Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[B-](F)(F)F.[N:29]1(OC(N(C)C)=[N+](C)C)[C:33]2[CH:34]=[CH:35][CH:36]=CC=2N=[N:30]1.C(N(CC)C(C)C)(C)C.Cl.NN1CCCC1.[Cl-].[Na+]>CN(C=O)C>[N:29]1([NH:30][C:20]([C:17]2[NH:18][N:19]=[C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH3:23])[CH:16]=2)=[O:22])[CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)[nH]n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Agent: NN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NN2CCCC2)[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
To a solution of 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid (100 mg, 0.32 mmol) in DMF (5 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (152 mg, 0.47 mmol), N,N-diisopropyl ethyl amine (270 μL, 1.6 mmol) and N-aminopyrrolidine HCl (58 mg, 0.47 mmol). The resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured into aqueous sodium chloride (saturated) and extracted with ethyl acetate. The combined organic layers were then washed with water, citric acid solution and saturated sodium hydrogen carbonate solution and then dried over sodium sulfate, filtered and evaporated. Concentration and purification by chromatography (silica, dichloromethane:methanol=100:0 to 9:1) afforded the title compound (91 mg, 75%) as a white solid. MS: m/e=386.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([OH:8])[N:5]2[N:9]=[C:10]([C:21]([F:24])([F:23])[F:22])[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[Cl:20])=[C:4]2[N:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(O)C.C(OCC)(=O)C>[Cl:20][C:14]1[C:15]([Cl:19])=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][C:11]1[C:10]([C:21]([F:24])([F:23])[F:22])=[N:9][N:5]2[C:6]([OH:8])=[CH:7][C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:3][C:4]=12
Reactant: C1COCCN1
Reactant: Oc1cc(Cl)nc2c(Cc3cccc(Cl)c3Cl)c(C(F)(F)F)nn12
Solvent: CCO
Solvent: CCOC(C)=O
Product: Oc1cc(N2CCOCC2)nc2c(Cc3cccc(Cl)c3Cl)c(C(F)(F)F)nn12

Procedure:
To a solution of 5-chloro-3-[(2,3-dichlorophenyl)methyl]-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7-ol (79 mg, 0.2 mmol) in ethanol (2 mL) was added morpholine (87 mg, 0.99 mmol) in a microwave reaction vessel. It was sealed and irradiated (microwave) at 150° C. for three hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed with 5% HCl solution (5 mL). Organic layer was dried, filtered, and concentrated. The crude product was purified by reverse-phase HPLC to provide the titled compound. (28 mg, 31%); LC/MS: MS (ES+) m/e 447 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 3.35 (br. s., 4H) 3.65-3.75 (m, 4H) 4.19 (s, 2H) 5.22 (s, 1H) 6.84 (s, 1H) 7.25 (t, J=7.96 Hz, 1H) 7.52 (s, 1H) 11.28 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]([N:13]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6][C:7]1([F:12])[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2].Cl.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:3][C:4](=[O:27])[CH:5]([NH2:13])[CH2:6][C:7]1([F:12])[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)C(CC1(F)CCCC1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(N)CC1(F)CCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 74.5 %

Procedure:
To a solution of 2-(benzhydrylidene-amino)-3-(1-fluoro-cyclopentyl)-propionic acid ethyl ester (1.36 g, 3.70 mmol) in dichloromethane (10 mL) at 0° C. was added a hydrochloric acid solution (1N, 7.4 mL) and the resulting mixture stirred at room temperature for 17 h. The mixture was separated, the aqueous layer diluted with water (10 mL) and cooled to 0° C. before sodium bicarbonate (1.24 g, 14.8 mmol) was added portionwise. The resulting mixture was extracted with dichloromethane (2×50 mL), the organic phases combined and dried over magnesium sulfate. The mixture was filtered and evaporated which afforded 2-amino-3-(1-fluoro-cyclopentyl)-propionic acid ethyl ester (0.56 g, 75%) as a clear oil: 1H NMR (300 MHz, CDCl3) δ ppm 1.29 (t, J=7.1 Hz, 3H), 1.68 (br. s., 6H), 1.77-1.89 (m, 2H), 1.89-2.15 (m, 3H), 2.15-2.36 (m, 1H), 3.72 (t, J=5.9 Hz, 1H), 4.19 (q, J=7.1 Hz, 2H).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].FC(F)(F)S(N(C1C=CC(Cl)=CN=1)S(C(F)(F)F)(=O)=O)(=O)=O.[CH2:46]([O:48][C:49]([C:51]1[CH:56]=[CH:55][C:54](B(O)O)=[CH:53][CH:52]=1)=[O:50])[CH3:47].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(#N)C>[CH2:46]([O:48][C:49]([C:51]1[CH:56]=[CH:55][C:54]([C:10]2[CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:12][CH:11]=2)=[CH:53][CH:52]=1)=[O:50])[CH3:47]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(N(c1ccc(Cl)cn1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: CCOC(=O)c1ccc(C2=CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a cooled (−78° C.) solution of 1-Boc-3-pyrollidinone (8.00 grams, 43.2 mmol) in anhydrous THF (70 mL) was added lithium bis(trimethylsilyl)amide (49.7 mL, 1.0 M in THF, 49.7 mmol) dropwise. After 45 min, a solution of 2-[N,N-bis(trifluoromethylsulfonyl)amino]5-chloropyridine (17.81 g, 45.4 mmol) in THF (65 mL) was added, and the resulting mixture was allowed to warm slowly to ambient temperature overnight, at which point it was quenched by pouring into brine. The mixture was extracted with EtOAc. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting enol triflate was filtered though silica gel, concentrated in vacuo, and used without further purification. To a flask containing the enol triflate obtained above (4.94 g, 15.6 mmol) were added 4-ethoxycarbonylphenylboronic acid (3.32 g, 17.1 mmol) and trans-dichlorobis(triphenylphosphine) palladium (II) (1.09 g, 1.56 mmol). Acetonitrile (78 mL) and sodium carbonate (39 mL, 1.0 M aqueous, 39 mmol) were added, and the resulting mixture was degassed via nitrogen sparge. The reaction mixture was stirred at 70° C. for 3 h, then was allowed to cool to room temperature and was poured into water. The mixture was extracted with EtOAc, and the organic phase was concentrated in vacuo. Purification by chromatography on silica gel (0 to 25% EtOAc in hexanes, then 25 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 261.9 [M-t-Boc]+; 1H NMR (500 MHz, CDCl3) δ 8.03 (d, J=8.0 Hz, 2 H), 7.44 (d, J=8.5 Hz, 2H), 6.29 (ddd, J=25.0, 4, 4 Hz, 1H), 4.58-4.46 (m, 2H), 4.41-4.28 (m, 2H), 4.38 (q, J=7.0 Hz, 2H), 1.53 and 1.51 (s, doubled (rotamers) 9H), 1.40 (t, doubled (rotamers) J=7.0 Hz, 1.5H), 1.39 (t, doubled (rotamers) J=7.0 Hz, 1.5H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][C:22]#[N:23]>>[F:11][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][C:8]=1[F:10])[N:1]=[C:22]([NH2:23])[C:21]([CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH3:12])=[CH:4]2
Reactant: Nc1cc(F)c(F)cc1C=O
Reactant: COc1ccccc1CCC#N
Product: COc1ccccc1Cc1cc2cc(F)c(F)cc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-4,5-difluorobenzaldehyde and 3-(2-methoxyphenyl)propionitrile.
Reaction SMILES: FC(F)(F)C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O.[Cl:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[CH:36]=[N:37][N:38]([CH2:40][C:41](O)=[O:42])[CH:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1.N1C=CC=CC=1.[F:50][C:51]1[CH:57]=[CH:56][CH:55]=[CH:54][C:52]=1[NH2:53].Cl>CN(C)C=O>[Cl:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[CH:36]=[N:37][N:38]([CH2:40][C:41]([NH:53][C:52]4[CH:54]=[CH:55][CH:56]=[CH:57][C:51]=4[F:50])=[O:42])[CH:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1
Reactant: O=C(O)Cn1cc(Nc2ncnc3cc(OCCCCl)ccc23)cn1
Reactant: Nc1ccccc1F
Agent: Cl
Agent: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cn1cc(Nc2ncnc3cc(OCCCCl)ccc23)cn1)Nc1ccccc1F
Reaction time: 5 h

Procedure:
Pentafluorophenyl trifluoroacetate (0.325 g, 1.16 mmol) was added dropwise, at room temperature, to a stirred suspension of (4-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)acetic acid (0.300 g, 0.83 mmol) and pyridine (0.092 g, 1.16 mmol) in dimethylformamide (3 ml). After stirring for 5 minutes 2-fluoroaniline (0.184 g, 1.66 mmol) was added and the reaction stirred for 5 hours. The mixture was poured into 0.2N aqueous hydrochloric acid (25 ml) to give 2-(4-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)-N-(2-fluorophenyl)acetamide as a cream coloured solid: MS (+ve ESI): 455 (M+H)+.
Reaction SMILES: Cl.[CH3:2][P:3]([CH2:6][CH2:7][NH2:8])([CH3:5])=[O:4].Br[CH2:10][C:11]1[CH:39]=[CH:38][C:14]([C:15]([NH:17][C:18]2[CH:19]=[C:20]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:21]=[CH:22][C:23]=2[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:16])=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C.C([O-])(O)=O.[Na+]>[C:27]([O:26][C:25](=[O:31])[NH:24][C:23]1[CH:22]=[CH:21][C:20]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:19][C:18]=1[NH:17][C:15](=[O:16])[C:14]1[CH:38]=[CH:39][C:11]([CH2:10][NH:8][CH2:7][CH2:6][P:3]([CH3:5])([CH3:2])=[O:4])=[CH:12][CH:13]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(CBr)cc1
Reactant: CP(C)(=O)CCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(CNCCP(C)(C)=O)cc1

Procedure:
2-(Dimethylphosphoryl)ethanamine hydrochloride (393 mg, 2.493 mmol), tert-butyl (3-{[4-(bromomethyl)benzoyl]amino}biphenyl-4-yl)carbamate (400 mg, 0.831 mmol), and DIEA (581 μl, 3.32 mmol) were combined in DMF (8 mL) and water (0.50 mL) and stirred at 60° C. overnight. The solution was diluted with saturated NaHCO3 and extracted with EtOAc (4×). The combined organics were dried (MgSO4), evaporated, and purified by reverse phase HPLC (25-95% MeCN/water w/0.025% TFA). Product fractions were neutralized with saturated NaHCO3, extracted with EtOAc (2×), dried (MgSO4), and evaporated to give a colorless solid.
Reaction SMILES: [C:1]1([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:20]([O:22][C:23](=O)[O:24]CC)[CH3:21]>C1C=CC=CC=1>[OH:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][C:9]=1[C:23]([O:22][CH2:20][CH3:21])=[O:24]
Reactant: O=C1CCN(c2ccccc2)c2ccccc21
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)C1=C(O)c2ccccc2N(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
A solution of 29 g of 2,3-dihydro-1-phenyl-4(1H)-quinolone in 200 ml of benzene was added, dropwise, to a stirred slurry of 7.2 g of sodium hydride in 200 ml of benzene. The slurry was stirred for one hour at room temperature, and then treated with 23.6 g of diethylcarbonate. The resulting suspension was refluxed for five hours, cooled to room temperature, and quenched with 200 ml of water. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and evaporated. Purification of the residue by means of high pressure liquid chromatography (silica gel; dichloromethane as the eluent) afforded 22.4 g (59%) of 1,2-dihydro-4-hydroxy-1-phenyl-3-quinolinecarboxylic acid, ethyl ester. Recrystallization from diethyl ether yielded the analytical sample, m.p. 103°-106° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([O:23][CH3:24])[CH:15]=2)[C:10]([F:26])([F:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([O:23][CH3:24])[CH:15]=2)[C:10]([F:26])([F:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2(F)F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2(F)F)ccc1N
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To a solution of (±)-3,3-difluoro-4-(3-methoxy-4-nitro-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (230.00 mg) in methanol (10 mL) was added palladium on carbon 10% (10:90, palladium:carbon black, 40 mg). The mixture was shaken in a Parr apparatus under an atmosphere of hydrogen (35 PSI) for 2 h. Filtration through Celite and evaporation of the solvent provided (±)-4-(4-amino-3-methoxy-phenyl)-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 95% yield), which was used without purification. 1H NMR (CDCl3): δ ppm 6.65-6.77 (m, 3H), 4.15-4.65 (m, 2H), 3.85 (s, 3H), 3.77 (br. s., 2H), 2.72-3.13 (m, 3H), 2.03-2.24 (m, 1H), 1.85 (d, J=12.4 Hz, 1H), 1.49 (s, 9H) 3124-67
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[N:14]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:11]2=[N:12][CH:13]=1)=[O:7])#[N:2].N1C=CN=C1.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].C(OCC)(=O)C>CN(C)C=O>[C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])=[CH:19][CH:18]=3)[N:14]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:11]2=[N:12][CH:13]=1)=[O:7])#[N:2]
Reactant: N#CCCNC(=O)c1cnc2c(c1)nc(-c1ccc(O)cc1)n2C1CCCCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2nc3cc(C(=O)NCCC#N)cnc3n2C2CCCCC2)cc1
Temperature: 35 °C
Reaction time: 20 h
Yield: 82.5 %

Procedure:
To a solution of intermediate 60 (1.5 g, 3.85 mmol) in dimethylformamide (5 mL) was added imidazole (0.917 g, 13.5 mmol) and tert-butyldimethylsilyl chloride (0.870 g, 5.77 mmol). The reaction mixture was stirred at 35° C. for 20 h, and then ethyl acetate (100 mL) was added. The resulting organic phase was washed with water (4×20 mL) and brine (1×) and then dried (Na2SO4). After concentrating on a rotary evaporator the resulting residue was purified by column chromatography (silica gel, 1:1 hexanes/ethyl acetate-3:7 hexanes/ethyl acetate) to afford intermediate 61 as a white solid (1.6 g, 83%). ESI-MS m/e 504.0 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=O.[NH2:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[NH:15][N:14]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO.CN1C(=O)N(C)CC1>[C:6]([C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=1)[CH2:1][NH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[NH:15][N:14]=1)([OH:8])=[O:7]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1cccc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Reaction time: 1 h

Procedure:
225 mg (1.50 mmol) of 3-formyl-benzoic acid are added to a solution of 261 mg (1.00 mmol) of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 26 ml of methanol, 13 ml of DMEU and 120 mg (2.0 mmol) of acetic acid under a N2 atmosphere. The reaction mixture is stirred for 1 hour, during which time a solid precipitates, and then 440 mg (7.0 mmol) of NaCNBH3 are added. Stirring is carried out for 5 days, the suspension changing to a clear solution. The methanol is evaporated off using a rotary evaporator. The residue is poured into 0.6 liter of water and stirred for 3 hours to complete the reaction. Filtering with suction, washing with water and diethyl ether, stirring in hot ethanol, cooling and filtering yield 3-(3-carboxy-benzylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (3-{[4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl-amino]methyl}-benzoic acid); m.p. 294-296° C.; HPLC: TRet (Grad5-40)=20.1; FAB-MS: (M+H)+ =395.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[NH:15][C:14](=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:14]1[N:13]=[C:12]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([CH3:1])[CH:3]=2)[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(-c2cc(C(F)(F)F)[nH]c(=O)n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-1H-pyrimidin-2-one (4.31 g, 13.4 mmol) and phosphoroxychloride (40 mL) according to the general procedure I. Obtained as a light yellow solid (4.47 g, 98%). MS (EI) 340.1 [(M)+]; mp 53° C.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH2:26]([CH2:28][NH2:29])[OH:27]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[NH:29][CH2:28][CH2:26][OH:27])=[O:13])[CH2:8]2
Reactant: NCCO
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1NCCO

Procedure:
5-(2-Hydroxy-ethylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and ethanolamine. Mass spectrum (ES) MH+=381.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21]C)[C:16]=2[F:23])=[CH:11][C:10]1=[O:24])[CH2:5][CH:6]([CH3:8])[CH3:7].B(Br)(Br)Br.Cl>ClCCl>[CH3:1][O:2][C:3](=[O:25])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[C:16]=2[F:23])=[CH:11][C:10]1=[O:24])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(OC)c2F)=CC1=O
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(O)c2F)=CC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
To a solution of (S)-2-[4-(2-fluoro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (1.35 g, 3.83 mmol) in dichloromethane (20 mL) was added a boron tribromide in dichloromethane solution (1 M, 11.50 mL, 11.50 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 2 h and then poured into ice water containing hydrochloric acid (2N, 30 mL). The organic phase was separated, washed with water and brine. The solvents were removed by evaporation and the residue purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 50 g, 30% to 100% (9:1 dichloromethane:methanol)/hexanes) which afforded (S)-2-[4-(2-fluoro-3-hydroxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (1.05 g, 81%) as a brown oil.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].CCS.[C:8]([CH2:13][CH2:14][C:15]1[C:20]2[CH:21]=[CH:22][C:23]([O:25]C)=[CH:24][C:19]=2[O:18][C:17](=[O:27])[CH:16]=1)([O:10][CH2:11][CH3:12])=[O:9]>ClCCl>[C:8]([CH2:13][CH2:14][C:15]1[C:20]2[CH:21]=[CH:22][C:23]([OH:25])=[CH:24][C:19]=2[O:18][C:17](=[O:27])[CH:16]=1)([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CCc1cc(=O)oc2cc(OC)ccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: CCOC(=O)CCc1cc(=O)oc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.1 %

Procedure:
To a suspension of 726 mg (5.4 mmol) of AlCl3 in 10 mL of dichloromethane at 0° C. was added 4 mL of EtSH. The suspension became a clear solution within seconds. Then, 298 mg (1.08 mmol) of 3 in 4 mL of dichloromethane was added, turning the yellow solution red in color. The ice bath was removed, and the reaction stirred to room temperature for 3 h. The solvents were removed in vacuo, and the residue thoroughly vacuum dried. The residue was extracted into EtOAc as much as possible, then the extract was flash chromatographed using 30/70 EtOAc/hexane. The long- and short-wave UV active band gave 76.7 mg (27%) of 4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].CCN(CC[O:17]C1C=CC(CC2C=CC=CC=2)=CC=1)CC.Cl>C1CCCCC1>[Br:1][C:2]1[CH:7]=[C:6]([OH:17])[CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9]
Reactant: Cc1cccc(Br)c1C
Reactant: CCN(CC)CCOc1ccc(Cc2ccccc2)cc1
Agent: Cl
Solvent: C1CCCCC1
Product: Cc1cc(O)cc(Br)c1C
Yield: 74 %

Procedure:
The general process was applied to a solution of 3-bromo-o-xylene (185 mg, 1.0 mmol) in 1.0 mL cyclohexane. The borylation step was carried out with HBPin (320 mg, 2.5 mmol) and dppe (8.0 mg, 0.02 mmol, 2 mol %) at 100° C. for 50 hours. After removal of the cyclohexane, the oxidation step was then performed as described above, after which the crude material was dissolved in CH2Cl2 and passed through a plug of silica gel. Evaporation of solvent gave 148 mg pure 10 (74%) as a white wax solid; mp 98-99° C. (lit. 101-102). 1H NMR (300 MHz, CDCl3): δ 6.91 (d, J=2.5 Hz, 1 H), 6.59 (d, J=2.7 Hz, 1 H), 2.25 (s, 6 H); 13C NMR (75 MHz, CDCl3): δ 153.2, 139.3, 128.3, 125.2, 116.9, 116.2, 21.4, 18.3; IR (neat): 3252, 2919, 1606, 1576, 1477, 1451, 1279, 1119, 839 cm−1; LRMS: m/e 200 (M+), 185, 121, 91; HRMS (EI): m/z 199.9839 [(M+); calcd for C8H9BrO: 199.9837]. For a previous preparation see Jacquesy et al., Chem. Soc., Chem. Commun. 110-111 (1980) (bromination of 3,4-dimethylphenol in superacid SbF5-HF, 83% yield) or Fischer and Henderson, Can. J. Chem. 61: 1045-1052 (1983).
Reaction SMILES: CS([O:5][CH:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)(=O)=O.[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:26]=[C:27](O)[C:28]3[N:29]=[CH:30][CH:31]=[N:32][C:33]=3[CH:34]=2)[CH2:21][CH2:20]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O>[N:14]1[CH:15]=[CH:16][CH:17]=[N:18][C:13]=1[O:12][C@H:9]1[CH2:10][CH2:11][C@H:6]([O:5][C:27]2[CH:26]=[C:25]([N:22]3[CH2:21][CH2:20][O:19][CH2:24][CH2:23]3)[CH:34]=[C:33]3[C:28]=2[N:29]=[CH:30][CH:31]=[N:32]3)[CH2:7][CH2:8]1
Reactant: Oc1cc(N2CCOCC2)cc2nccnc12
Reactant: CS(=O)(=O)OC1CCC(Oc2ncccn2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: c1cnc(O[C@H]2CC[C@H](Oc3cc(N4CCOCC4)cc4nccnc34)CC2)nc1
Temperature: 110 °C

Procedure:
As shown in step 7-iv of Scheme 7, a mixture of (4-pyrimidin-2-yloxycyclohexyl) methanesulfonate (105 mg, 0.386 mmol), 7-morpholinoquinoxalin-5-ol (178.3 mg, 0.7712 mmol), and Cs2CO3 (125.6 mg, 0.3856 mmol) in dioxane (1.5 mL) was sealed in a 5 mL microwave tube and heated to 110° C. for 14 hours using an oil bath. The reaction mixture was cooled to room temperature, diluted with EtOAc, and filtered through diatomaceous earth which was subsequently washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue purified via preparative reversed-phase HPLC (10-90% CH3CN/water gradient containing 0.1% TFA). Fractions containing a mixture of cis and trans isomers were further purified via SFC using a chiral OJ column and eluting with 40% MeOH in CO2 to provide 21 mg of 4-(8-(((trans)-4-(pyrimidin-2-yloxy)cyclohexyl)oxy)quinoxalin-6-yl)morpholine (compound 34): 1H NMR (300 MHz, Chloroform-d) δ 8.69 (dd, J=3.4, 1.9 Hz, 1H), 8.62 (dd, J=3.6, 1.9 Hz, 1H), 8.51 (dd, J=4.8, 2.2 Hz, 2H), 7.01-6.83 (m, 3H), 5.18 (tt, J=7.0, 3.4 Hz, 1H), 4.79 (tt, J=6.9, 3.1 Hz, 1H), 4.00-3.85 (m, 4H), 3.34 (dq, J=4.8, 2.6 Hz, 4H), 2.44-2.16 (m, 4H), 1.92 (tdd, J=16.4, 7.7, 2.8 Hz, 4H); ESMS (M+H+)=408.56, and 22 mg of 4-(8-(((cis)-4-(pyrimidin-2-yloxy)cyclohexyl)oxy)-quinoxalin-6-yl)morpholine (compound 42): 1H NMR (300 MHz, Chloroform-d) δ 8.70 (d, J=1.9 Hz, 1H), 8.63 (d, J=1.9 Hz, 1H), 8.52 (d, J=4.8 Hz, 2H), 7.01-6.87 (m, 3H), 5.17 (ddt, J=8.7, 6.7, 3.4 Hz, 1H), 4.76-4.58 (m, 1H), 4.00-3.87 (m, 4H), 3.40-3.27 (m, 4H), 2.43-2.22 (m, 4H), 2.05-1.87 (m, 2H), 1.86-1.71 (m, 2H); ESMS (M+H+)=408.56.