 1H) 7.42 (d, J=7.88 Hz, 1H) 4.88-5.09 (m, 1H) 4.60-4.76 (m, 1H) 4.24-4.46 (m, 1H) 3.76-3.88 (m, 1H) 3.56 (d, J=13.08 Hz, 3H) 3.38-3.51 (m, 1H) 3.10-3.28 (m, 2H) 1.31-1.47 (m, 9H). Tr=3.71 min m/z (ES+) (M+H+) 283, 285.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[CH:11]([NH2:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:12]1([CH:11]([NH:24][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: NC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N#Cc1ccc(CNC(c2ccccc2)c2ccccc2)cc1

Procedure:
A mixture of para-cyanobenzyl bromide (13.72 g, 70 mmol), benzhydrylamine (13.79 g, 70 mmol) and potassium carbonate (16.8 g, 70 mmol) in ethanol (200 ml) was stirred under reflux for 5 hours. The mixture was allowed to cool, the resulting precipitate filtered off and the filtrate evaporated under reduced pressure. The residue was recrystallised from 80-100 petrol/isopropanol to give the title compound as an oil, 14.5 g.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O)[CH3:30]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:32]=3[O:31][CH2:29][CH3:30])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CCOc1c(C=O)cccc1OC
Product: CCOc1c(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cccc1OC

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-ethoxy-3-methoxy-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 543.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])(C)C.S(=O)(=O)(O)O.COC[O:25][CH3:26]>>[CH2:1]([C:4]1[CH:1]=[C:5]([CH3:10])[CH:6]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:26]=1[OH:25])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:6]=1[OH:16]
Reactant: COCOC
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=S(=O)(O)O
Product: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Temperature: 120 °C
Yield: 84.1 %

Procedure:
Into a reactor provided with a stirrer, thermometer and a heating bath there are charged 220 g (1 g.-mol) of 2,6-ditert.butyl-4-methylphenol, 2.2. g of concentrated sulfuric acid and the mixture is heated to the temperature of 120° C. While maintaining the temperature at 120° C., 94 g (1.24 g-mol) of methylal are fed into the reactor for 1.5 hour. On completion of the reaction, the catalyst is separated, volatile products are distilled under vacuum to give 143.0 g of 2,2'-methylene-bis(4-methyl-6-tert.butylphenol) which corresponds to 97.8% of theory as calculated for the reacted 2,6-ditert.butyl-4-methylphenol (conversion degree of the latter is 86.0%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[O:12][C:11]=2[CH:21]([N:23]2[C:27]3=[N:28][CH:29]=[N:30][C:31]([NH2:32])=[C:26]3[C:25]([C:33]3[CH:38]=[C:37]([OH:39])[CH:36]=[C:35]([F:40])[CH:34]=3)=[N:24]2)[CH3:22])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:41][C:42]([Si:45](Cl)([CH3:47])[CH3:46])([CH3:44])[CH3:43].N1C=CN=C1>CN(C)C=O.C(Cl)Cl>[C:1]([N:4]1[CH2:5][CH:6]=[C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[O:12][C:11]=2[CH:21]([N:23]2[C:27]3=[N:28][CH:29]=[N:30][C:31]([NH2:32])=[C:26]3[C:25]([C:33]3[CH:34]=[C:35]([F:40])[CH:36]=[C:37]([O:39][Si:45]([C:42]([CH3:44])([CH3:43])[CH3:41])([CH3:47])[CH3:46])[CH:38]=3)=[N:24]2)[CH3:22])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC=C(c2c(C(C)n3nc(-c4cc(O)cc(F)c4)c4c(N)ncnc43)oc(=O)c3ccccc23)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)N1CC=C(c2c(C(C)n3nc(-c4cc(F)cc(O[Si](C)(C)C(C)(C)C)c4)c4c(N)ncnc43)oc(=O)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.2 %

Procedure:
4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1H-isochromen-1-one (Example 72, 726 mg, 1.343 mmol) was dissolved in N,N-Dimethylformamide (7.5 ml), followed by the addition of TBDMSCl (405 mg, 2.69 mmol) and imidazole (366 mg, 5.37 mmol). The mixture stirred for 3 hrs at rt, then further 0.3 eq of TBDMSCl and imidazole were added to achieve full reaction completion The reaction was diluted with DCM (100 ml) and washed twice with 0.5M HClaqueous (50 ml), filtered through a phase separator, and concentrated under reduced pressure. The residue was purified via flash chromatography on silica gel using a Biotage 100G SNAP with a gradient of DCM and EtOH to give the title compound (635 mg, 72.2%) as pinky foam.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)[CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.C(O)C.[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:27]([NH2:34])[C@@H:26]1[OH:35]>ClC(Cl)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=3)[O:15][CH2:16][CH:17]([OH:18])[CH2:19][NH:34][C@@H:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:25][CH:26]3[OH:35])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3cccc(OC[C@H]4CO4)c3)noc2c1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Solvent: CCO
Solvent: CC(Cl)Cl
Product: OC(CN[C@@H]1c2ccccc2CC1O)COc1cccc(-c2noc3cc(F)ccc23)c1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(3-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dichloroethane, (1S, 2R)-(−)-cis-1-amino-2-indanol, and ethanol, essentially as described above in Example 57. Purity by LC/MS=100%, [M+H]+=435.