Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([NH:18][C:19]3[C:24]([F:25])=[CH:23][N:22]=[C:21](Cl)[N:20]=3)[CH:15]=[CH:16][CH:17]=2)[CH:5]=1.C(N(CC)CC)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:25][C:24]1[CH:23]=[N:22][C:21]2[NH:3][C:4]3[CH:9]=[CH:8][N:7]=[C:6]([CH:5]=3)[CH2:10][CH2:11][C:12]3[CH:13]=[C:14]([NH:18][C:19]=1[N:20]=2)[CH:15]=[CH:16][CH:17]=3
Reactant: Nc1ccnc(CCc2cccc(Nc3nc(Cl)ncc3F)c2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Fc1cnc2nc1Nc1cccc(c1)CCc1cc(ccn1)N2
Yield: 40.7 %

Procedure:
To a mixture of N-{3-[2-(4-aminopyridin-2-yl)ethyl]phenyl}-2-chloro-5-fluoropyrimidin-4-amine dihydrochloride (50.0 mg, 0.12 mmol) and triethylamine (0.05 mL, 0.36 mmol) in dry 1,4-dioxane (1.0 mL) was added (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4.16 mg, 0.007 mmol), palladium acetate (1.1 mg, 0.0048 mmol) and cesium carbonate (78.2 mg, 0.24 mmol). The cloudy mixture was degassed by bubbling N2 through the solution. The sealed tube was then microwaved at 150° C. for 30 min. The reaction mixture was diluted with THF, filtered and concentrated to give the residue, which was then triturated with MeOH/THF/EtOAc to provide the desired product as a white powder (15 mg, 41%). LCMS for C17H15FN5 (M+H)+: m/z=308.0. 1H NMR (400 MHz, DMSO-d6): δ 9.68 (s, 1H), 9.58 (s, 1H), 8.14 (m, 3H), 7.84 (s, 1H), 7.26 (dd, J=15.2, 7.2 Hz, 1H), 7.04 (dd, J=7.2, 2.0 Hz, 2H), 6.84 (dd, J=5.6, 2.0 Hz, 1H), 2.90 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH:16]3[CH2:17][CH2:18][CH:12]2[CH2:13][O:14][CH2:15]3)[N:3]=1.CI.[C:21]([O-])([O-])=O.[K+].[K+]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:21])=[C:4]([N:11]2[CH:12]3[CH2:18][CH2:17][CH:16]2[CH2:15][O:14][CH2:13]3)[N:3]=1
Reactant: Clc1nc(N2C3CCC2COC3)c2nc[nH]c2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1cnc2c(N3C4CCC3COC4)nc(Cl)nc21
Reaction time: 65 h
Yield: 98.2 %

Procedure:
A mixture of 2-chloro-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-9H-purine (650 mg, 2.45 mmol), methyl iodide (183 μL, 2.94 mmol) and K2CO3 (473 mg, 3.43 mmol) in THF (15 mL) was stirred at r.t. for 18 h before further methyl iodide (50 μL, 0.80 mmol) was added. The resulting mixture was allowed to stir for 65 h then concentrated in vacuo. The resulting residue was partitioned between EtOAc and H2O, the organic phase washed with brine, then dried (Na2SO4) and concentrated in vacuo affording the title compound as an off-white solid (673 mg, 98%). LCMS (method H): RT 2.63 min [M+H]+ 280.3
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:25]=[CH:26][C:27]=1[F:28])[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1.C(N(CC)CC)C>C(Cl)Cl>[F:28][C:27]1[CH:26]=[CH:25][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:8][C:7]=1[NH:6][C:2]([O:4][CH3:5])=[O:3]
Reactant: COC(=O)Cl
Reactant: COc1cc2ncnc(Nc3ccc(F)c(N)c3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Nc1cc(Nc2ncnc3cc(OC)c(OC)cc23)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 8.4 %

Procedure:
Methyl chloroformate (0.048 ml) was added to a suspension of 4-(3-amino-4-fluoroanilino)-6,7-dimethoxyquinazoline (161 mg) and triethylamine (0.14 ml) in dry methylene chloride (3.5 ml) and the resulting mixture was stirred at ambient temperature for 18 hours. Methylene chloride (100 ml) was added and the mixture washed with water and brine, dried over magnesium sulphate, filtered and evaporated to dryness. The residue was purified by silica column chromatography, eluting with 3% methanol in methylene chloride to yield the title compound as a solid (16 mg, 8.4%); NMR: 3.66 (s, 3H), 3.92 (s, 3H), 3.96 (s, 3H), 7.16 (s, 1H), 7.22 (t, 1H), 7.57 (m, 1H), 7.82 (s, 1H), 8.01 (m, 1H), 8.42 (s, 1H), 9.34 (s, 1H), 9.47 (s, 1H); m/s: M+H+ 373.
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([NH:9][C:10]2[CH:29]=[CH:28][C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([OH:27])=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][N:16]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.CN(C)C=O>O>[C:1]([C:5]1[CH:31]=[CH:30][C:8]([NH:9][C:10]2[CH:29]=[CH:28][C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH2:40][CH2:41][N:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][N:16]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)cc3)ncnc2cc1O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)cc3)ncnc2cc1OCCN1CCOCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
4-{4-[4-(Tert-butyl)anilino]phenoxy}-6-methoxy-7-quinazolinol (starting compound 11) (100 mg), potassium carbonate (50 mg), and 4-(2-chloroethyl)morpholine hydrochloride (67 mg) were added to N,N-dimethylformamide (2 ml), and the mixture was stirred at 80° C. overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and was dried over sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude thus obtained was purified by thin-layer chromatography on silica gel using chloroform/methanol for development to give the title compound (120 mg, yield 94%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[S:17][C:13]=3[C:12](=[O:24])[N:11]=[C:10]2SC)[CH:5]=[CH:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1>ClCCl>[Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[S:17][C:13]=3[C:12](=[O:24])[NH:11][C:10]2=[O:36])[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1c(Cl)cccc1Cn1c(=O)[nH]c(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[(3-chloro-2-methylphenyl)methyl]-5-(methylthio)-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (25 mg, 0.059 mmol) in Dichloromethane (DCM) (500 μl) was added m-CPBA (13.25 mg, 0.059 mmol) in Dichloromethane (DCM) (300 μl) at 0° C. After stirring at room temperature for 3 h, the solution was washed with 5% aqueous sodium hydrogen sulfite followed by saturated aqueous sodium bicarbonate. The organic layer was dried (sodium sulfate), filtered, and concentrated. The crude was purified by reversed-phase HPLC to provide 4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione. (11 mg, 47%); LC/MS: MS (ES+) m/e 393 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 3H), 3.47-3.54 (m, 4H), 3.63-3.71 (m, 4H), 5.18 (s, 2H), 6.90 (d, J=7.3 Hz, 1H), 7.15 (m, 1H), 7.34 (d, J=7.3 Hz, 1H), 11.37 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:6]1[N:7]=[C:8]([NH:11]C(OCC(Cl)(Cl)Cl)=O)[S:9][CH:10]=1)[CH3:2]>C(O)=O.[Zn]>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Agent: [Zn]
Solvent: O=CO
Product: CCOC(=O)C(NC(=O)OC(C)(C)C)c1csc(N)n1
Yield: 71.2 %

Procedure:
To a solution of 2.80 g of α-t-butyloxycarbonylamino-α-[2-(trichloroethoxycarbonylamino)thiazol-4-yl]acetic acid ethyl ester in 60 ml of 90% formic acid is added 2.80 g of zinc dust under cooling and stirring. The mixture is stirred for 1 hour and zinc dust is filtered off. The filtrate is poured into water and the resultant solution is extracted with ethyl acetate. The organic layer is washed with saturated sodium bicarbonate aq. solution and then water, and dried over anhydrous magnesium sulfate. The distillation of the solvent gives 1.26 g (yield, 71.2%) of α-t-butyloxycarbonylamino-α-(2-aminothiazol-4-yl)acetic acid ethyl ester as crystals. Melting point: 143°-144° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([NH:23][C@@H:24]3[CH2:28][CH2:27][CH2:26][C@@H:25]3[NH:29]C(=O)OC(C)(C)C)[N:17]=[CH:16]4)=[C:9]([O:37][CH3:38])[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.Cl>O1CCOCC1.ClCCl>[NH2:29][C@H:25]1[CH2:26][CH2:27][CH2:28][C@H:24]1[NH:23][C:18]1[N:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:6])=[CH:8][C:9]=3[O:37][CH3:38])[CH:14]=2)[N:19]=1
Reactant: COc1cc(C(=O)NC2CC2)ccc1-c1ccc2nc(N[C@@H]3CCC[C@@H]3NC(=O)OC(C)(C)C)ncc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CC2)ccc1-c1ccc2nc(N[C@@H]3CCC[C@@H]3N)ncc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl ((1S,2R)-2-((6-(4-(cyclopropylcarbamoyl)-2-methoxyphenyl)quinazolin-2-yl)amino)cyclopentyl)carbamate (58 mg, 0.11 mmol) and 4M HCl in Dioxane (0.8 mL) in dichloromethane (1.5 mL) was stirred at room temperature for 120 minutes. LC-MS indicated complete consumption of SM. The reaction mixture was concentrated and used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:33])[O:5][C:6]1[CH:7]=[C:8]([CH:19]=[C:20]([C:22]2[NH:23][C:24]([C:27]3[O:28][C@@H:29]([CH3:32])[CH2:30][N:31]=3)=[CH:25][CH:26]=2)[CH:21]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1.[Cl-].[Na+].O>[CH3:1][O:2][CH2:3][C@H:4]([CH3:33])[O:5][C:6]1[CH:7]=[C:8]([CH:19]=[C:20]([C:22]2[NH:23][C:24]([C:27]3[O:28][C@@H:29]([CH3:32])[CH2:30][N:31]=3)=[CH:25][CH:26]=2)[CH:21]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([N:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)=[O:17])=[N:14][CH:15]=1
Reactant: CN1CCNCC1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)O)nc2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCN(C)CC3)nc2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)pyridine-2-carboxylic acid (270 mg, 0.60 mmol) synthesized in Example (129f) was dissolved in tetrahydrofuran (5 mL), and N-methylpiperazine (199 μl, 1.79 mmol), HATU (454 mg, 1.19 mmol) and N,N-diisopropylethylamine (624 μL, 3.58 mmol) were added, followed by stirring at room temperature for 3 days under nitrogen atmosphere. To the reaction solution, saturated brine (15 mL) was added, and extraction was carried out twice with ethyl acetate (15 mL), followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired compound (208 mg, yield 65%) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.Cl.CO>O>[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[C:8]2=[O:12])=[CH:16][CH:15]=1
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1C(=Cc2ccc(O)cc2)CCc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
After 6-hydroxy-1-tetralone 1.0 g and 4-hydroxybenzaldehyde 0.903 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for one hour and cooled to room temperature, and water 200 ml was added and allowed to stand for one hour. The precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for four hours under reduced pressure to obtain the desired compound 0.941 g.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:12][O:11][C:10](=[O:13])[CH2:9]1.[CH3:14][CH2:15][Mg+].[Br-]>C1COCC1>[OH:11][CH2:12][CH:8]([O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:9][C:10]1([OH:13])[CH2:15][CH2:14]1
Reactant: CC[Mg+]
Reactant: O=C1CC(OC2CCCCO2)CO1
Agent: [Br-]
Solvent: C1CCOC1
Product: OCC(CC1(O)CC1)OC1CCCCO1
Reaction time: 2 h
Yield: 74 %

Procedure:
To a solution of 4-(tetrahydro-2H-pyran-2-yloxy)-dihydrofuran-2(3H)-one (2.23 g, 12 mmol) and Ti(Oi-Pr)4 (0.68 g, 2.4 mmol, Aldrich) in 40 mL of dry THF at 15° C. under N2 was added EtMgBr (30 mmol, 10 mL, 3M ether solution, Aldrich) dropwise via a syringe pump over 2 hrs. The temperature of the reaction was always kept below 20° C. After stirring for 2 hrs, the reaction mixture was quenched with 30 mL of saturated NH4Cl aqueous solution, and was extracted with ethyl acetate (50 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (1:1 (v/v) EtOAc/n-hexane) to afford 1-(3-hydroxy-2-(tetrahydro-2H-pyran-2-yloxy)propyl)cyclopropanol as yellow oil (1.92 g, 73%).2
Reaction SMILES: Br[C:2]1[C:31]2=[N:32][C:28]3=[CH:29][N:30]2[C:5]([N:6]2[CH2:38][CH2:37][C:9]([CH3:39])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([CH3:36])[O:16][C:17]4[CH:18]=[CH:19][C:20]([F:35])=[C:21]([F:34])[C:22]=4[C:23]4[CH:33]=[C:27]3[CH:26]=[CH:25][CH:24]=4)[CH2:8][CH2:7]2)=[C:4]([C@H:40]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:41]([O:43][CH3:44])=[O:42])[C:3]=1[CH3:50].[C:51](O[C@@H](C1C(C)=C(C=C)C2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(F)=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)[CH3:52]>>[C:46]([O:45][C@@H:40]([C:4]1[C:3]([CH3:50])=[C:2]([CH:51]=[CH2:52])[C:31]2=[N:32][C:28]3=[CH:29][N:30]2[C:5]=1[N:6]1[CH2:38][CH2:37][C:9]([CH3:39])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([CH3:36])[O:16][C:17]2[CH:18]=[CH:19][C:20]([F:35])=[C:21]([F:34])[C:22]=2[C:23]2[CH:33]=[C:27]3[CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7]1)[C:41]([O:43][CH3:44])=[O:42])([CH3:48])([CH3:49])[CH3:47]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Br)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1
Reactant: C=Cc1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Product: C=Cc1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1c(ccc(F)c1F)O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 52.5 %

Procedure:
Prepared in 52.5% yield from methyl(2S)-2-[(22S)-5-bromo-16,17-difluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]-2-(tert-butoxy)acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-5-ethenyl-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. LCMS (ESI, M+1): 702.4.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[C:4]([O:36][CH3:37])=[CH:5][C:6]([O:34][CH3:35])=[C:7]([N:9]=[C:10]2[N:14]([CH3:15])[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([S:24](=[O:33])(=[O:32])[N:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])[CH:18]=3)(O)[CH2:12][S:11]2)[CH:8]=1>C(O)(=O)C>[BrH:1].[Cl:2][C:3]1[C:4]([O:36][CH3:37])=[CH:5][C:6]([O:34][CH3:35])=[C:7]([N:9]=[C:10]2[N:14]([CH3:15])[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([S:24](=[O:33])(=[O:32])[N:25]([CH2:26][CH2:27][CH3:28])[CH2:29][CH2:30][CH3:31])[CH:18]=3)=[CH:12][S:11]2)[CH:8]=1
Reactant: CCCN(CCC)S(=O)(=O)c1cc(C2(O)CSC(=Nc3cc(Cl)c(OC)cc3OC)N2C)ccc1Cl
Agent: Br
Solvent: CC(=O)O
Product: CCCN(CCC)S(=O)(=O)c1cc(-c2csc(=Nc3cc(Cl)c(OC)cc3OC)n2C)ccc1Cl

Procedure:
Obtained by a procedure analogous to that indicated in Example 1(b), from 2-(5-chloro-2,4-dimethoxyphenyl-imino)-4-(4-chloro-3-dipropylsulfamoylphenyl)-3-methylthiazolidin-4-ol hydrobromide, by boiling in glacial acetic acid and stirring the residue under water after distilling off the solvent. Amorphous, glassy solid; melting point 130°-150° C.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]=2[O:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[OH-].[Na+]>>[Cl:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:3][O:4][C:5]=2[CH:10]=1
Reactant: Clc1ccc2c(Cl)noc2c1
Reactant: C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc2c(N3CCNCC3)noc2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 71.1 %

Procedure:
3,6-dichlorobenzisoxazole (5.2 g, 27.8 mmol), and anhydrous piperazine (24 g, 278 mmol) are placed in an egg type flask and react at 120° C. for 24 hours. After completion of the reaction, 52 ml of an ice-water mixture is added for quenching the reaction. Further 15 ml of 50% NaOH solution is added to the reaction solution. The reaction solution is stirred for 5 minutes and extracted with dichloromethane (30 ml×3). The dichloromethane layer is combined, washed with 20 ml of saturated saline, dried over anhydrous MgSO4, evaporated to dryness, and subjected to a separation on a column of alumina (200-300 mesh), eluting with dichloromethane:methanol-100:1, to obtain 4.7 g of 6-chloro-3-piperazinyl-benzisoxazole, with a yield of 71%.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[N:21]=1>CN(C)C=O>[Cl:26][C:22]1[N:21]=[C:20]([CH2:19][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])[CH:25]=[CH:24][CH:23]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: Clc1cccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1cccc(Cl)n1
Yield: 91 %

Procedure:
By using (3,3,3-trifluoropropyl)malononitrile (226 mg), N,N-dimethylformamide (5 ml), potassium carbonate (193 mg) and 2-(bromomethyl)-6-chloropyridine (335 mg) according to the similar method described in Production Example 4 was obtained 365 mg of 2-((6-chloro-2-pyridyl)methyl)-2-(3,3,3-trifluoropropyl)malononitrile represented by the following formula (the present invention compound (8)).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])/[C:5](/[F:25])=[C:6](\[C:8]1[CH:9]=[C:10]([CH:22]([CH3:24])[CH3:23])[CH:11]=[C:12]2[C:17]=1[N:16]([CH2:18][CH3:19])[CH2:15][CH2:14][C:13]2([CH3:21])[CH3:20])/[CH3:7])[CH3:2].[H-].[CH2:28]([Al+]CC(C)C)C(C)C>C1COCC1>[CH2:1]([O:3][C:4](=[O:26])/[C:5](/[F:25])=[C:6](\[C:8]1[CH:9]=[C:10]([CH:22]([CH3:24])[CH3:23])[CH:11]=[C:12]2[C:17]=1[N:16]([CH2:18][CH2:19][CH3:28])[CH2:15][CH2:14][C:13]2([CH3:21])[CH3:20])/[CH3:7])[CH3:2]
Reactant: CC(C)C[Al+]CC(C)C
Reactant: CCOC(=O)/C(F)=C(/C)c1cc(C(C)C)cc2c1N(CC)CCC2(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CCCN1CCC(C)(C)c2cc(C(C)C)cc(/C(C)=C(/F)C(=O)OCC)c21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (E)-3-(1-ethyl-6-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-8-yl)-2-fluoro-but-2-enoic acid ethyl ester (Intermediate 15, 199 mg, 0.55 mmol) in 10 ml of anhydrous THF under argon at 0° C. was added a 1.0 M solution of diisobutylaluminum hydride (2.20 ml, 2.20 mmol) in hexanes. The resulting mixture was stirred at 0° C. to 25° C. for 1 h. The reaction was cooled to 0 ° C. and quenched slowly with saturated NH4Cl (0.5 ml), Celite (200 mg), and diluted with diethyl ether (10 ml). The resulting mixture was stirred at 25 ° C. for 1 hour. The product was filtered through a pad of Celite. The solution was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography using ethyl acetate: hexane (1:4) to yield the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[O:10][C:9](=[O:11])[C:8]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])=[C:7]([OH:21])[C:6]=1[Cl:22])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>C(OCC)(=O)C.C1(C)C=CC=CC=1.CC(C)=O>[C:30]([O:21][C:7]1[C:6]([Cl:22])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[O:10][C:9](=[O:11])[C:8]=1[C:12]1[C:13]([CH3:20])=[CH:14][C:15]([CH3:19])=[CH:16][C:17]=1[CH3:18])(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: Cc1cc(C)c(-c2c(O)c(Cl)c(C(C)(C)C)oc2=O)c(C)c1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1c(Cl)c(C(C)(C)C)oc(=O)c1-c1c(C)cc(C)cc1C
Temperature: 20 °C
Reaction time: 20 h
Yield: 56.5 %

Procedure:
6.4 g (20 mmol) of 6-tert-butyl-5-chloro-4-hydroxy-3-(2,4,6-trimethylphenyl)-2-pyrone (Ex. I-a-4) are initially charged in 50 ml of ethyl acetate. At 20° C., 2.02 g (20 mmol) of triethylamine are added, and at 0° C. a solution of 1.6 g (20 mmol) of acetyl chloride in 20 ml of ethyl acetate is added dropwise. The mixture is subsequently stirred at 20° C. for 20 h. Precipitated triethylamine hydrochloride is filtered off with suction and washed with ethyl acetate. The combined mother liquors are washed twice with 50 ml of half-concentrated sodium chloride solution each time, dried over magnesium sulphate and concentrated under reduced pressure. 7.2 g of crude product are obtained. Flash chromatography over silica gel 60 (35-70 μm) using toluene:acetone 30:1 as eluent yields 4.1 g (57% of theory) of 4-acetyloxy-6-tert-butyl-5-chloro-(2,4,6-trimethylphenyl)-2-pyrone of melting point 116-118° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:4][CH:5]=[CH:6][CH:7]=[CH:8][C:9](Cl)=[O:10].[C:20]1([NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:26].CN1CCOCC1>C(Cl)Cl>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:27][C:9](=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH2:4][CH:3]([O:2][CH3:1])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: Nc1ccccc1N
Reactant: COc1ccc(C(CC=CC=CC(=O)Cl)OC)cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(C(CC=CC=CC(=O)Nc2ccccc2N)OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.5 %

Procedure:
To a stirred solution of acid chloride 5 (115 mg,0.41 mmol) in CH2Cl2 (5 mL) at 0° C. was added 1,2-phenylenediamine (133 mg,1.23 mmol) followed by N-methylmorpholine (49 μL, 0.45 mmol). The mixture was stirred at 0° C. for 1 h, and then was allowed to warm to rt over 1 h. After being stirred for an additional 1 h at rt, the reaction mixture was partitioned between CHCl3 (2×15 mL) and water (15 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by flash silica gel chromatography (50% ethyl acetate in hexane) afforded the desired benzamide 18 (21 mg, 15% yield): 1H NMR (300 MHz, CDCl3) δ 6.65-7.40 (m, 9H), 5.96-6.20 (m, 2H), 5.92 (d, J=15.3 Hz, 1H), 4.18 (m, 1H), 3.82 (br s, 2H), 3.81 (s, 3H ), 3.19 (s, 3H), 2.61 (m, 1H), 2.43 (m, 1H); 13CNMR (75.4 MHz,CDCl3) δ 41.7, 55.2, 56.4, 82.7, 113.8, 118.2, 119.5, 121.8, 124.4, 125.0, 127.0, 127.8, 130.1, 133.1, 139.5, 140.7, 142.4, 159.2, 164.6.