Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[CH:8][C:9]([OH:15])=[C:10]([C:12](=[O:14])[CH3:13])[CH:11]=1>C(O)(=O)C>[F:5][C:6]1[CH:7]=[C:8]([N+:1]([O-:4])=[O:2])[C:9]([OH:15])=[C:10]([C:12](=[O:14])[CH3:13])[CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1cc(F)ccc1O
Solvent: CC(=O)O
Product: CC(=O)c1cc(F)cc([N+](=O)[O-])c1O
Reaction time: 3 h
Yield: 98.48 %

Procedure:
Conc. HNO3 (22.49 g, 357 mmol) was added to a solution 1-(5-fluoro-2-hydroxyphenyl)ethanone (50 g, 325 mmol) in acetic acid (300 mL) at 0° C. and stirring was continued at 20° C. for 3 h. The reaction mixture was quenched with ice cold water. The separated solid was filtered and washed with cold water and dried to afford 1-(5-fluoro-2-hydroxy-3-nitrophenyl)ethanone (Int-19) (65 g, 98.48% yield) as pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.6 (1H, s), 8.3-8.2 (1H, dd), 8.2-8.1 (1H, dd), 2.7 (3H, s) ppm.
Reaction SMILES: [F:1][C:2]([F:9])([CH2:6][CH:7]=[CH2:8])[C:3](O)=[O:4].[Cl:10]CCl.C1(C)C=CC=CC=1>CN(C)C=O>[F:1][C:2]([F:9])([CH2:6][CH:7]=[CH2:8])[C:3]([Cl:10])=[O:4]
Reactant: C=CCC(F)(F)C(=O)O
Reactant: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=CCC(F)(F)C(=O)Cl

Procedure:
For example, 2,2-difluoro-4-pentenoic acid 8c is contacted with about 1.0 to 1.5 molar equivalents of an appropriate chlorinating agent. The reaction is carried out in a suitable solvent, such as dichloromethane, toluene or dimethylformamide. The reaction is carried out at a temperature of from about 20° C. to about 35° C. and generally requires about 4 to 24 hours. The product, 2,2-difluoro-4-pentenoyl chloride 8a, can be isolated by fractional distillation and purified by techniques well known in the art, such as chromatography.
Reaction SMILES: OO.Cl.[CH2:4]([S:6][C:7]1[CH:27]=[CH:26][C:10]2[N:11]([CH3:25])[C:12]3[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=3[CH:14]=[C:15]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[C:9]=2[CH:8]=1)[CH3:5].[OH2:28].[OH-:29].[Na+]>C(O)(=O)C>[CH2:4]([S:6]([C:7]1[CH:27]=[CH:26][C:10]2[N:11]([CH3:25])[C:12]3[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=3[CH:14]=[C:15]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[C:9]=2[CH:8]=1)(=[O:29])=[O:28])[CH3:5]
Reactant: O
Reactant: CCSc1ccc2c(c1)C(CCN(C)C)=Cc1ccccc1N2C
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CCS(=O)(=O)c1ccc2c(c1)C(CCN(C)C)=Cc1ccccc1N2C
Temperature: 65 °C
Reaction time: 4 h

Procedure:
5.1 ml of 30% hydrogen peroxide were added dropwise in 10 minutes to a solution of 4.25 g of 2-ethylthio-5-methyl-11-(β-dimethylaminoethyl) [5H] dibenzo (b,f) azepine hydrochloride in 42.5 ml of acetic acid heated to 65°C and the mixture was stirred at 65°C for 4 hours and then was cooled. The mixture was poured into 200 ml of ice and water and the solution was made alkaline by addition of sodium hydroxide. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried over magnesium sulfate and distilled to dryness under reduced pressure. The residue was chromatographed over silica gel with a 95-5 mixture of chloroform-methanol as eluant which was distilled to obtain 2.85 g of 2-ethylsulfonyl-5-methyl-11-(β-dimethylaminoethyl) [5H] dibenzo (b,f) azepine.
Reaction SMILES: COC1C=C(C2OC3C=CC=CC=3N=2)C=CC=1CN1C=CN=N1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:33][C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[N:36]=2)=[CH:28][C:27]=1[O:41][CH3:42].[Br:43][C:44]1[N:45]=[CH:46][NH:47][CH:48]=1>>[Br:43][C:44]1[N:45]=[CH:46][N:47]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[O:33][C:34]4[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=4[N:36]=3)=[CH:28][C:27]=2[O:41][CH3:42])[CH:48]=1
Reactant: Brc1c[nH]cn1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Agent: COc1cc(-c2nc3ccccc3o2)ccc1Cn1ccnn1
Product: COc1cc(-c2nc3ccccc3o2)ccc1Cn1cnc(Br)c1

Procedure:
Utilizing the general procedure outlined for 2-[3-methoxy-4-(1H-1,2,3-triazol-1-ylmethyl)phenyl]-1,3-benzoxazole, reaction of 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole (300 mg, 1.0 mmol) and 4-bromo-1H-imidazole (150 mg, 1.0 mmol) afforded the desired 2-{4-[(4-bromo-1H-imidazol-1-yl)methyl]-3-methoxyphenyl}-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 7.94–7.99 (m, 3H), 7.85–7.87 (m, 1H), 7.75–7.78 (m, 1H), 7.65–7.68 (m, 1H), 7.43–7.49 (m, 2H), 7.20 (s, 1H), 5.55 (s, 2H), 4.09 (s, 3H). MS (ESI) 384 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH:22]1([CH2:26]O)[CH2:25][CH2:24][CH2:23]1.CO>ClCCl>[CH:22]1([CH2:26][O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: OCC1CCC1
Solvent: ClCCl
Solvent: CO
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)OCC1CCC1
Yield: 92 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using cyclobutanemethanol (32 μL, 0.34 mmol) as the coupling partner. Chromatography (1:1 methanol:dichloromethane) through SiO2 yielded 56 mg (92%) of the titled compound. ESI-MS m/z 360 (MH+), 358 (M−H−).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:22]=[CH:21][C:11]([C:12]([NH:14][CH:15]([CH3:20])[C:16]([O:18]C)=[O:17])=[O:13])=[C:10]([F:23])[CH:9]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=2)O1>O.C1(C)C=CC=CC=1.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>[NH2:38][C:35]1[N:36]=[CH:37][C:32]([C:8]2[CH:22]=[CH:21][C:11]([C:12]([NH:14][CH:15]([CH3:20])[C:16]([OH:18])=[O:17])=[O:13])=[C:10]([F:23])[CH:9]=2)=[CH:33][N:34]=1
Reactant: COC(=O)C(C)NC(=O)c1ccc(Br)cc1F
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(NC(=O)c1ccc(-c2cnc(N)nc2)cc1F)C(=O)O
Temperature: 120 °C
Yield: 101.1 %

Procedure:
A solution of potassium carbonate (0.35 g, 2.5 mmol) in water (2 mL) was added to a mixture of methyl 2-[(4-bromo-2-fluorobenzoyl)amino]propanoate (0.5 g, 1.6 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.28 g, 1.3 mmol), and tetrakis(triphenylphosphine)palladium (0.07 g, 0.06 mmol) in toluene (4 mL) and ethanol (2 mL). The resulting mixture was heated at 120° C. for 15 min The reaction mixture was extracted with ether (3×10 mL) to remove impurity. The aqueous layer was adjusted to pH 7 with aqueous HCl and purified by RP-HPLC (pH 10) to afford the desired product (0.40 g, 100%). LCMS: (M+H)=305.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][CH2:6]2.[NH2:14][C:15]([NH2:17])=[O:16].[CH2:18](OC(OCC)OCC)C>CS(O)(=O)=O.C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:9]3[N:17]=[C:15]([OH:16])[N:14]=[CH:18][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: CCOC(OCC)OCC
Reactant: NC(N)=O
Agent: CS(=O)(=O)O
Solvent: CCO
Product: COc1ccc2c(c1)CCc1cnc(O)nc1-2
Temperature: 90 °C
Yield: 38 %

Procedure:
A mixture of 6-Methoxy-3,4-dihydro-2H-naphthalen-1-one (90 g, 0.511 M), urea (30.7 g, 0.511 M), triethylorthoformate (159 g, 1.07 M), ethanol (300 ml) and methane sulfonic acid (300 drops) was heated in the microwave at 90° C. for 1 hr. then cooled to room temperature. The solvent was removed under reduced pressure and the residue dried under vaccuo. The solid residue was then suspended in ethanol (250 ml) cooled to 0° C. and the precipitate was isolated via filtration and washed with ethanol (2×50 ml) and dried in vaccuo to give 8-Methoxy-5,6-dihydro-benzo[h]quinazolin-2-ol (43.95 g, 38% yield as a 1:1 urea complex) ES-MS MH+ 229.3 1H NMR (300 MHz, ppm, DMSO-d6): 11.45 (br S, 1H), 8.08 (d, 1H), 7.76 (br S, 1H), 6.95 (d, 1H), 6.91 (s, 1H), 5.4 (br S, 6H), 3.83 (s, 3H), 2.85 (m, 2H), 2.66 (m, 2H).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[CH3:21][C:22]1[CH:23]=[C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:25]=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1>C(Cl)(Cl)(Cl)Cl>[Br:8][CH2:21][C:22]1[CH:23]=[C:24]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:25]=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(-c2ccccc2)cc([N+](=O)[O-])c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc(CBr)cc(-c2ccccc2)c1
Temperature: 80 °C

Procedure:
NBS (184 mg, 1.032 mmol) and AIBN (15.4 mg, 0.04 mmol) were added to a solution of 3-methyl-5-nitrobiphenyl (200 mg, 0.938 mmol) in carbon tetrachloride (1.88 mL) and then the reaction mixture was heated to 80° C. for 3 hours. Additional AIBN (15.4 mg, 0.04 mmol) was added to the reaction mixture and was heated for additional 1 hour. The mixture was purified directly by silica gel column chromatography (ethyl acetate/hexanes) to yield 3-(bromomethyl)-5-nitrobiphenyl.
Reaction SMILES: [S:1]([O-:5])([O-])(=[O:3])=[O:2].[Ca+2].S(=O)(=O)=O.[Cl:11][C:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13].ClC([O-])=O>C(Cl)Cl>[Cl:11][C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([S:1]([OH:5])(=[O:3])=[O:2])=[CH:17][CH:16]=1)=[O:13]
Reactant: O=S(=O)([O-])[O-]
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])Cl
Agent: O=S(=O)=O
Agent: [Ca+2]
Solvent: ClCCl
Product: O=C(Cl)Oc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a 100 mL 3-necked round bottom flask equipped with a magnetic stirrer, addition funnel topped with a drying tube containing calcium sulfate was added 35 mLs of methylene chloride. The reaction solvent was cooled with an ice water bath. To the flask was added 2.8 grams (0.035 mole) of liquid sulfur trioxide. Thereupon the reaction solution became a very pale clear yellow liquid. The ice water bath cooled reaction vessel was then charged with 5.48 grams (0.035 mole) of phenyl chloroformate added dropwise so as to control the reaction exotherm. When approximately half of the chloroformate had been added, a white precipitate began to form. Upon completion of the addition, the reaction mixture was allowed to warm to room temperature. After six hours at room temperature, a 95%+ conversion was noted by proton nmr analysis. Solvent was removed under vacuum and the remaining white to slightly off-white crystalline solid was used as is for the condensation reaction. The following spectroscopic data was obtained for this material:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]([OH:16])=O)=[CH:10][N:9]2[CH3:17])=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([O:23][C:24]2[CH:25]=[CH:26][C:27]3[N:28]([CH:30]=[C:31]([NH:33][C:34]([CH:36]4[CH2:38][CH2:37]4)=[O:35])[N:32]=3)[CH:29]=2)=[C:21]([F:41])[CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:36]1([C:34]([NH:33][C:31]2[N:32]=[C:27]3[CH:26]=[CH:25][C:24]([O:23][C:22]4[CH:39]=[CH:40][C:19]([NH:18][C:14]([C:11]5[C:12](=[O:13])[N:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)[N:9]([CH3:17])[CH:10]=5)=[O:16])=[CH:20][C:21]=4[F:41])=[CH:29][N:28]3[CH:30]=2)=[O:35])[CH2:37][CH2:38]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cn1cc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccc(F)cc1
Yield: 80.3 %

Procedure:
In the same manner as in Example 46 and using 2-(4-fluorophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid (280 mg, 1.2 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (260 mg, 0.80 mmol), HATU (460 mg, 1.2 mmol), N,N-diisopropylethylamine (310 mg, 2.4 mmol) and N,N-dimethylformamide (6 mL) as starting materials, the title compound (350 mg, 81%) was obtained as a white solid.
Reaction SMILES: [OH-].[Na+].BrBr.[C:5]([C:8]1[C:9]([Cl:23])=[C:10]2[C:15](=[C:16]([Cl:18])[CH:17]=1)[S:14](=[O:20])(=[O:19])[CH2:13][CH2:12][C:11]2([CH3:22])[CH3:21])(=[O:7])C.C(OCC)(=[O:26])C>O>[Cl:23][C:9]1[C:8]([C:5]([OH:7])=[O:26])=[CH:17][C:16]([Cl:18])=[C:15]2[C:10]=1[C:11]([CH3:22])([CH3:21])[CH2:12][CH2:13][S:14]2(=[O:20])=[O:19]
Reactant: CCOC(C)=O
Reactant: CC(=O)c1cc(Cl)c2c(c1Cl)C(C)(C)CCS2(=O)=O
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)CCS(=O)(=O)c2c(Cl)cc(C(=O)O)c(Cl)c21
Temperature: 100 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
1.04 Grams (26.1 mmol) of sodium hydroxide was dissolved in 20 ml of water, and 0.5 ml (8.7 mol) of bromine was added. Further, 0.93 g (2.9 mmol) of 6-acetyl-5,8-dichloro-4,4-dimethylthiochroman-1,1-dioxide was added, and the mixture was stirred for 3 hours. Then the mixture was heated at 100° C. for 5 hours. After the completion of the reaction, ethyl acetate was added, the mixture was liquid-separated, and hydrochloric acid was added to an aqueous layer to adjust the aqueous layer to a pH of 1. The extraction of the aqueous layer was carried out by adding ethyl acetate, and an organic layer was dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure to give 0.84 g (yield 90%) of 5,8-dichloro-4,4-dimethylthiochroman-6-carboxylic acid-1,1-dioxide.
Reaction SMILES: I[C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[C:26]([S:31]([O-:33])=[O:32])[CH:25]=[CH:24]3)=[CH:17][CH:16]=1.[Na+]>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[C:26]([S:31]([C:2]2[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=2[CH2:4][N:5]2[CH:9]=[N:8][CH:7]=[N:6]2)(=[O:33])=[O:32])[CH:25]=[CH:24]3)=[CH:17][CH:16]=1
Reactant: Ic1ccccc1Cn1cncn1
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Agent: [Na+]
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3)ccc2c1)c1ccccc1Cn1cncn1

Procedure:
Prepared according to the method of Example 6 Step 4 using 1-(2-iodobenzyl)-1H-1,2,4-triazole and sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate, to give the title compound as a white solid (11 mg). 1H NMR (500 MHz, d6-DMSO): δ 8.78 (1H, s), 8.59 (1H, s), 8.37 (1H, s), 8.32 (1H, d, J=8.6 Hz), 8.25-8.19 (2H, m), 8.05 (1H, dd, J=1.7, 8.5 Hz), 7.94-7.90 (3H, m), 7.86 (1H, dd, J=1.8, 8.6 Hz), 7.71-7.65 (2H, m), 7.38 (2H, t, J=8.8 Hz), 6.88 (1H, d, J=6.8 Hz), 5.81 (2H, s); m/z (ES+) 444 [MH+].
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1F)([O-:10])=[O:9].[CH3:21][C:22]1[NH:23][CH:24]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:26]=1>C1(C)C=CC=CC=1>[N+:8]([C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[N:23]1[CH:24]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:26]=[C:22]1[CH3:21])([O-:10])=[O:9]
Reactant: CCOC(=O)c1c[nH]c(C)n1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c(C)n1

Procedure:
16 ml of triethylamine was added to 14.5 g (0.078 mol) of 2,4-dinitrofluorobenzene, 12 g (0.078 mol) of ethyl 2-methylimidazole-4-carboxylate and 500 ml of toluene, and the mixture was refluxed for 18 hours. The solvent was then distilled off under reduced pressure and the residue was chromatographed using pentane/ethyl acetate as mobile phase.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:14])[CH2:12][NH2:13].[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1.O>ClCCl>[CH3:9][O:10][C:11](=[O:14])[CH2:12][NH:13][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:16][CH:17]=1)=[O:22]
Reactant: COC(=O)CN
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)c1ccc(-c2ccccc2)cc1
Temperature: -5 °C
Yield: 61.4 %

Procedure:
Dichloromethane (50 mL) and then triethylamine (11.2 mL, 79.6 mmol, 2.0 eq) were added to glycine methyl ester hydrochloride (5.0 g, 39.8 mmol, 1.0 eq). The mixture was stirred and cooled to −5° C. using an ice/methanol bath. A suspension of biphenyl-4-carbonyl chloride (8.26 g, 39.8 mmol, 1.0 eq) in dichloromethane (25 mL) was added over 22 minutes. The mixture was stirred for 3 hours at −5° C., and then left to stir at room temperature overnight (16 hours). Water (75 mL) was added and the mixture was stirred rapidly for 30 minutes at room temperature. The layers were separated. The organic layer was washed with water (75 mL), then evaporated to dryness using a rotary evaporator to give an off-white solid (6.58 g, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:16][CH:17]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[Cl:27]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:16][C:17]=3[Cl:27])[CH:10]=[N:9]2)=[CH:25][CH:26]=1
Reactant: COc1ccc(Cn2cc(-c3csc(Nc4ccccn4)n3)cn2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(-c3nc(Nc4ccccn4)sc3Cl)cn2)cc1
Yield: 84.1 %

Procedure:
According to Scheme 4 Step 1 Method A: A solution of N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-2-yl)pyridin-2-amine (1.38 mmol, 500 mg) and N-chlorosuccinimide (1.38 mmol, 184 mg) in DMF (3 mL) was stirred for 1 hour at 50° C. The reaction mixture was diluted with AcOEt (250 mL) and the organic phase was washed with a saturated solution of Na2CO3. The organic phase was dried over MgSO4, was filtered and was concentrated to yield N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-chlorothiazol-2-yl)pyridin-2-amine (1.16 mmol, 460 mg, 84%) as a beige solid.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC.[CH3:39][O:40][C:41]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]2[C:42]=1[C:43](=[O:65])[NH:44][C:45]([C:53]1[CH:58]=[CH:57][C:56]([N:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)=[CH:55][CH:54]=1)=[N:46]2>C1COCC1>[CH3:39][O:40][C:41]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]2[C:42]=1[C:43](=[O:65])[NH:44][C:45]([C:53]1[CH:58]=[CH:57][C:56]([N:59]3[CH2:60][CH2:61][N:62]([C:1](=[O:9])[C:2]4[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=4)[CH2:63][CH2:64]3)=[CH:55][CH:54]=1)=[N:46]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(=O)c5cccnc5)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.6 %

Procedure:
To a solution of nicotinic acid (0.066 g, 0.54 mmol) in THF (20 mL) was added HOBt (0.079 g, 0.59 mmol), EDCl (0.113 g, 0.59 mmol), Et3N (0.08 mL, 0.59 mmol) and 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.200 g, 0.54 mmol). The resulting solution was stirred overnight at room temperature. The solution was concentrated in vacuo and the resulting solid was purified by flash chromatography on silica gel, eluting with 10% to 60% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, to afford the title compound (0.050 g, 19%): 1H NMR (300 MHz, DMSO-d6): δ 11.79 (s, 1H), 8.59-8.78 (m, 2H), 8.12 (d, J=8.8 Hz, 2H), 7.82-7.99 (m, 1H), 7.37-7.60 (m, 1H), 7.04 (d, J=9.1 Hz, 2H), 6.69 (s, 1H), 6.47 (s, 1H), 3.63-3.97 (m, 8H), 3.20-3.63 (m, 6H). APCI MS m/z 472 [M+H]+.
Reaction SMILES: C([NH:4][OH:5])(=O)C.CC(C)([O-])C.[K+].[CH2:12]1[CH2:16][O:15][CH2:14][CH2:13]1.F[C:18]1[CH:25]=[C:24]([C:26]2[CH:27]=[C:28]([N:35]([CH2:42][C:43]3C=CC(OC)=[CH:45][CH:44]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:29]3[N:30]([CH:32]=[CH:33][N:34]=3)[N:31]=2)[CH:23]=[CH:22][C:19]=1[C:20]#[N:21]>CN(C=O)C.CO>[CH3:14][O:15][C:16]1[CH:12]=[CH:13][C:43]([CH2:42][N:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:28]2[C:29]3[N:30]([CH:32]=[CH:33][N:34]=3)[N:31]=[C:26]([C:24]3[CH:23]=[CH:22][C:19]4[C:20]([NH2:21])=[N:4][O:5][C:18]=4[CH:25]=3)[CH:27]=2)=[CH:44][CH:45]=1
Reactant: CC(=O)NO
Reactant: C1CCOC1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(-c3ccc(C#N)c(F)c3)nn3ccnc23)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(CN(c2ccccc2)c2cc(-c3ccc4c(N)noc4c3)nn3ccnc23)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of acetohydroxamic acid (50 mg, 0.667 mmol) in DMF (1 mL) was added a solution of potassium t-butoxide in THF (0.667 mL, 0.667 mmol). The reaction solution was stirred at RT for 15 minutes and then a solution of 2-fluoro-4-(8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-yl)benzonitrile (30 mg, 0.067 mmol) from (X) in DMF (1 mL) was added. The reaction solution was stirred at RT for 24 hours. The solution was diluted with methanol and purified by preparative HPLC to give 6-(8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-yl)benzo[d]isoxazol-3-amine. LC/MS, m/e 463 (M+1). HPLC Rt, 3.08 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min. hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[N:6]=1.[CH3:23][N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:28]2[N:24]([CH3:23])[CH:25]=[N:26][CH:27]=2)=[CH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[N:6]=1
Reactant: Cn1ccnc1
Reactant: CC(C)(C)CN(Cc1ccc(I)cc1)c1ccnc(C#N)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cncc1-c1ccc(CN(CC(C)(C)C)c2ccnc(C#N)n2)cc1
Temperature: 120 °C
Reaction time: 18 h
Yield: 57.7 %

Procedure:
4-{(2,2-Dimethyl-propyl)-[4-iodo-benzyl]-amino}-pyrimidine-2-carbonitrile (200 mg, 0.5 mmoles), 1-methyl imidazole (0.2 ml, 2.5 mmoles), triphenylphosphine (26 mg, 0.10 mmoles) and CsCO3 (160 mg, 0.5 mmoles) are dissolved in 3 ml of DMF and Pd(OAc)2 (10 mg, 0.05 mmoles) is added at rt. The mixture is stirred at 120° C. for 18 h. Water is added and the organic layer is extracted with AcOEt, washed with brine, dried over magnesum sulfate and concentrated. The crude product is purified by silica gel column chromatography to give 104 mg of desired 4-{(2,2-dimethyl-propyl)-[4-(3-methyl-3H-imidazol-4-yl)-benzyl]-amino}-pyrimidine-2-carbonitrile in 59% yield.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:11]1[CH:16]=[C:15](C#N)[CH:14]=[CH:13][N:12]=1.[CH3:19][N:20]1CCCC1=O>O>[CH:1]1([O:7][C:15]2[CH:14]=[CH:13][N:12]=[C:11]([C:19]#[N:20])[CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: OC1CCCCC1
Reactant: CN1CCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: N#Cc1cc(OC2CCCCC2)ccn1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
To a stirred solution of cyclohexanol (2.84 g, 3.00 mL, 2.84 mmol) in 1-methyl-2-pyrrolidinone (20 mL) was added sodium hydride (1.19 g of 60% dispersion, 29.8 mmol) in small portions over 5 minutes. After stirring for an additional 5 minutes, 2-chloro-4-cyanopyridine (3.75 g, 27.0 mmol) was added and the resulting red-brown solution was heated at 100° C. for 10 minutes. The reaction mixture then was poured onto ice. The mixture was diluted with water and extracted with ether. The combined organic phases were washed with water and brine, dried (magnesium sulfate) and concentrated to provide a yellow oil. Flash chromatography over silica (hexanes/ethyl acetate) afforded 4.17 g (76%) of the desired product as a cloudy oil which solidified on standing: 1H NMR (CDCl3) δ 8.44 (d, J=5.8 Hz, 1H), 7.17 (d, J=2.4 Hz, 1H), 6.95 (dd, J=2.4, 5.8 Hz, 1H), 4.40-4.33 (m, 1H), 1.98-1.95 (m, 2H), 1.82-1.79 (m, 2H), 1.60-1.52 (m, 3H), 1.45-1.32 (m, 3H) ppm. 13C NMR (CDCl3) δ 164.3, 152.2, 135.0, 117.3, 116.4, 113.9, 76.4, 31.1, 25.2, 23.4 ppm.