Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@:19]3([CH3:30])[O:23][C:22]4=[N:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][N:21]4[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])=[CH:5][CH:4]=1.[CH3:33]N(C=O)C.[H-].[Na+].CI>O>[CH3:33][N:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:8][CH:7]=1)[C:10]([N:12]1[CH2:13][CH2:14][N:15]([CH2:18][C@:19]2([CH3:30])[O:23][C:22]3=[N:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][N:21]3[CH2:20]2)[CH2:16][CH2:17]1)=[O:11]
Reactant: C[C@]1(CN2CCN(C(=O)Nc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CN(C(=O)N1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 17 %

Procedure:
A mixture of (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylic acid (4-trifluoromethylphenyl)amide prepared in Example 477 (200 mg, 0.44 mmol), DMF (4 ml), and sodium hydride (26 mg, 0.66 mmol) was stirred at room temperature for 1.5 hours. To the mixture, methyl iodide (0.5 ml, 0.76 mmol) was added followed by stirring at room temperature overnight. To the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with water three times and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylic acid N-methyl-N-(4-trifluoromethylphenyl)amide (35 mg, yield 17%) as a white powder.
Reaction SMILES: S[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:5]=2[N:6]=1.O=P(Cl)(Cl)[Cl:14].P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Cl:14][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:5]=2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Fc1ccc2oc(S)nc2c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: Fc1ccc2oc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 86.9 %

Procedure:
The 2-mercapto-5-fluorobenzoxazole (2.0 g, 11.8 mmol) is slurried into POCl3 (9.7 mL, 104 mmol). The slurry is treated with PCl5 (3.0 g, 14.2 mmol) and 5.0 mL of anhydrous CH2Cl2. The mixture is stirred at room temperature for 5.5 hours. After this time excess POCl3 is removed under reduced pressure. The residue is treated with saturated aqueous NaHCO3 and the mixture is poured into a separatory funnel. The mixture is extracted with EtOAc and the combined extracts are washed with brine and dried over anhydrous Na2SO4. Filtration and concentration gives 1.76 g of 2-chloro-5-fluorobenzoxazole as a waxy solid. The crude chloride is used in the piperazine displacement reaction.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][Li]>C(OCC)C>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [Li]C
Reactant: c1ccc(-c2cccnc2)cc1
Solvent: CCOCC
Product: Cc1ccc(-c2ccccc2)cn1
Temperature: 25 °C

Procedure:
To a cooled (−70° C.) solution of 3-phenylpyridine (1.43 mL, 10.0 mmoles) in diethyl ether (7.5 mL) is added dropwise methyllithium (LiBr complex, 1.5 M in diethyl ether, 7.33 mL, 11.0 mmoles). After letting warm to room temperature over 16 hours the reaction is cooled (0° C.) and quenched with distilled water (5 mL). The reaction is then extracted with methylene chloride, the organic layer isolated and concentrated, and the resulting residue purified by column chromatography (silica, 3:1 hexane: EtOAc) to yield the title compound as a pale yellow oil. MS(ESI) 170 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)([O-:10])=[O:9].Cl.[CH3:21][NH:22][O:23][CH3:24].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:24][O:23][N:22]([CH3:21])[C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (4.89 mL, 35.184 mmol) was added slowly to a mixture of commercially available 4-nitrobenzoic acid (3.0 g, 17.592 mmol), N,O-dimethylhydroxylamine hydrochloride (1.92 g, 19.351 mmol), and EDCI (4.05 g, 21.11 mmol) in CH2Cl2 (30 mL). The mixture was stirred at room temperature overnight then quenched with saturated aqueous NaHCO3. Water (50 mL) was added followed by additional CH2Cl2. The mixture as stirred for 10 minutes and layers were separated. The CH2Cl2 layer was dried over Na2SO4, then filtered. The solvent was removed under reduced pressure and the residual oil chromatographed (CH2Cl2/EtOAc) to provide the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([S:18](Cl)(=[O:20])=[O:19])[S:17][C:11]=2[N:10]=[C:9]1[CH3:22].O.[NH3:24]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([S:18](=[O:20])(=[O:19])[NH2:24])[S:17][C:11]=2[N:10]=[C:9]1[CH3:22]
Reactant: N
Reactant: Cc1nc2sc(S(=O)(=O)Cl)cc2c(=O)n1-c1ccccc1Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2sc(S(N)(=O)=O)cc2c(=O)n1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
In 200 ml of tetrahydrofuran was suspended 23 g of 3,4-dihydro-3-(2-chlorophenyl)-6-chlorosulfonyl-2-methyl-4-oxothieno[2,3-d]pyrimidine, and this suspension was poured onto 200 ml of ammonia water at one time. The mixture was stirred at room temperature for 40 minutes. The reaction mixture was concentrated, and water was added to the residue. The crystals were collected by suction-filtration to afford 15.8 g of the title compound, m.p. 251° C.
Reaction SMILES: [Cl:1][C:2]([Cl:23])([Cl:22])[C:3]1[N:8]=[C:7]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:6]=[C:5]([C:13]2[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=2)[N:4]=1.[O:24]1CCCC1.O>C(N(CC)CC)C>[Cl:1][C:2]([Cl:22])([Cl:23])[C:3]1[N:8]=[C:7]([C:9]([Cl:11])([Cl:10])[Cl:12])[N:6]=[C:5]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:18])=[O:24])=[CH:15][CH:14]=2)[N:4]=1
Reactant: O=C(Cl)c1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)c1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1
Reaction time: 0.17 h

Procedure:
4-(4,6-Bis(trichloromethyl)-s-triazin-2-yl)-benzoyl chloride pw) is added to a mixture of tetrahydrofuran (10 pw) and water (5 pw). To complete the reaction, 1 pw of triethylamine is added after 6 minutes, and the mixture is stirred for another 10 minutes. The solvent is removed by distillation, and the residue is recrystallized from toluene/benzine. The product is identical with the compounds described in Examples 12 and 16.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][N:32]([C:2]3[C:3]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:4][C:5]4[C:10]([N:11]=3)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=4)[CH2:31][CH2:30]2)=[CH:27][CH:28]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccc(Cl)cc4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 1-(4-chlorophenyl)piperazine (172.5 mg, 0.88 mmol, 5.00 equiv), and DIEA (170.3 mg, 1.32 mmol, 3.00 equiv) in DMF (4 mL) was placed in a 8-mL sealed tube, stirred overnight at 100° C. in an oil bath, then concentrated under vacuum. Purification via silica gel column (ethyl acetate/petroleum ether (1:50)) afforded 153.4 mg (69%) of methyl 3-(4-(4-chlorophenyl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])=[N:6][C:7]=1F.[CH:22]1([C:25]2[NH:29][N:28]=[C:27]([NH2:30])[CH:26]=2)[CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>C1COCC1>[CH:22]1([C:25]2[NH:29][N:28]=[C:27]([NH:30][C:7]3[C:2]([F:1])=[CH:3][C:4]([N+:19]([O-:21])=[O:20])=[C:5]([NH:9][C@H:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[CH3:11])[N:6]=3)[CH:26]=2)[CH2:24][CH2:23]1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: C[C@H](Nc1nc(F)c(F)cc1[N+](=O)[O-])c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1[N+](=O)[O-])c1ccc(F)cc1
Temperature: 55 °C
Yield: 66.2 %

Procedure:
To a solution of (S)-5,6-difluoro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine (Method 23, 0.60 g, 2.0 mmol) in THF (10 ml) at room temperature was added 5-cyclopropyl -1H-pyrazol-3-amine (0.50 g, 4.0 mmol), and DIEA (0.26 g, 2.0 mmol). The reaction was then heated to 55° C. for 24 hours, cooled to room temperature, and quenched with water. The reaction was then extracted with DCM (2×75 ml), and the combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=100:1) to give the title compound (0.53 g, 66%). 1H NMR (400 MHz, CD3OD) δ 8.00 (d, J=11.1 Hz, 1H), 7.38-7.35 (m, 2H), 7.07-7.02 (m, 2H), 6.17 (s, 1H), 5.41-5.39 (m, 1H), 1.93-1.87 (m, 1H), 1.61 (d, J=7.0 Hz, 3H), 1.02-1.00 (m, 2H), 0.69-0.66 (m, 2H). MS: Calcd.: 400. Found: [M+H]+ 401.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:10][C:9]([O-:11])=[C:8](C(OC)=O)[C:7]=1[CH3:16])=[O:5])[CH3:2].[Na+].CC(O)=O.[I-].[Na+]>COCCOCCOC>[CH3:16][C:7]1[CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][C:9](=[O:11])[CH:8]=1
Reactant: CCOC(=O)C1=C(C)C(C(=O)OC)=C([O-])C1
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COCCOCCOC
Product: CCOC(=O)C1CC(=O)C=C1C
Temperature: 25 °C
Yield: 57.5 %

Procedure:
A round-bottom flask was charged with sodium 4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclopenta-1,3-dienolate (105 g, 0.420 mol) and diglyme (1 L) to give a yellow suspension. AcOH (100 mL, 1.7 mol) was added to the resulting mixture and sodium iodide (280 g, 1.9 mol) was added portion-wise over about 5-10 min. The reaction mixture was then heated to reflux for about 3 h, cooled to room temperature, and poured over ice water (800 mL). The resulting material was extracted with Et2O (3×500 mL). The combined organic extracts were washed with brine (2×500 mL), dried over anhydrous MgSO4, and filtered. The solvent was removed under reduced pressure to give a brown liquid that was purified by vacuum distillation (80-85° C., 0.3 Torr) to give ethyl 2-methyl-4-oxocyclopent-2-enecarboxylate (40.6 g, 57%) as a yellow oil: 1H NMR (CDCl3) δ 6.06-5.98 (m, 1H), 4.30-4.11 (m, 2H), 3.72-3.65 (m, 1H), 2.77-2.66 (m, 1H), 2.66-2.57 (m, 1H), 2.17 (s, 3H), 1.30 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>>[CH:28]1([NH:31][C:24]([CH2:25][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[N:7]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[C:6]=2[C:22]([OH:23])=[O:27])=[O:26])[CH2:30][CH2:29]1
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Reactant: NC1CC1
Product: O=C(Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccc(F)cc12)NC1CC1

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from Example 68.1.) was ring opened with cyclopropylamine at 22° C. to give the title compound as a white solid. MS: 415.0 ([M−H]−).
Reaction SMILES: [CH2:1]([C:4]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9][CH2:8][N:7]([C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH2:11][CH3:12])[C:6](=[O:20])[CH2:5]1)[CH:2]=[CH2:3].[OH2:27].O=O>CN(C=O)C.CCOC(C)=O.[Cu]Cl.[Pd](Cl)Cl>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([C@@H:10]([N:7]2[CH2:8][CH2:9][C:4]([CH2:1][C:2](=[O:27])[CH3:3])([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:5][C:6]2=[O:20])[CH2:11][CH3:12])=[CH:18][CH:17]=1
Reactant: C=CCC1(c2ccccc2)CCN([C@@H](CC)c2ccc(Br)cc2)C(=O)C1
Reactant: O
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: O=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[C@@H](c1ccc(Br)cc1)N1CCC(CC(C)=O)(c2ccccc2)CC1=O
Yield: 78 %

Procedure:
A round-bottom flask was charged with copper(I) chloride (0.3100 g, 3.13 mmol), and a solution of 4-allyl-1-((S)-1-(4-bromophenyl)propyl)-4-phenylpiperidin-2-one (0.3045 g, 0.74 mmol) in DMF (7.5 mL) was added, followed by H2O (2 mL) and palladium(II) chloride (0.0670 g, 0.38 mmol). The reaction mixture was vigorously stirred under a balloon of oxygen for 20 h at rt and diluted with EtOAc, dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford 0.2475 g (78%) of 1-((S)-1-(4-bromophenyl)propyl)-4-(2-oxopropyl)-4-phenylpiperidin-2-one. LC-MS Method 3 tR=1.87, 1.93 min, m/z 428, 430 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][N:11]3[CH:17]=[N:18][CH:19]=[C:10]23)=[CH:5][CH:4]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[CH3:15][C:14]1([CH3:16])[CH2:13][CH2:12][N:11]2[CH:17]=[N:18][CH:19]=[C:10]2[CH:9]1[C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=1
Reactant: COc1ccc(C2c3cncn3CCC2(C)C)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CCn2cncc2C1c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3.30 mmol of 8-(4-methoxyphenyl)-7,7-dimethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine in 50 ml of dichloromethane is admixed dropwise at 0-5° C. with 8.25 mmol of boron tribromide (1M solution in dichloromethane). The reaction solution is subsequently stirred at 0° C. for 1 hour, then admixed with saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane (3×). The combined organic phases are dried over magnesium sulphate and evaporated. The residue is taken up in 0.5N NaOH and the mixture is extracted with ethyl acetate (3×). The combined organic phases are dried over magnesium sulphate and evaporated. The title compound is obtained as a beige solid and used without further purification for the next stage. Rt=4.91 (Gradient 1).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=1>CN(C=O)C.O>[Br:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[N:16]([CH2:26][C:27]3[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=3)[N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1
Reactant: N#Cc1ccc(CCl)nc1
Reactant: O=c1[nH]nc2c(Br)c(-c3ccc(Cl)cc3)ccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Cn2nc3c(Br)c(-c4ccc(Cl)cc4)ccn3c2=O)nc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
To a stirred mixture of 8-bromo-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (1.07 g, 3.31 mmol) in DMF (15 mL) at room temperature under argon was added K2CO3 (0.91 g, 6.62 mmol) and 6-(chloromethyl)nicotinonitrile (0.63 g, 4.14 mmol). The mixture was then heated to 60° C. for 7 h, after which HPLC indicated complete reaction. The mixture was cooled to room temperature, diluted with water (100 mL), and stirred for 30 min. Solid was collected by filtration and washed with water (10 mL×5), then methanol (3 mL×3), and finally dried under vacuum. The title compound (0.98 g) was obtained as a tan solid. HPLC/MS: retention time=3.4 min, [M+H]+=442.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[S:10]([O:13]C(C)C)(=[O:12])=[O:11].[OH-].[Na+:20]>O1CCCC1.O>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[S:10]([O-:13])(=[O:11])=[O:12].[Na+:20]
Reactant: Cc1cccc(C(F)(F)F)c1S(=O)(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(C(F)(F)F)c1S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
A solution of 83 g of the crude isopropyl 2-trifluoromethyl-6-methylbenzenesulfonate (which contained about 10% of isopropyl 2-trifluoromethylbenzenesulfonate) in 300 mL of tetrahydrofuran was treated with a solution of 24.8 g of 50% aqueous sodium hydroxide in 150 mL of water and heated to reflux for 4 hours, then stirred at room temperature overnight. The mixture was assayed by capillary GC (10 m DB-1, 100°-250° C. at 20° C./min) to ascertain that the isopropyl 2-trifluoromethyl-6-methylbenzenesulfonate was consumed. The tetrahydrofuran was removed in vacuo, then the remainder was poured into 100 mL of water and 200 mL of hexane. The aqueous phase was washed with hexane, then the water removed in vacuo to yield 71 g sodium 2-trifluoromethyl-6-methylbenzenesulfonate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)[CH:7]=[CH:6][C:4]=1[NH2:5].[Cl:19][C:20]1[CH:21]=[C:22]2[CH:28]=[C:27]([C:29](OC)=[O:30])[N:26]([CH3:33])[C:23]2=[N:24][CH:25]=1>O1CCCC1>[Cl:19][C:20]1[CH:21]=[C:22]2[CH:28]=[C:27]([C:29]([NH:5][C:4]3[CH:6]=[CH:7][C:8]([B:10]4[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]4)=[CH:9][C:3]=3[O:2][CH3:1])=[O:30])[N:26]([CH3:33])[C:23]2=[N:24][CH:25]=1
Reactant: COC(=O)c1cc2cc(Cl)cnc2n1C
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Solvent: C1CCOC1
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2cc(Cl)cnc2n1C
Temperature: 25 °C
Yield: 84 %

Procedure:
To 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.073 g, 8.32 mmol) in tetrahydrofuran (dry) (20 ml) under a nitrogen atmosphere was added 2-Methylmagnesium chloride in tetrahydrofuran (4.16 ml, 8.32 mmol) and the mixture was heated at reflux for one hour. To the warm reaction mixture was added methyl 5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (0.89 g, 3.96 mmol) in tetrahydrofuran (10 ml) and the resulting mixture was heated overnight. Then the reaction was cooled to room temperature and the solvent was evaporated. The residue was taken up in ethyl acetate and washed four times with 0.5 N hydrochloric acid. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; gradient of heptane to heptane/ethyl acetate 1/1) to give 5-chloro-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (1.47 g).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH:25]1([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37][O:38]S(C3C=CC(C)=CC=3)(=O)=O)[N:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37][O:38][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=4)([CH3:14])[C:4]([OH:24])=[O:3])=[CH:12][CH:11]=3)[N:35]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccc(F)c(F)c2)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(3,4-difluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester using the method of Example 56. 1H NMR (400 MHz, CDCl3) δ 9.37 (bs, 1H), 7.16 (d, 2H, J=8.4 Hz), 6.99 (dd, 1H, J=9.5 Hz), 6.78 (d, 2H, J=8.4 Hz), 6.77-6.72 (m, 1H), 6.63-6.58 (m, 1H), 4.12 (t, 2H, J=6.4 Hz), 3.21 and 3.08 (d of ABq, 2H, J=14.0 Hz), 2.97 (t, 2H, J=6.4 Hz), 2.91 (tt, 1H, J=12.0, 3.6 Hz), 2.32 (s, 3H), 2.04-1.98 (m, 2H), 1.85-1.78 (m, 2H), 1.76-1.68 (m, 1H), 1.62-1.49 (m, 2H), 1.41-1.19 (m, 3H), 1.37 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11](OC)=[O:12])=[CH:10][C:4]=2[N:3]=1.CC(C[AlH]CC(C)C)C.C(OCC)(=O)C>C1COCC1>[CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:4]=2[N:3]=1
Reactant: COC(=O)c1ccc2[nH]c(C)nc2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc2cc(CO)ccc2[nH]1
Temperature: 20 °C

Procedure:
27.8 g (10.146 mol) of 18b in 500 ml of THF are treated with 365.4 ml (0.438 mol) of DIBAL (20% strength solution in toluene) at -70° C. overnight in analogy to Example 1a. The crude product is vigorously stirred in boiling ethyl acetate and, after cooling to 20° C., the remaining material is filtered off with suction.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][CH:19]([CH2:24][CH3:25])[CH2:20][C:21](O)=[O:22].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:4]3[CH:3]=[C:2]([NH:1][C:21](=[O:22])[CH2:20][CH:19]([CH3:18])[CH2:24][CH3:25])[CH:7]=[CH:6][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: Nc1cccc(-n2ncc3c(N)ncnc32)c1
Reactant: CCC(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Product: CCC(C)CC(=O)Nc1cccc(-n2ncc3c(N)ncnc32)c1
Reaction time: 0.17 h
Yield: 56.3 %

Procedure:
Title compound 11B, 1-(3-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (40 mg, 1.1 eq, 0.18 mmol) was added to a solution 3-methylpentanoic acid (20 μl, 1.0 eq, 0.16 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27 mg, 1.1 eq, 0.18 mmol), 1-hydroxybenzotriazole (22 mg, 1.0 eq, 0.17 mmol) in DMF (1 ml) which had been stirred for 10 minutes under an inert atmosphere. The reaction was stirred at room temperature for 48 hours, after which methanol (1 ml) was added, and the solvents were removed in vacuo. The residue was purified by mass direct preparative HPLC to yield the title compound as a white solid (28 mg, 0.09 mmol, 54%). LCMS: [M+H]+=325, Rt=1.67 min, 100% purity.
Reaction SMILES: [CH3:1][C:2]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][Br:17])=[CH:14][CH:15]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1ccc(OCC2(C)CCCCC2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(COc2ccc(CBr)cc2)CCCCC1
Temperature: 25 °C

Procedure:
A solution of 2.2 g (10 mmol) of 4-[((1-methyl)cyclohexyl)methoxy]toluene, 1.8 g (10 mmol) of N-bromosuccinimide and 0.02 g of benzoyl peroxide in 60 ml of carbon tetrachloride was refluxed for 16 hours. The reaction was cooled to room temperature, filtered and the filtrate evaporated to give the product which was used without further purification.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:2]=[CH2:3].C(O)[CH2:17][CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14][CH2:15][CH2:17][CH2:18][OH:19])=[O:13])[CH:2]=[CH2:3]
Reactant: OCCCO
Reactant: C=CCNc1ccccc1CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CCNc1ccccc1CC(=O)OCCCO

Procedure:
A mixture of 2.25 g. of methyl 2-(allylamino)phenylacetate, 280 mg. of 1,3-propanediol and 1.37 g. p-toluenesulfonic acid is heated at 180° C. for 18 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield 3-hydroxypropyl 2-(allylamino)phenylacetate.