Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[C:12](=[O:21])[NH:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1.[N+:22](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C=O)C>[NH2:22][N:13]1[C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=2[Cl:3])[C:12]1=[O:21]
Reactant: O=c1[nH]c(C(F)(F)F)ccc1-c1ccc(Cl)cc1Cl
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nn1c(C(F)(F)F)ccc(-c2ccc(Cl)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
10 ml of DMF was added to 0.10 g of 60% sodium hydride, and 0.72 g of 3-(2,4-dichlorophenyl)-6-trifluoromethyl-2(1H)-pyridone was added thereto under cooling with ice, followed by stirring further at room temperature for 30 minutes. Then, 0.47 g of 2,4-dinitrophenoxyamine was added thereto at room temperature. Then, the mixture was stirred at 50° C. for 1 hour to complete the reaction. After completion of the reaction, the reaction solution was washed with water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off to obtain a crude product. This crude product was purified by silica gel column chromatography to obtain 0.50 g (yield: 68%) of the desired product. Melting point: 98-100° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C(F)(F)F)(=O)=O)=[C:5]([O:17][CH3:18])[CH:4]=1)=[O:2].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C)C=O>[CH3:18][O:17][C:5]1[CH:4]=[C:3]([CH:1]=[O:2])[CH:8]=[CH:7][C:6]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]([F:31])([F:30])[F:19]
Reactant: COc1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1-c1ccccc1C(F)(F)F
Temperature: 120 °C
Yield: 73.3 %

Procedure:
A stirred solution of trifluoromethanesulfonic acid 4-formyl-2-methoxy-phenyl ester of Step A (6.9 g, 22.1 mmol), 2-trifluoromethyl phenyl boronic acid (5.4 g, 28.6 mmol) and potassium phosphate (13.2 g, 62.2 mmol) in N,N-dimethylformamide (120 mL) was degassed with nitrogen, whereupon a catalytic amount (0.285 g) of [1,4-bis-(diphenylphosphine)butane]palladium (II) dichloride was added. The solution was heated to 120° C. for 5 hours, poured into water and extracted with ethyl acetate. The combined extracts were washed with water, dried over anhydrous magnesium sulfate and filtered through a plug of silica gel. Removal of the solvent provided the crude title compound (4.54 g) as an oil, which was used as such in the next step.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[S:21])[NH:12][C:13]2[C:18](Br)=[CH:17][CH:16]=[CH:15][C:14]=2Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].CC(C)([O-])C.[Na+].[NH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:21][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([N:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)[C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CNCCN1
Reactant: CC(C)(C)c1ccc(C(=S)Nc2c(Br)cccc2Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(-c2nc3c(N4CCNCC4)cccc3s2)cc1
Temperature: 80 °C
Yield: 42 %

Procedure:
4-tert-butyl-N-(2,6-dibromophenyl)benzenecarbothioamide prepared as in Example 19 (0.200 g, 0.468 mmol) was dissolved in dioxane (4 mL) and treated with Pd2 dba3 (4.3 mg, 0.0468 mmol), o-biphenyl(tBu)2P (15.4 mg, 0.0515 mmol) and Cs2CO3 (0.229 g, 0.702 mmol). The mixture was heated to 80° C. for 2 h until the starting material was consumed and cooled. To the reaction mixture was then added toluene (2 mL), Pd2 dba3 (4.3 mg, 0.0468 mmol), o-biphenyl(tBu)2P (15.4 mg, 0.0515 mmol), sodium tert-butoxide (0.090 g, 0.936 mmol) and piperazine (0.403 g, 4.68 mmol). The mixture was heated at 80° C. for 1 h and filtered through celite. The filtrate was diluted with dichloromethane, washed with water and saturated sodium chloride, and concentrated. The crude material was purified by reverse-phase HPLC to yield 69.5 mg (42%) of the product. MS (ES) m/z 352.1; HPLC Method B, purity 100% at 210-370 nm, 9.8 min.; 99.4% at 310 nm, 9.8 min.; HRMS: calcd for C21H25N3S+H+, 352.18419; found (ESI, [M+H]+), 352.1841.
Reaction SMILES: [SH:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[N:3]=1.[O-]Cl.[Na+].[OH-].[NH4+:18]>[OH-].[Na+].O>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[N:3]=[C:2]([S:1][NH2:18])[S:6][N:5]=1
Reactant: [NH4+]
Reactant: Sc1nc(-c2ccccc2Cl)ns1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: NSc1nc(-c2ccccc2Cl)ns1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 25 g of 5-mercapto-3-(2-chlorophenyl)-1,2,4-thiadiazole in 500 ml of 4% sodium hydroxide and a solution prepared by diluting 238 ml of 5.25% NaOCl to 500 ml with water were added dropwise simultaneously to 1020 ml of ammonium hydroxide solution while maintaining the mixture at 0° C. with an ice/methanol bath. The resulting mixture was stirred for 15 minutes and the solids were collected, washed with water and dried under high vacuum (P2O5) to give 15.4 g of solid, m.p. 143°-145°.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[O:11][CH3:12].[F:13][CH:14]([F:17])[CH2:15][OH:16]>>[F:13][CH:14]([F:17])[CH2:15][O:16][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: OCC(F)F
Reactant: COc1cc(C(C)=O)cnc1Cl
Product: COc1cc(C(C)=O)cnc1OCC(F)F
Yield: 72 %

Procedure:
The title compound is prepared in 72% yield (0.94 g, a white solid) from 1-(6-chloro-5-methoxypyridin-3-yl)ethanone (1.04 g, 5.60 mmol, Step-2 of Amine-22) and 2,2-difluoroethanol instead of 2,2,2-trifluoroethanol by the similar manner in Step-1 of Amine-2.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1[C:25]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[C:24]([S:36]([CH3:39])(=[O:38])=[O:37])[CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].[CH3:40][C:41]([N:44]1[C:48]([OH:49])=[CH:47][CH:46]=[N:45]1)([CH3:43])[CH3:42].C(N(CC)CC)C.CC(C)(O)C#N>C(#N)C>[CH3:40][C:41]([N:44]1[C:48]([OH:49])=[C:47]([C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:24]([S:36]([CH3:39])(=[O:37])=[O:38])=[C:25]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:28][CH:27]=3)[C:17]=2[CH3:16])[CH:46]=[N:45]1)([CH3:43])[CH3:42]
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1-c1ccc(S(C)(=O)=O)cc1
Reactant: CC(C)(C)n1nccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(O)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)c2cnn(C(C)(C)C)c2O)ccc(S(C)(=O)=O)c1-c1ccc(S(C)(=O)=O)cc1
Reaction time: 3 h

Procedure:
A solution of 560 mg (2.7 mmol) of 1,3-dicyclohexylcarbodiimide in 5 mL of acetonitrile was added with stirring to a mixture of 2-methyl-4-methylsulfonyl-3-(4-methylsulfonylphenyl)benzoic acid and 378 mg (2.7 mmol) of 1-(1,1-dimethylethyl)-5-hydroxypyrazole in 15 mL of acetonitrile. The mixture was allowed to react for 1 hour and was then filtered. The solids were washed with a little acetonitrile. Triethylamine (1.13 mL, 8.1 mmol) and 274 microliters (2.7 mmol) of acetone cyanohydrin were added with stirring to the combined filtrate and acetonitrile wash. After 3 hours, the mixture was diluted with dichloromethane and the resulting solution was washed with 2N aqueous hydrochloric acid, filtered, and concentrated by evaporation under reduced pressure. The residue was dissolved in the minimum amount of hot ethanol and the solution was then cooled. The precipitate that formed was collected by filtration and dried to obtain the title compound as a pale yellow powder melting at 187-188° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]2[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:13]=[C:14]([CH2:15][C:16](O)=[O:17])[C:3]1=2.O1CCCC1.C(N1C=CN=C1)([N:32]1C=CN=C1)=O.N>O.CN(C)C=O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]2[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:13]=[C:14]([CH2:15][C:16]([NH2:32])=[O:17])[C:3]1=2
Reactant: O=C(O)Cc1nn(-c2ccccn2)c2[nH]c3ccccc3c(=O)c12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)Cc1nn(-c2ccccn2)c2[nH]c3ccccc3c(=O)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
To a solution of 2-[4-oxo-1-(2-pyridinyl)-4,9-dihydro-1H-pyrazolo[3,4-b]quinolin-3-yl]acetic acid (1.60 g, 5.0 mmol) in a mixed solvent of tetrahydrofuran (100 mL) and N,N-dimethylformamide (20 mL), 1,1′-carbonyldiimidazole (0.89 g, 5.5 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Subsequently, 25% aqueous ammonia solution was added to the mixture and the resulting solution was stirred at room temperature for 1 hour. The solution was poured into water, and the resulting precipitate was collected by filtration. The collected crude crystals were washed with water, and dried to give the title compound (0.94 g, 59% yield).
Reaction SMILES: [F:1][C:2]1([F:22])[CH:6](OS(C(F)(F)F)(=O)=O)[CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.[N-:23]=[N+:24]=[N-:25].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.CC(OC)(C)C>[N:23]([CH:6]1[CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][C:2]1([F:22])[F:1])=[N+:24]=[N-:25]
Reactant: CC(C)(C)OC(=O)N1CC(OS(=O)(=O)C(F)(F)F)C(F)(F)C1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(N=[N+]=[N-])C(F)(F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
tert-Butyl 3,3-difluoro-4-{[(trifluoromethyl)sulfonyl]oxy}pyrrolidine-1-carboxylate (5.56 g, 15.2 mmol) was dissolved in DMF (20 mL) and cooled in an ice bath under nitrogen atmosphere. Tetrabutylammonium azide (TBA-N3, 4.8 g, 17 mmol, 1.1 mol eq) in DMF (15 mL) was added slowly over 15 min via an addition funnel. The reaction mixture was stirred in the cold bath and was allowed to warm to ambient temperature gradually. After 16 hr, the reaction was diluted with MTBE (300 mL), washed with sat. aq. NaHCO3 (2×30 mL), and brine (2×30 mL), dried over Na2SO4 and evaporated to give a residue. This crude material was purified on silica (40 g) with gradients from 100% heptane to 20% ethyl acetate-80% heptane to give the title product as a colorless oil (3.02 g, 80% yield, >95% purity). 1H NMR (400 MHz, chloroform-d) δ ppm 4.06 (dtd, J=8.86, 5.41, 5.41, 3.91 Hz, 1 H) 3.65-3.83 (m, 3 H) 3.36-3.57 (m, 1 H) 1.47 (s, 9 H). 19F NMR (376 MHz, chloroform-d) δ ppm −106.10-−102.44 (m, 1 F) −120.14-−116.68 (m, 1 F). m/z (ESI+) for C9H14F2N4O2 149 (small)/123 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.[H-].[Na+].[CH2:14]([O:16][CH2:17][CH2:18]Cl)[CH3:15]>CN(C)C=O.C(Cl)(Cl)Cl.[Cl-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH2:15][CH2:14][O:16][CH2:17][CH3:18])=[N:7][C:6]=2[CH:11]=1
Reactant: Sc1nc2cc(Cl)ccc2s1
Reactant: CCOCCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOCCSc1nc2cc(Cl)ccc2s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
5.00 g (24.8 mmol) of 5-chloro-2-mercaptobenzothiazole was dissolved in 25 ml of N,N-dimethylformamide. 710 mg (29.6 mmol) of sodium hydride was added to the above solution and the mixture was stirred for one hour. Then, 5.44 ml (49.6 mmol) of 2-chloroethyl ethyl ether was added to the resulting suspension. and the mixture was stirred for two hours while heating at 50° C. The reaction mixture was diluted with 500 ml of chloroform and 500 ml of 20% aqueous solution of sodium chloride was added thereto. After shaking and washing the mixture, the chloroform layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was separated and purified by silica gel chromatography using a solution of hexane/ethyl acetate (10/1 by volume) as a developing solvent. Thus, 5.40 g of the desired compound was obtained in the form of a colorless oily substance. Yield: 80%.
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1(=[O:14])[CH2:13][CH2:12][CH:11]=[CH:10]1.[Cl-].[NH4+].C(OCC)C>C1COCC1>[C:1]1([C:10]2[CH2:11][CH2:12][CH2:13][C:9]=2[OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C=CCC1
Reactant: Cl[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1=C(c2ccccc2)CCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 160 ml (120 mmol) of a THF solution of phenylmagnesium chloride, a solution of 8.38 ml (100 mmol) of 2-cyclopentenone in 70 ml of THF was dropwise added with ice cooling. The mixture was stirred at 0° C. for 1 hour and then further stirred at room temperature for 1 hour. Then, 200 ml of an ammonium chloride saturated aqueous solution was added. To the reaction solution, diethyl ether was added to perform extraction. The resulting ether solution was dried over magnesium sulfate, and the solvent was distilled off to obtain of a crude product of phenylcyclopentenol as a gold liquid (17.5 g). In a glass tube oven, 6 g of the crude product was placed, and the product was heated at 180 to 190° C. for 1 hour at atmospheric pressure, then cooled to room temperature and slowly heated (finally) to 195° C. under reduced pressure (1 to 4 mmHg) As a result, 2.5 g of a white crystal was sublimed (51.3%).
Reaction SMILES: C(OC([N:8]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([F:40])([F:39])[F:38])[C:9]1[CH:21]=[CH:20][C:12]([C:13](C2N=CNC=2)=[O:14])=[CH:11][CH:10]=1)=O)(C)(C)C.[OH-].[Na+].[NH2:43][CH2:44][CH:45]([OH:48])[CH2:46][OH:47]>C(Cl)(Cl)Cl>[OH:48][CH:45]([CH2:46][OH:47])[CH2:44][NH:43][C:13](=[O:14])[C:12]1[CH:11]=[CH:10][C:9]([NH:8][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([F:38])([F:39])[F:40])=[CH:21][CH:20]=1
Reactant: NCC(O)CO
Reactant: CC(C)(C)OC(=O)N(CCCCCCCCCCCCCCCC(F)(F)F)c1ccc(C(=O)c2c[nH]cn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C(NCC(O)CO)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a mixture containing 4.3 g. of 1-{4-[N-(tert-butyloxycarbonyl)-4-[15-(trifluoromethyl)pentadecylamino]benzoyl}imidazole, 50 ml. of chloroform, and 50 ml. of 5 N sodium hydroxide is added 1.1 g. of 3-amino-1,2-propanediol. The solution is vigorously stirred for 24 hours, the layers are separated, and the chloroform solution is washed once with 50 ml. of 1 N sodium hydroxide. The solvent is evaporated and the residue is heated for 30 minutes at 40° C. in 50 ml. of anhydrous trifluoroacetic acid. The solvent is again evaporated and the oil is crystallized from acetone to yield the product as a light yellow solid.
Reaction SMILES: [C:1]([Si:5]([CH3:36])([CH3:35])[O:6][CH2:7][C:8]#[C:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[N:14]=[C:13]2[NH:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([Cl:34])[CH:28]=1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.CO>[Si:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[N:14]=[C:13]2[NH:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([Cl:34])[CH:28]=1)([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)OCC#Cc1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCc1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
A suspension of 6-(3-(tert-butyldimethyl silyloxy)prop-1-ynyl)-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine (0.20 g, 0.39 mmol) and 5% Pd—S—C (40 mg) in EtOAc (5 mL) and MeOH (5 mL) was stirred overnight at room temperature under hydrogen atmosphere. The reaction mixture was filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluted with hexane/ethyl acetate 6:1 to 2:3) to give 0.15 g of 6-(3-(tert-butyldimethylsilyloxy)propyl)-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine as yellow solid (74%). LCMS m/z=523 (M+1) (Method D) (retention time=3.35 min). 1H NMR (300 MHz, CDCl3) δ 9.69 (dd, J=2.2, 0.8 Hz, 1H), 8.79-8.65 (m, 2H), 8.07 (dd, J=6.5, 2.7 Hz, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.76-7.61 (m, 3H), 7.47-7.37 (m, 2H), 7.31-7.18 (m, 1H), 3.68 (t, J=6.1 Hz, 2H), 3.01-2.83 (m, 2H), 2.03-1.86 (m, 2H), 0.94 (s, 9H), 0.08 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([C:18]2[CH:19]=[N:20][N:21]([CH2:27][CH2:28][O:29]C)[C:22]=2[C:23]([F:26])([F:25])[F:24])[O:11][N:10]=1.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([C:18]2[CH:19]=[N:20][N:21]([CH2:27][CH2:28][OH:29])[C:22]=2[C:23]([F:25])([F:24])[F:26])[O:11][N:10]=1
Reactant: COCCn1ncc(-c2onc(-c3c(F)cccc3Cl)c2C(=O)OC)c1C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(CCO)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(2-chloro-6-fluorophenyl)-5-(1-(2-methoxyethyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylate (example I-102) (27 mg, 0.06 mmol) in CH2Cl2 (1 mL) was added Bortribromide (0.06 mmol). The mixture was stirred at 0° C. for 1 h. The mixture was poured into iced water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was purified by pTLC (PE:EE 1:1) to yield example I-83 as an oil (10 mg, 34%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11]([CH:14]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)[C:15]([O:17][CH3:18])=[O:16])(O)[CH2:10]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.N1(C2CCCCCCCCCC2)CCCCCCCCCN1>ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][C:11](=[C:14]([C:19]3[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=3)[C:15]([O:17][CH3:18])=[O:16])[CH2:12]2)=[CH:32][CH:31]=1
Reactant: COC(=O)C(c1cc(F)cc(F)c1)C1(O)CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: 25 °C

Procedure:
A solution of 0.71 g (1.44 mmol) of methyl {1-[bis(4-chlorophenyl)methyl]-3-hydroxyazetidin-3-yl}(3,5-difluorophenyl)acetate, 0.295 g (1.73 mmol) of methanesulfonyl anhydride, and 0.400 mL pyridine in 5 mL of dichloromethane was stirred at room temperature overnight. To this was added 0.400 mL of diazabicycloundecane and the solution remained stirring at room temperature. The mixture was partitioned between ether and water and the aqueous layer was washed with 20 mL of ether. The organic layers were washed with brine, combined, dried over MgSO4 and concentrated. The residue was filtered through a pad of silica gel using 20% ether-hexane to afford the title compound; 1NMR (CDCl3) δ 3.67 (s, 3H), 3.84 (m, 2H), 4.25 (m, 2H), 4.54 (s, 1H), 6.76 (m, 1H), 6.78 (m, 2H), 7.33 (m, 4H), 7.38 (m, 4H); Mass Spectrum: m/e=474 (M+1 35Cl, 35Cl) and 476 (M+1 35Cl, 37Cl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21](C)[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.BrC1C(N2CCC(C3NC=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)=NC=NC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[NH:21][CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:33])([F:35])[F:34])[CH:26]=4)[N:24]=3)[CH2:18][CH2:19]2)=[CH:6][CH:7]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Agent: Fc1ccc(-c2c[nH]c(C3CCN(c4ncncc4Br)CC3)n2)cc1C(F)(F)F
Product: Nc1ncnc(N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)c[nH]3)CC2)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 5-bromo-4-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine instead of 5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine. LC-MS: (M+1=501, obsd.=501).
Reaction SMILES: [C:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH3:17])[C:11]([CH3:19])([CH3:18])[CH2:10]1)(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C.O.C1(C)C=CC=CC=1>[C:4]([O:6][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:5])[CH2:3][CH2:2][C:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:15])([CH3:16])[N:12]([CH3:17])[C:11]([CH3:19])([CH3:18])[CH2:10]1)=[O:7]
Reactant: CN1C(C)(C)CC(OC(=O)CCC(=O)[O-])CC1(C)C
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCCCCCOC(=O)CCC(=O)OC1CC(C)(C)N(C)C(C)(C)C1
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
A mixture of 35.3 g (0.13 mol) of mono(1,2,2,6,6-pentamethyl-4-piperidyl) succinate, 25.1 g (0.13 mol) of 1-bromooctane and 13.2 g (0.13 mol) of triethylamine in 70 ml of anhydrous N,N-dimethylacetamide is heated for 4 hours at 85° C. After cooling to ambient temperature, 200 ml of water and 150 ml of toluene are added and a solution of 18 g (0.13 mol) of K2CO3 in 50 ml of water is then added slowly. After the end of the addition, the mixture is stirred for 15 minutes, the aqueous phase is separated off and the organic phase is washed with water until neutral and evaporated. The residue is distilled in vacuo. The product obtained has a boiling of 170° C./4 mbar.
Reaction SMILES: [CH:1]1[C:13]2[O:12][N:11]=[C:6]3[N:7]=[CH:8][CH2:9][O:10][C:4]([C:5]=23)=[CH:3][CH:2]=1.[H-].[Na+].[CH3:16][N:17]=[C:18]=[O:19]>CN(C)C=O>[CH3:16][NH:17][C:18]([C:3]1[CH:2]=[CH:1][C:13]2[O:12][N:11]=[C:6]3[N:7]=[CH:8][CH2:9][O:10][C:4]=1[C:5]=23)=[O:19]
Reactant: C1=Nc2noc3cccc(c23)OC1
Reactant: CN=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc2onc3c2c1OCC=N3
Reaction time: 0.25 h
Yield: 49 %

Procedure:
A solution of 4,5-dihydroisoxazolo[3,4,5-ef][1,4]benzoxazepine of Example 7(b) (3.7 g; 21.0 mmole) in 60 ml dimethylformamide (DMF) was added to a suspension of sodium hydride (1.2 g; 25.2 mmole) in DMF. After 15 minutes, a solution of methylisocyanate in 15 ml DMF was added. The reaction was quenched into a dilute solution of HCl and extracted thrice with ethyl acetate. The organics were washed with water and dried (saturated NaCl solution, MgSO4). The desired urea was purified via flash chromatography (6% ethylacetate/dichloromethne) to give a solid which was triturated with pentane to give 2.4 g (49%) of 4,5-dihydro-3-methylaminocarbonylisoxazolo[3,4,5-ef][1,4]benzoxazepine, mp 177°-179.5° C.