Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:12][C:13](N)=[O:14].O>CN1C(=O)CCC1>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:13](=[O:14])[NH:12][C:4]2=[O:5]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: NC(N)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: O=c1[nH]c(=O)c2cc(I)ccc2[nH]1
Temperature: 160 °C
Yield: 87.4 %

Procedure:
A mixture of 2-amino-5-iodobenzoic acid (3.5 g) and urea (1.56 g) in NMP (15 ml) was heated at 160° C. for 6 hours then cooled. Water (200 ml) was added and the resultant precipitate was collected, washed with water and dried to give the title compound (3.35 g) as a solid. MS (CI): 289 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:12][CH:13]=1.Br[C:32]1[N:33]([CH2:40][C:41]2([CH3:44])[CH2:43][O:42]2)[CH:34]=[C:35]([N+:37]([O-:39])=[O:38])[N:36]=1.C(N(C(C)C)CC)(C)C>C(OC(O)C)C>[F:1][C:2]1[CH:3]=[C:4]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH2:43][C:41]3([CH3:44])[O:42][C:32]4=[N:36][C:35]([N+:37]([O-:39])=[O:38])=[CH:34][N:33]4[CH2:40]3)[CH2:16][CH2:15]2)=[CH:12][CH:13]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(N4CCNCC4)nc3)c(F)c2)C(=O)O1
Reactant: CC1(Cn2cc([N+](=O)[O-])nc2Br)CO1
Agent: CCOC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(N4CCN(CC5(C)Cn6cc([N+](=O)[O-])nc6O5)CC4)nc3)c(F)c2)C(=O)O1
Yield: 12 %

Procedure:
A solution of N-[((5S)-3-{3-fluoro-4-[6-(1-piperazinyl)-3-pyridinyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide (0.147 g, 0.355 mmol), 2-bromo-1-[(2-methyl-2-oxiranyl)methyl]-4-nitro-1H-imidazole (0.092 g, 0.35 mmol) and diisopropylethylamine (70 μL, 0.40 mmol) in ethoxyethanol (10 mL) was refluxed for 2.5 h. The solution was evaporated onto silica gel, column chromatography (0-10% MeOH/EtOAc, gradient elution) gave a solid which was reprecipitated from refluxing MeOH to give the titled compound (25 mg, 12%) as a cream solid. APCI MS m/z 595 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.28 (bs, 1H), 8.21 (t, J=5.8 Hz, 1H), 8.12 (s, 1H), 7.70 (bdt, J=9.0, 2.2 Hz, 1H), 7.51-7.59 (m, 2H), 7.37 (dd, J=8.6, 2.2 Hz, 1H), 6.88 (d, J=9.0 Hz, 1H), 4.71-4.79 (m, 1H), 4.29 (d, J=10.7 Hz, 1H), 4.15 (t, J=9.0 Hz, 1H), 4.09 (d, J=10.7 Hz, 1H), 3.77 (dd, J=9.2, 6.5 Hz, 1H), 3.31-3.47 (m, 6H), 2.82 (d, J=14.7 Hz, 1H), 2.78 (d, J=14.7 Hz, 1H), 2.72-2.79 (m, 4H), 1.84 (s, 3H), 1.58 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH:18]1C=CC=C[CH:19]=1>C(O)C.S(=O)(=O)(O)O>[CH2:18]([O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=1[O:6][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:17][CH:16]=1)[CH3:19]
Reactant: O=C(O)c1ccccc1Oc1ccc(Br)cc1
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)c1ccccc1Oc1ccc(Br)cc1

Procedure:
A mixture of 560.0 g of 2-(4-bromophenoxy)benzoic acid in 1940 ml of absolute benzene, 218 ml of absolute ethanol and 32.6 ml of concentrated sulphuric acid is boiled under reflux for 32 hours, the water that forms being removed in a water separator. The reaction mixture is cooled to 10° and, with the addition of ice, is washed with 1000 ml of water, 500 ml of a 2N aqueous sodium carbonate solution and then once more with 1000 ml of water. The organic phase is separated off, dried over magnesium sulphate and concentrated by evaporation at 40° at a pressure of 11 mm Hg. The residue is distilled in a high vacuum and yields the 2-(4-bromophenoxy)benzoic acid ethyl ester. Boiling point 140°-150°/0.05 mm Hg.
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CO.[CH2:22]([O:29][C:30]1[CH:45]=[CH:44][C:43]([CH:46]=[O:47])=[CH:42][C:31]=1[C:32]([O:34][CH2:35]C1C=CC=CC=1)=[O:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)(=O)C.O>[CH2:22]([O:29][C:30]1[CH:45]=[CH:44][C:43]([C:46]2[O:47][CH:12]=[N:11][CH:10]=2)=[CH:42][C:31]=1[C:32]([O:34][CH3:35])=[O:33])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(-c2cnco2)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
p-Toluenesulfonylmethyl isocyanide (0.55 g) and potassium carbonate (0.39 g) were added to a methanol (9 mL) suspension of the obtained benzyl 2-(benzyloxy)-5-formylbenzoate (0.93 g), followed by heating to reflux for 1 hour and 40 minutes. The reaction mixture was cooled to room temperature, and then p-toluenesulfonylmethyl isocyanide (0.079 g) and potassium carbonate (0.058 g) were added thereto, followed by heating to reflux for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 70-50% hexane/ethyl acetate] to obtain 0.56 g of methyl 2-(benzyloxy)-5-(oxazol-5-yl)benzoate as a light yellow solid.
Reaction SMILES: [C:1]([O:4][C:5]([CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH2:6])(=[O:3])[CH3:2]>O1CCCC1.F[B-](F)(F)F.C1([Rh+]C2CCCCC=CC=2)CCCCC=CC=1>[C:1]([O:4][CH:5]([CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:6])(=[O:3])[CH3:2]
Reactant: C=C(C=CCCCCC)OC(C)=O
Agent: C1=CCCCCC([Rh+]C2=CC=CCCCC2)=C1
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CCCCCC=CC(C)OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.5 %

Procedure:
Bis(cyclooctadienyl)rhodium tetrafluoroborate (10 mg; 0.005 mmol; 0.02 equiv) and R,R-1,2-bis(2,5-dimethylphospholano)benzene (6, R"=CH3 ; 9 mg; 0.03 mmol; 0.006 equiv) were combined in a pressure tube equipped with a magnetic stir bar under argon. The tube was evacuated and filled with argon five times, and then 2.5 mL of degassed tetrahydrofuran (THF) was added to afford a yellow-orange solution. 1,3-Nonadien-2-yl acetate (1a; 911 mg; 5 mmol) dissolved in 2.5 mL of degassed THF was then added. The reaction mixture was evacuated and filled with argon five times and then was evacuated and filled with hydrogen three times. The reaction mixture was placed under 30 psi of hydrogen and stirred at room temperature overnight, at which time hydrogen uptake had ceased. The vessel was vented and flushed with nitrogen, and the reaction mixture was concentrated to afford 981 mg of crude 3-nonen-2-yl acetate (2a) containing a small amount of the fully saturated analog. Analysis of this material by chiral GC and comparing to authentic racemate showed a 96:4 ratio of enantiomers (92% ee). Conversion to 2-nonanol (hydrolysis and hydrogenation) and comparison with authentic material indicated the (R) absolute configuration. Thus, the asymmetric hydrogenation of the present invention yielded the desired product having high optical purity. The spectra is shown below:
Reaction SMILES: BrCCBr.[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1)#[N:6].[C:15]([N:34]1[CH:38]=[C:37](I)[N:36]=[CH:35]1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>C1COCC1.[Zn].C(Cl)(Cl)Cl>[C:15]([N:34]1[CH:38]=[C:37]([CH2:11][C:10]2[CH:13]=[CH:14][C:7]([C:5]#[N:6])=[CH:8][CH:9]=2)[N:36]=[CH:35]1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: BrCCBr
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reaction time: 3 h

Procedure:
To an oven dried 500 ml flask was added Zn (92 mmol, 5.96 g) and then 45 mL of distilled THF via syringe. To this well stirred mixture was added 1,2-dibromoethane (9.2 mmol, 1.72 g) via pipet. This mixture was stirred at ambient temperature for 3 hr and then a solution of p-cyanobenzylbromide (59.5 mmol, 11.68 g) in THF (50 mL) was added via addition funnel over 20 minutes. The resulting mixture was stirred at ambient temperature for 6 hr. Then a mixture of 1-trityl-4-iodoimidazole (45.8 mmol, 20 g) and bis-triphenylphosphinedichloronickel (4.6 mmol, 3.0 g) was added. This was stirred at ambient temperature for 36 hr. A saturated ammonium chloride solution (125 mL) was added. Stirring was continued for 3 hr and then 1 L of chloroform was added to this mixture. The chloroform layer was drawn off, washed with dilute sodium bicarbonate then saturated sodium chloride. Dried with sodium sulfate and evaporated to a thick oil. Purified on a silica gel column eluted with chloroform to provide the title compound. 1H-NMR (CDCl3): 4.0 ppm (s, 2H); 7.1-7.6 ppm (20H); 6.6 ppm(s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:36][CH3:37])[C:13]([O:34][CH3:35])=[C:14]([C:16]3[CH:25]=[C:24]4[C:19]([C:20](=[O:33])[C:21]([C:28]([O:30]CC)=[O:29])=[CH:22][N:23]4[CH2:26][CH3:27])=[CH:18][CH:17]=3)[CH:15]=2)=[CH:4][N:3]=1.[OH-].[Na+].[ClH:40]>C(O)C>[ClH:40].[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:36][CH3:37])[C:13]([O:34][CH3:35])=[C:14]([C:16]3[CH:25]=[C:24]4[C:19]([C:20](=[O:33])[C:21]([C:28]([OH:30])=[O:29])=[CH:22][N:23]4[CH2:26][CH3:27])=[CH:18][CH:17]=3)[CH:15]=2)=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn(CC)c2cc(-c3cc(Cc4cnc(N)nc4N)cc(OC)c3OC)ccc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1cc(C(=O)O)c(=O)c2ccc(-c3cc(Cc4cnc(N)nc4N)cc(OC)c3OC)cc21
Temperature: 25 °C
Yield: 59 %

Procedure:
82 mg of ethyl 7-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenyl]-1-ethyl-1,4-dihydro-4-oxo-quinoline-3-carboxylate (Example 2t)) are held at reflux in 1 ml of ethanol and 1 ml of 2N aqueous sodium hydroxide solution for one hr. The reaction mixture is cooled to room temperature and acidified with 25% aqueous hydrochloric acid. The precipitated substance is filtered off under suction, washed with water, ethanol and ether and dried. 49 mg (59%) of 7-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenyl]-1-ethyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride are obtained as a colourless solid. M.p.>230° C. Mass spectrum (ISP): peaks: inter alia at 476 (M++H, 100%).
Reaction SMILES: I[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:5]=[N:4][C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:18]1([C:3]2[N:4]=[N:5][N:6]([CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=3)[CH:2]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: FC(F)(F)c1cccc(Cn2nnc(-c3ccccc3)c2I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CO
Product: FC(F)(F)c1cccc(Cn2cc(-c3ccccc3)nn2)c1
Temperature: 55 °C
Yield: 97.2 %

Procedure:
Route A: Pd(OAc)2 (0.449 g, 2.000 mmol) was added to a solution of 3 (0.858 g, 2 mmol) and TEA (0.281 ml, 2.000 mmol) in MeOH (10 ml). The sample was warmed to 55° C. for 4 h and monitored by LC-MS. Once the starting material had been consumed the sample was cooled and the volatile components were removed under vacuum. The crude residue was then purified by column chromatography (9:1 Hex:EtOAc-4:1 Hex:EtOAc) to give 4 (0.59 g, 1.945 mmol, 97% yield) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([CH3:8])=[C:5]([N:9]([CH3:18])[S:10]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=[O:12])=[O:11])[CH:4]=1>O1CCCC1.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[S:7][C:6]([CH3:8])=[C:5]([N:9]([CH3:18])[S:10]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:12])[CH:4]=1)=[O:1]
Reactant: Cc1sc(CO)cc1N(C)S(=O)(=O)c1cccs1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Cc1sc(C=O)cc1N(C)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of N-[5-(hydroxymethyl)-2-methyl-3-thienyl]-N-methylthiophene-2-sulfonamide (31.1 g) in tetrahydrofuran (300 mL) was added manganese dioxide (43 g), and the mixture was stirred at room temperature overnight. The manganese dioxide was filtered off and the filtrate was concentrated and crystallized from diethyl ether to give N-(5-formyl-2-methyl-3-thienyl)-N-methylthiophene-2-sulfonamide (26.4 g, yield 86%) as yellow crystals.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9](=[O:11])[NH:8][C:7]=2[CH:12]=1.[Br:15][C:16]1[CH:17]=[N:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28]Cl)[CH:23]=2)=[N:20][CH:21]=1.O>CN(C=O)C>[Br:15][C:16]1[CH:21]=[N:20][C:19]([C:22]2[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=2)[CH2:28][N:8]2[C:7]3[CH:12]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=[CH:5][C:6]=3[S:10][C:9]2=[O:11])=[N:18][CH:17]=1
Reactant: ClCc1cccc(-c2ncc(Br)cn2)c1
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2s1
Solvent: O
Solvent: CN(C)C=O
Product: O=c1sc2ccc(C(F)(F)F)cc2n1Cc1cccc(-c2ncc(Br)cn2)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
1 g (4.56 mmol) of 5-trifluoromethyl-3H-benzothiazol-2-one, 1.3 g (4.56 mmol) of 5-bromo-2-(3-chloromethylphenyl)pyrimidine and 4.5 g (13.69 mmol) of caesium carbonates are suspended in 15 ml of DMF and stirred at room temperature for 15 h and at 80° C. for 3 h. The suspension is added to water, and the precipitate is filtered off with suction, washed with methanol and dried in vacuo, giving beige crystals; HPLC: Rt.=3.72 min (method A);
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[C:22]([C:21]([F:20])([F:29])[F:30])[CH:23]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCOCC
Product: O=C(Nc1cccc(C(F)(F)F)c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-fluoro-benzyl)-piperidine-1-yl]-oxo-acetic acid (Example 1b) and 3-(trifluoromethyl)-aniline (Aldrich) according to the method described in Example 94. Melting Point: 113-115° C. (diethylether
Reaction SMILES: [K].[CH3:2][C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26](Cl)(=[O:28])=[O:27]>O1CCCC1>[CH3:2][C:3]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:7][C:6](=[O:8])[N:5]([S:26]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)(=[O:28])=[O:27])[C:4]1=[O:9]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CC1(c2ccccc2)NC(=O)NC1=O
Agent: [K]
Solvent: C1CCOC1
Product: CC1(c2ccccc2)NC(=O)N(S(=O)(=O)c2ccc3ccccc3c2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.6 %

Procedure:
5-Methyl-5-phenylimidazolidine-2,4-dione potassium salt (1.00 g) was suspended in tetrahydrofuran (10 mL), 2-naphthalenesulfonyl chloride (1.02 g) was added slowly, and the mixture was stirred at room temperature overnight. After the solvent was distilled off, ethyl acetate (100 mL) was added to the reaction solution, and the solution was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and a saturated brine in turn. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further purification by silica gel chromatography (hexane:ethyl acetate=2:1) afforded 242 mg of white crystals.
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6]([C:8]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[C:12]([C:22]([NH2:24])=[O:23])=[C:11]([NH2:25])[N:10]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:9]=1[CH3:36])=[O:7]>CN(C)C=O.O1CCCC1.O>[NH2:25][C:11]1[N:10]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=2)[C:9]([CH3:36])=[C:8]([C:6]([OH:7])=[O:5])[CH:13]([C:14]2[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=2)[C:12]=1[C:22]([NH2:24])=[O:23]
Reactant: CC1=C(C(=O)OCC[Si](C)(C)C)C(c2ccc(C#N)cc2)C(C(N)=O)=C(N)N1c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)C(C(N)=O)=C(N)N1c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 650 mg (1.2 mmol) of the compound of Example 59 in 2.4 ml dimethylformamide are added 1.2 ml (1.2 mmol) of a 1 M solution of tris(dimethylamino)sulfoniumdifluoro(trimethyl)silicate in tetrahydrofuran under argon at 0° C. After stirring the reaction mixture for 15 minutes at 0° C., stirring is continued at room temperature overnight. The reaction mixture is diluted with water and extracted four times with ethyl acetate. The combined organic phases are dried with sodium sulfate and concentrated in vacuo. The residue is purified by preparative HPLC (column: YMC C18 ODS-AQ 250 mm×30 mm, 11 μm; solvent A: acetonitrile, solvent B: water; gradient: 0 min 10% A, 3 min 10% A, 11 min 90% A, 13 min 90% A, 13.2 min 10% A, 15 min 10% A; wavelength: 220 nm; injection volume: ca. 1000 μl and 2000 μl methanol solution; number of injections: 2). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:28](=[O:40])[N:29]([C:33]6[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=6)[N:30]=[CH:31][CH:32]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([NH:42][CH:43]3[CH2:47][CH2:46][NH:45][CH2:44]3)=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>>[F:41][C:19]1[CH:20]=[C:21]([NH:24][C:25]([C:27]2[C:28](=[O:40])[N:29]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[N:30]=[CH:31][CH:32]=2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([NH:42][CH:43]3[CH2:47][CH2:46][NH:45][CH2:44]3)[C:11]=12
Reactant: COc1ccc(Cn2nc(NC3CCNC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Oc2ccnc3[nH]nc(NC4CCNC4)c23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 5.7 %

Procedure:
A 100 mL round-bottomed flask was charged with N-(4-(1-(4-methoxybenzyl)-3-(pyrrolidin-3-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (40.8 mg, 0.0614 mmol) and CF3COOH (5 mL). The reaction mixture was stirred at 80° C. overnight. The solvent was removed and the residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to give product, which was further purified by preparative HPLC to afford product (1.9 mg, 5.68%). LRMS (APCI pos): m/e 545 (M+1). 1H NMR (400 MHz, CD3OD δ 11.96 (s, 1H), 8.36 (d, 1H), 8.31 (d, 1H), 8.19 (d, 1H), 8.04 (dd, 1H), 7.68 (m, 2H), 7.51 (d, 1H), 7.40 (t, 1H), 7.29 (m, 2H), 6.16 (d, 1H), 4.48 (m, 1H), 3.56 (m, 3H), 3.39 (m, 1H), 2.42 (m, 1H), 2.32 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:22][N:23]([CH3:26])C=O>CNCCC1C=CC=CC=1.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:23]([CH3:26])[CH2:22][CH2:6][C:5]4[CH:20]=[CH:21][CH:2]=[CH:3][CH:4]=4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Reactant: CN(C)C=O
Agent: CNCCc1ccccc1
Solvent: CCO
Product: CN(CCc1ccccc1)C[C@H](O)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and N-methylphenethylamine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=421.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:9]([C:10]2[CH:14]=[CH:13][S:12][C:11]=2[C:15]([O:17][CH3:18])=[O:16])[C:8](=[O:19])[N:7]([CH3:20])[N:6]=1>CO.C(COC)OC.CO>[CH3:1][O:2][C:5]1[N:9]([C:10]2[CH:14]=[CH:13][S:12][C:11]=2[C:15]([O:17][CH3:18])=[O:16])[C:8](=[O:19])[N:7]([CH3:20])[N:6]=1
Reactant: COC(=O)c1sccc1-n1c(Cl)nn(C)c1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Product: COC(=O)c1sccc1-n1c(OC)nn(C)c1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Sodium methoxide (16.5 mL of a 30% solution in methanol) was added to a solution of the title compound of Step C (7.9 g) in anhydrous dimethoxyethane/methanol (85 mL/35 mL). The resulting yellow solution was heated to 50° C. for 2 h under N2 and then left to stir overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in methylene chloride. The resulting mixture was washed with water and then with saturated aqueous NaCl. The aqueous layer was filtered through Celite® and the filtrate was extracted three times with methylene chloride. The combined methylene chloride layers were dried (MgSO4), filtered, and concentrated under reduced pressure to give 5.4 g of an off-white solid. The crude product was purified by flash chromatography (20-100% ethyl acetate/hexane as eluent) to afford 3.9 g of the title compound of Step D as a white solid. 1H NMR (CDCl3): δ 7.58 (d,1H), 7.12 (d,1H), 3.93 (s,3H), 3.83 (s,3H), 3.44(s,3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.Br[CH2:30][C:31]([CH3:33])=[CH2:32]>C1COCC1>[CH3:32][C:31](=[CH2:30])[CH2:33][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:18][CH:17]=1)[C:20]([OH:22])=[O:21]
Reactant: C=C(C)CBr
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=C(C)CC(C(=O)O)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
To a stirring solution of diisopropylamine (0.537 g, 5.31 mmol) in THF (5.2 mL) at 0° C. was added n-butyllithium (2.1 mL, 5.22 mmol, 2.5M in hexane) dropwise. After stirring for 15 min at 0° C., the mixture was cooled to −78° C. and a solution of 4-biphenylacetic acid (0.500 g, 2.36 mmol) in THF (2 mL) was added dropwise. After again warming to 0° C. and coolling to −78° C., 3-bromo-2-methylpropene (0.485 g, 3.54 mmol) was added to the mixture in one portion. After stirring at −78° C. for 1 h, the reaction was quenched with 2 mL of water then concentrated. The residue was redissolved in water and extracted with ether (100 mL). The aqueous layer was acidified (3N HCl) and extracted with ether (3×100 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated to yield a white solid (0.449 g, 72%). MS(ESI): 265.3 (M+H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=3)[CH:17]=2)=[C:11]([CH3:27])[N:10]=[N:9]1.[NH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:28][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:23])=[CH:20][N:19]=3)[CH:17]=2)=[C:11]([CH3:27])[N:10]=[N:9]1
Reactant: NN1CCOCC1
Reactant: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Product: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)NN3CCOCC3)cn2)cn1
Yield: 62 %

Procedure:
As described for example 43c, 6-(4-(1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (74 mg, 0.203 mmol) was converted, using 4-aminomorpholine instead of isopropylamine, to the title compound (56 mg, 62%) which was obtained as a white foam after purification by chromatography (reverse phase HPLC then silica, ethyl acetate). MS: m/e=449.2 [M+H]+.