Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]1O)[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([C:3]1[CH2:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCC1Cc2c(-c3ccccc3)cccc2C1O
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1=Cc2c(cccc2-c2ccccc2)C1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 72.1 %

Procedure:
To a 300-ml four-necked round flask (equipped with stirrer chip, dropping funnel and thermometer) were introduced 9.78 g (41.3 mmol) of the 2-ethyl-1-hydroxy-4-phenylindan obtained above, 17.2 ml (123.8 mmol) of triethylamine, 0.25 g (2.1 mmol) of 4-dimethylaminopyridine and 98 ml of methylene chloride. In a nitrogen atmosphere under ice cooling, to the flask was dropwise added slowly a solution obtained by dissolving 6.4 ml (82.5 mmol) of methanesulfonyl chloride in 6.5 ml of methylene chloride. After the dropping was completed, the reaction was further performed for 3.5 hours. After the reaction mixture was poured into 250 ml of ice water, the organic phase was separated, and the aqueous phase was extracted twice with 50 ml of methylene chloride, followed by mixing the organic phases together. The whole organic phase was washed with a saturated NaHCO3 aqueous solution and then washed with a saturated saline solution, followed by drying with anhydrous Na2SO4. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel chromatography (developed with hexane) to obtain 6.56 g of the aimed product (mixture of two kinds of isomers) as a light yellow liquid (yield: 73%) The properties of the product thus obtained are described below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[OH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.O.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([OH:14])[CH:16]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1cccc(O)c1
Reactant: COc1ccc(OCCCN)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(OCCCNCc2cccc(O)c2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3-(4-Methoxyphenoxy)propylamine (10.0 g) was dissolved in methanol (50 mL) at room temperature, a solution of 3-hydroxybenzaldehyde (6.7 g) in methanol (50 mL) was added dropwise within 5 minutes at water temperature (about 20° C.), and then the resulting mixture was stirred at room temperature for 20 hours. Then, sodium borohydride (2.1 g)/water (100 mL) was added dropwise at water temperature (about 20° C.) for 5 minutes, and the mixture was stirred at room temperature for 12 hours. Precipitates were removed, washed with water and then dried under reduced pressure at 80° C. for 5 hours. Pale yellow crystals were obtained (13.9 g, 87.4%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]([C:14]2[CH:28]=[CH:27][C:17]([C:18]([NH:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[O:19])=[CH:16][N:15]=2)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH:5]=[C:4]([CH3:29])[C:3]=1[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1.[Li+].[OH-].Cl>O.O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]([C:14]2[CH:28]=[CH:27][C:17]([C:18]([NH:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:19])=[CH:16][N:15]=2)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH:5]=[C:4]([CH3:29])[C:3]=1[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Nc2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(NC(CC(C)C)c2ccc(C(=O)NCCC(=O)O)cn2)cc(C)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 13 %

Procedure:
Methyl 3-(6-(1-(2,6-dimethyl-4′-(trifluoromethyl) biphenyl-4-yl amino)-3-methylbutyl)nicotinamido)propanoate (400 mg, 0.74 mmol) was dissolved in H2O (3 mL) and tetrahydrofuran (3 mL). Then 1N LiOH (93.0 mg, 2.2 mmol) was added. The mixture was stirred at ambient temperature for 5 hours. The mixture was neutralized with 1N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by HPLC (column: Boston Analytics Symmetrix ODS-H 150×30 mm, 5 μm; modifier: formic acid 0.225%; gradient: 10 to 80% MeCN in water) gave (+/−)-3-(6-(1-(2,6-dimethyl-4′-(trifluoromethyl)biphenyl-4-ylamino)-3-methylbutyl)nicotinamido)propanoic acid (50.7 mg, 13%) as a yellow solid. 1H NMR (400 MHz, CD3CN, δ): 8.85 (s, 1H), 8.02 (m, 1H), 7.64 (d, 2H), 7.46 (d, 1H), 7.22 (d, 3H), 6.32 (s, 2H), 4.59 (m, 1H), 3.54 (m, 2H), 2.55 (m, 2H), 1.93 (m, 6H), 1.78 (s, 2H), 1.72 (m, 2H), 1.60 (m, 1H), 0.96 (d, 3H), 0.91 (d, 3H). MS (M+1): 528.2.
Reaction SMILES: [Mg].[CH3:2]I.[Cl:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8][CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]=1[CH:21]=[O:22].[Cl-].[NH4+]>O.O1CCCC1.C(OCC)C>[Cl:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8][CH:7]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6]=1[CH:21]([OH:22])[CH3:2]
Reactant: CI
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(O)C1=C(Cl)c2ccccc2OC1c1ccccc1
Temperature: 0 °C

Procedure:
2.88 g magnesium is allowed to react with 16.82 g methyl iodide in 80 ml refluxing dry diethylether. After disappearance of magnesium, one adds a solution of 21.4 g 4-chloro-3-formyl-flav-3-ene in 100 ml of a mixture of diethylether and tetrahydrofuran. After cooling to 0° C., a solution of 12.68 g ammonium chloride in 160 ml water is added. The two phases are separated and the aqueous solution is extracted with 50 ml diethyl ether. The combined organic phases are washed with 50 ml water, dried over magnesium sulfate and evaporated. The crude solid is crystallized in hexane. A racemate of one diastereomer of 4-chloro-3-(α-hydroxyethyl)-flav-3-ene is obtained as yellow crystals; m.p. 111°-113° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:19])([F:18])[F:17])=[CH:5][CH:4]=1)=O.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1.O>[F:17][C:16]([F:19])([F:18])[O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[C:24]2[S:20][C:21](=[O:26])[NH:22][C:23]2=[O:25])=[CH:4][CH:5]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(-c2ccccc2OC(F)(F)F)cc1
Agent: O=C(O)c1ccccc1
Solvent: O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(=Cc2ccc(-c3ccccc3OC(F)(F)F)cc2)S1

Procedure:
To a solution of 4-formyl-(2′-trifluoromethoxy-1,1′-biphenyl) (0.31 g, 1.16 mmol) and 2,4-thiazolidinedione (0.164 g, 1.4 mmol) in toluene (20 mL) were added piperidine (0.015 mL, 0.152 mmol) and benzoic acid (0.021 mg, 0.175 mmol), and the reaction was refluxed for 3 h with continuous removal of water. The solvent was then distilled off and the residue was crystallized from ether-pet ether to yield titled product as a solid.
Reaction SMILES: O1CCCC1.[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[CH2:14][S:15]([OH:18])(=O)=[O:16].C(Cl)(=O)C([Cl:22])=O>CN(C)C=O>[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[CH2:14][S:15]([Cl:22])(=[O:18])=[O:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cccc(C)c1CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1CS(=O)(=O)Cl
Temperature: -20 °C
Yield: 84.5 %

Procedure:
Tetrahydrofuran (3.0 L), (2,6-dimethyl-phenyl)-methanesulfonic acid (300 g, containing 12% water by KF analysis, or 266 g corrected for water content), and N,N-dimethylformamide (15 g) were combined in a 5 L multi-necked flask equipped with overhead stirring. The reaction mixture was cooled to −20° C. and oxalyl chloride (655.5 g) was added slowly over 1 h. The reaction mixture was clarified by filtration and concentrated to a volume of 1 L. The filtrate was transferred to a flask equipped with overhead stirring and cooled to −40° C. Water (900 mL) was added over 30 minutes, maintaining an internal temperature of <−10° C. The product was collected by filtration, washed with water and heptane, and dried to give (2,6-dimethyl-phenyl)-methanesulfonic chloride (277 g, 96%). 1H NMR (300 MHz, CDCl3): δ 7.25-7.04 (m, 3H, ArH), 5.17 (s, CH2), and 2.50 (s, 6H, CH3).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8](O)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11](=[O:14])([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][CH2:21][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][CH2:37][CH2:38][CH3:39]>CN(C)C=O>[CH2:18]([O:1][C:2]1[CH:9]=[C:8]([O:14][CH2:11][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH2:19][CH2:20][CH2:21][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][CH2:37][CH2:38][CH3:39]
Reactant: O=C([O-])[O-]
Reactant: CCCCCCCCCCCCCCCCCCCCCCBr
Reactant: O=Cc1ccc(O)cc1O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C=O)c(OCCCCCCCCCCCCCCCCCCCCCC)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Under an argon atmosphere, 2,4-dihydroxybenzaldehyde (3.00 g, 21.7 mmol), potassium carbonate (30.0 g, 217 mmol) and 1-bromodocosane (17.3 g, 44.5 mmol) were added to dehydrating N,N-dimethylformamide (150 mL), and the mixture was stirred at 70° C. overnight. After completion of the reaction, the reaction mixture was poured into purified water (1 L), the mixture was stirred for 1 hr, and the precipitated solid was collected by filtration. The obtained solid was slurry-washed in methanol and filtered, and the obtained solid was dried under reduced pressure to give the title compound (16.3 g, 99.3%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9][C:10]([C:12]2[C:13]([CH3:20])=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9]/[C:10](/[C:12]2[C:13]([CH3:20])=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:29]\[OH:30])=[CH:4][CH:3]=1
Reactant: Cc1cc(=O)n(C)cc1C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(=O)n(C)cc1/C(CC(c1ccc(Br)cc1)c1ccccc1C)=N/O

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1,4-dimethyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=439.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[O:3][C@H:4]([C:27]([F:30])([F:29])[F:28])[CH2:5][C@:6]([C:10]2[CH:11]=[C:12]([NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22](Br)=[CH:21][N:20]=3)[CH:13]=[CH:14][C:15]=2[F:16])([CH2:8][F:9])[N:7]=1.C(NCC)C.[CH:36]1([C:39]#[CH:40])[CH2:38][CH2:37]1.C1(C)C=CC=CC=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[NH2:1][C:2]1[O:3][C@H:4]([C:27]([F:30])([F:29])[F:28])[CH2:5][C@:6]([C:10]2[CH:11]=[C:12]([NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22]([C:40]#[C:39][CH:36]4[CH2:38][CH2:37]4)=[CH:21][N:20]=3)[CH:13]=[CH:14][C:15]=2[F:16])([CH2:8][F:9])[N:7]=1
Reactant: NC1=N[C@](CF)(c2cc(NC(=O)c3ccc(Br)cn3)ccc2F)C[C@@H](C(F)(F)F)O1
Reactant: C#CC1CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: NC1=N[C@](CF)(c2cc(NC(=O)c3ccc(C#CC4CC4)cn3)ccc2F)C[C@@H](C(F)(F)F)O1

Procedure:
N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-bromopicolinamide (Example 52) was transferred to a microwave vial followed by the addition of diethylamine (0.580 ml, 5.55 mmol), tetrakis(triphenylphosphine)palladium (0.053 g, 0.046 mmol), copper(I) iodide (0.021 g, 0.111 mmol), cyclopropylacetylene, 70 wt. % solution in toluene (0.179 ml, 1.480 mmol) and DMF (1.5 mL). The vial was sealed, purged with N2 and heated in microwaved at 90° C. for 45 min. The reaction went to completion, diluted in water (10 mL) and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-3% MeOH/DCM and 0-50% EtOAc/hexanes to afford a light yellow solid as N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-(cyclopropylethynyl)picolinamide. MS m/z=479 [M+H]+. Calculated for C23H19F5N4O2: 478.14
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH2:31][CH3:32])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.CN1CCCN(C)C1=O.[NH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>C1(C)C=CC=CC=1>[CH2:31]([C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[CH:22][C:14]=2[NH:13][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([N:42]4[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]4)=[CH:3][C:4]3=[N:10][CH:9]=2)=[O:12])[N:18]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=2)[N:17]=1)[CH3:32]
Reactant: C1CNCCN1
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Solvent: Cc1ccccc1
Solvent: CN1CCCN(C)C1=O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(N5CCNCC5)ccn34)c12
Temperature: 105 °C
Reaction time: 16 h
Yield: 80.9 %

Procedure:
N-(3-Ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide (12 mg, 0.03 mmol; Example 74, Step A) was dissolved in toluene (0.2 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (0.1 mL) and piperazine (24 mg, 0.28 mmol) was added in one portion. The mixture was heated to 105° C. and stirred for 16 hours. The crude mixture was loaded onto a Biotage 12+ C-18 samplet and purified using a gradient of 10-65% acetonitrile/water to give N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(piperazin-1-yl)imidazo[1,2-a]pyridine-3-carboxamide as a white solid (12 mg). MS m/z 495.3 (M+1, APCI+)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][OH:7].N1C=CN=C1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CN(C=O)C>[Si:13]([O:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccs1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccs1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 110 %

Procedure:
A 100 ml round-bottom flask, equipped with a magnetic stirring bar, septum, and nitrogen inlet, was charged with 500 μl (3.98 mmol, 1.0 equiv) 2-thiophenemethanol and 5 ml DMF (over sieves). This clear solution was cooled down to 0° C. 825 mg (11.95 mmol, 3.0 equiv) imidazole was added in one portion, followed by the addition of 930 mg (5.97 mmol, 1.5 equiv) t-butyldimethylsilyl chloride. The reaction was kept at 0° C. for 5 minutes, warmed up to room temperature to go for half an hour, and then quenched with distilled water. Ethyl acetate was added to dissolve the organics. Layers were separated, and the aqueous layer was extracted with 5×10 ml ethyl acetate. The combined organic portion was washed with 5×20 ml H2O, dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographed on a silica gel column (5 cm×24 cm, 100:1=hexane:ethyl acetate) to afford 1 gram of the title compound: Rf=0.26 (100:1=hexane:ethyl acetate), 1H NMR δ4.87 (s, OCH2), 0.91 (s, tBu), 0.09 (s, CH3).
Reaction SMILES: ClC1C=CC([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:32])([F:31])[C:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][N:19]=[N:18]3)=[N:12][CH:13]=2)=C(F)C=1.BrC[C:38]1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[C:40]([F:46])[CH:39]=1>>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:15]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][N:19]=[N:18]1)[C:14]([C:11]1[N:12]=[CH:13][C:8]([O:7][CH2:6][C:38]2[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[C:40]([F:46])[CH:39]=2)=[CH:9][CH:10]=1)([F:32])[F:31]
Reactant: N#Cc1ccc(CBr)cc1F
Reactant: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(OCc2ccc(Cl)cc2F)cn1
Product: N#Cc1ccc(COc2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)cc1F

Procedure:
Compound 10 was prepared in a similar manner to compound 1 from 4-(bromomethyl)-2-fluorobenzonitrile to afford a white solid (90 mg, 36%). 1H NMR (500 MHz, CDCl3): δ 8.73 (s, 1H), 8.23 (s, 1H), 7.70-7.67 (m, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.38-7.36 (m, 2H), 7.32-7.29 (m, 3H), 6.78-6.74 (m, 1H), 6.71-6.68 (m, 1H), 5.50 (d, J=14.5 Hz, 1H), 5.17 (s, 2H), 5.15 (d, J=14.5 Hz, 1H). MS(ESI): m/z 503 [M++1]. HPLC: 95.84%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[C:3]=1[N+:19]([O-])=O.[N:22]([O-])=O.[Na+]>ClCCl.C(O)(=O)C.O>[Cl:1][C:2]1[C:3]2[N:19]=[N:22][N:8]([C:9]3[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(Cl)c2[N+](=O)[O-])cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-n2nnc3c(Cl)ncnc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.8 %

Procedure:
To a solution of (6-chloro-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine in dichloromethane (8 mL) and 50% aqueous acetic acid (6 mL) was added sodium nitrite (64.6 mg, 0.937 mmol) in water (1 mL) dropwise at room temperature. After the addition was complete, the reaction was stirred for additional 15 minutes at room temperature. The organic layer was then separated, washed with water, and dried over anhydrous magnesium sulfate. Filtration followed by removal of volatiles under high vacuum afforded the desired product as a yellow solid (205 mg, 77.8%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([OH:22])=O)=[CH:18][NH:17][C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[NH2:43][C:44]([CH3:55])([CH3:54])[CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50]>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[CH3:55][C:44]([NH:43][C:20]([C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=4)[NH:8][N:7]=3)[N:12]=2)[NH:17][CH:18]=1)=[O:22])([CH3:54])[CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:51])([CH3:50])[CH3:52]
Reactant: CC(C)(N)CNC(=O)OC(C)(C)C
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)n[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)CNC(=O)OC(C)(C)C)c4n3)n[nH]c2c1
Reaction time: 16 h
Yield: 63.5 %

Procedure:
To a stirred solution of 2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.34 mmol), EDCI (130 mmol, 0.68 mmol), DMAP (83 mg, 0.68 mmol) and DIEA (88 mg, 0.68 mmol) in 6 mL of DMF was added tert-butyl 2-amino-2-methylpropylcarbamate (128 mg, 0.68 mmol) in one portion at room temperature, then the mixture was stirred for 16 hours. The reaction mixture was poured into 40 mL of water, filtered and the filter cake was washed with petroleum ether to give crude tert-butyl 2-methyl-2-(2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)propylcarbamate (100 mg, 63.4%) as a pale yellow solid. MS: (M+H)+=463.2.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=1[CH2:15][OH:16].C1N=CN([C:22](N2C=NC=C2)=[O:23])C=1>C1COCC1.O>[O:23]=[C:22]1[NH:1][C:2]2[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=2[CH2:15][O:16]1
Reactant: CCOC(=O)COc1ccc(N)c(CO)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)COc1ccc2c(c1)COC(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.4 %

Procedure:
To a solution of ethyl 2-(4-amino-3-(hydroxymethyl)phenoxy)acetate (0.2 g, 0.888 mmol) in THF (5 mL) was added CDI (0.216 g, 1.332 mmol) at 0° C. and stirred at RT for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel using hexane/ethyl acetate as eluent to yield ethyl 2-((2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazin-6-yl)oxy)acetate (0.03 g, 13%). 1H NMR: 400 MHZ, DMSO-d6: δ 1.22 (t, J=7.20 Hz, 3H), 4.17 (q, J=6.80 Hz, 2H), 4.72 (s, 2H), 5.23 (s, 2H), 6.79-6.86 (m, 3H), 10.01 (s, 1H).
Reaction SMILES: COCCOCCOC.[Cl:10][C:11]1[CH:12]=[C:13]([C:18]([C:32]([F:35])([F:34])[F:33])=[CH:19][C:20]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([CH3:31])[CH:23]=2)=O)[CH:14]=[C:15]([Cl:17])[CH:16]=1.C1(C)C=CC=CC=1.[OH2:43].S(O)(O)(=O)=O.[NH2:49]O>[OH-].[Na+]>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2([C:32]([F:35])([F:34])[F:33])[O:43][N:49]=[C:20]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([CH3:31])[CH:23]=3)[CH2:19]2)[CH:14]=[C:15]([Cl:17])[CH:16]=1
Reactant: O
Reactant: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)O
Reactant: NO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: COCCOCCOC
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 0 °C

Procedure:
3.2 g of diglyme was added to a solution in which 1.61 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid was dissolved into 8.51 g of toluene, and the mixture was cooled to 0° C. A solution in which 0.64 g of sodium hydroxide was dissolved into 1.6 g of water was added to the mixture, and a solution in which 0.46 g of hydroxylamine sulfate was dissolved into 1.11 g of water was slowly added in dropwise with care not to generate heat. After reacting the mixture for 1 hour with stirring while keeping the reaction temperature at 0° C., the resultant solution was analyzed by high-performance liquid chromatography (wavelength 254 nm). The target product of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid was produced in 88.32% of relative area.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[NH2:15][C:16]1[C:24]2[O:23][C:22]([CH3:26])([CH3:25])[CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.[C:27]([C:30]1[S:31][CH:32]=[CH:33][N:34]=1)(=O)[CH3:28]>>[CH3:25][C:22]1([CH3:26])[CH2:21][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:15][C:8]3[CH:7]=[CH:6][C:5]4[C:4]([NH:1][CH:27]([C:30]5[S:31][CH:32]=[CH:33][N:34]=5)[CH3:28])=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=3)[C:24]=2[O:23]1
Reactant: CC(=O)c1nccs1
Reactant: CC1(C)Cc2cccc(N)c2O1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: CC(Nc1cccc2nc(Nc3cccc4c3OC(C)(C)C4)ccc12)c1nccs1

Procedure:
The title compound, MS: m/e=417.4 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 7-amino-2,3-dihydro-2,2-dimethylbenzofuran (CAS 68298-46-4) and 2-acetylthiazole as described in example 26.