Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[CH:5](O)[C:6]([OH:8])=[O:7].C(N(S(F)(F)[F:20])CC)C.[F:23][C:24]1[CH:25]=[C:26]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH:27]([OH:32])[C:28]([O:30][CH3:31])=[O:29].[OH-].[Li+]>C(Cl)Cl>[F:23][C:24]1[CH:25]=[C:26]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH:27]([OH:32])[C:28]([O:30][CH3:31])=[O:29].[F:1][C:2]1[CH:3]=[C:4]([CH:5]([F:20])[C:6]([OH:8])=[O:7])[CH:10]=[C:11]([F:13])[CH:12]=1
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Reactant: CCN(CC)S(F)(F)F
Agent: COC(=O)C(O)c1cc(F)cc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(O)C(F)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl 3,5-difluoromandelate was prepared following General Procedure G below and using commmerically available 3,5-difluoromandelic acid. The resultant α-hydroxy methyl ester was fluorinated according to the general procedure described in W. J. Middleton, et al., Org. Synth. Col. Vol. VI, 835. Specifically, a solution of diethylaminosulfur trifluoride (1.1 eq) in CH2Cl2 was cooled to 0° C. and treated with methyl 3,5-difluoromandelate (1.0 eq) as a solution in CH2Cl2. After 10 min. the cooling bath was removed and the reaction was stirred at ambient temperature for 30 min. The reaction was monitored by tic (Rf=0.65, 1:1 ethyl acetate/hexanes). The mixture was then poured onto ice and the layers separated. The organic phase was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by LC2000 chromatograpy (180 mL/min) using 10% EtoAc/hexanes as the eluent. The resulting methyl 3,5-difluorophenyl-α-fluoroacetate was hydrolyzed by dissolving the ester in 70% aqueous dioxane and treating with lithium hydroxide (2.0 eq.). No starting material remained by tic after 2 h. The dioxane was removed via rotary evaporation. The aqueous mixture was first washed with ethyl acetate and then acidified with 0.01 N HCl. The aqueous layer was extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude solid was recrystallized from ethyl acetate/hexanes affording 3,5-difluorophenyl-α-fluoroacetic acid as a white solid having a melting point of 90-110° C. C8H5F3O2 (MW=190.1); mass spectroscopy: 190.1.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:20][C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:24]([NH:26][CH3:27])=[O:25])=[N:5][C:6](S(C)(=O)=O)=[N:7][C:8]=1[N:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])#[N:2].[CH3:32][NH2:33]>O1CCOCC1>[C:1]([C:3]1[C:4]([NH:20][C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:24]([NH:26][CH3:27])=[O:25])=[N:5][C:6]([NH:33][CH3:32])=[N:7][C:8]=1[N:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])#[N:2]
Reactant: CNC(=O)c1ccc(C)c(Nc2nc(S(C)(=O)=O)nc(N(C)CC(C)(C)C)c2C#N)c1
Reactant: CN
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(C)c(Nc2nc(NC)nc(N(C)CC(C)(C)C)c2C#N)c1
Temperature: 80 °C

Procedure:
3-{5-Cyano-6-[(2,2-dimethyl-propyl)-methyl-amino]-2-methanesulfonyl-pyrimidin-4-ylamino}-4,N-dimethyl-benzamide (44 mg, 0.1 mmol) and methylamine (1 mL, 1M in THF) were mixed in p-dioxane (1 mL) in a sealed tube. The mixture was heated to 80° C. for overnight. The solvent was removed in vacuo, and the product (23 mg) was purified by the silica gel column chromatography. MS (m/z): 396 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])[CH2:2][CH2:3][CH3:4].[CH2:23]([CH:25]1[O:27][CH2:26]1)Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:23][CH:25]1[O:27][CH2:26]1)[CH2:2][CH2:3][CH3:4]
Reactant: ClCC1CO1
Reactant: CCCCc1oc2ccccc2c1C(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCc1oc2ccccc2c1C(=O)c1ccccc1OCC1CO1

Procedure:
A mixture of 7.5 g. (0.025 mol.) of 2-n-butyl-3-(2'-hydroxybenzoyl)benzofuran, 25 ml. of epichlorohydrin and 15.0 g. of potassium carbonate in 150 ml. of ethanol was refluxed for three hours. After cooling the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in water and the aqueous solution was extracted with methylene chloride. The extracts were combined, dried (Na2SO4) and concentrated to give an oily residue that was chromatographed on alumina with chloroform as the eluant to give 2-n-butyl-3-[2'-(2,3-epoxy)propoxybenzoyl]benzofuran.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].I[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:16][CH:17]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:18][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][CH2:9][N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)[CH:17]=[CH:16][CH:15]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: ICCCc1cccc(OCc2ccccc2)c1
Reactant: c1c[nH]nn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(COc2cccc(CCCn3ccnn3)c2)cc1
Reaction time: 0.5 h
Yield: 37.4 %

Procedure:
In an argon atmosphere, 1H-1,2,3-triazole (0.9 g) was dissolved in DMF (20 ml); 65% oily sodium hydride (0.48 g) was added. After stirring for 30 minutes, a solution of benzyl 3-(3-iodopropyl)phenyl ether (3.53 g) in DMF (5 ml) was added, followed by stirring at room temperature for 19 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated saline. Under reduced pressure, the solvent was distilled off; the residue was subjected to column chromatography to yield the titled compound (1.1 g) as colorless crystals.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH3:17][C:18]([O:21][C:22]([N:24]1[CH2:31][C:30]2[O:29][C:28]([CH2:32][OH:33])=[N:27][C:26]=2[CH2:25]1)=[O:23])([CH3:20])[CH3:19].[C:34]1(O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CO>[CH3:20][C:18]([O:21][C:22]([N:24]1[CH2:31][C:30]2[O:29][C:28]([CH2:32][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:27][C:26]=2[CH2:25]1)=[O:23])([CH3:17])[CH3:19]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1Cc2nc(CO)oc2C1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2nc(COc3ccccc3)oc2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.3 %

Procedure:
Di-tert-butyl azodicarboxylate (0.079 g, 0.34 mmol) was added portionwise to a stirred solution of 4,6-dihydro-2-(hydroxymethyl)-5H-pyrrolo[3,4-d]oxazole-5-carboxylic acid 1,1-dimethylethyl ester (0.055 g, 0.23 mmol), phenol (0.032 g, 0.34 mmol) and triphenylphosphine (0.090 g, 034 mmol) in THF (1 mL) at 0° C. The mixture was stirred at room temperature for 10 minutes, diluted with MeOH and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 10/90). The desired fractions were collected and evaporated in vacuo to yield 4,6-dihydro-2-(phenoxymethyl)-5H-pyrrolo[3,4-d]oxazole-5-carboxylic acid 1,1-dimethylethyl ester (0.073 g, quantitative yield) as a clear oil that was used in the next step without further purification. C17H20N2O4 LCMS: Rt 3.06, m/z 317 [M+H]+ (using method, LC-MS Method 6).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([O:16][CH2:17][CH:18]2[O:20][CH2:19]2)[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH:21]1([O:27][N:28]2[C:33]([CH3:35])([CH3:34])[CH2:32][CH:31]([OH:36])[CH2:30][C:29]2([CH3:38])[CH3:37])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.P(O)(O)O>C(OCC)(=O)C>[OH:1][C:2]1[CH:15]=[C:14]([O:16][CH2:17][CH:18]([OH:20])[CH2:19][O:36][CH:31]2[CH2:32][C:33]([CH3:34])([CH3:35])[N:28]([O:27][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:29]([CH3:38])([CH3:37])[CH2:30]2)[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: O=C(c1ccccc1)c1ccc(OCC2CO2)cc1O
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Agent: OP(O)O
Solvent: CCOC(C)=O
Product: CC1(C)CC(OCC(O)COc2ccc(C(=O)c3ccccc3)c(O)c2)CC(C)(C)N1OC1CCCCC1
Yield: 2.1 %

Procedure:
A mixture of 5.0 g (18.5 mmol) of 2-hydroxy-4-(2,3-epoxypropoxy)benzophenone and 15.0 g (58.7 mmol) of 1-cyclohexyloxy-4-hydroxy-2,2,6,6-tetramethylpiperidine is heated to 80° and then treated with 0.5 g of phosphorous acid (99%). The reaction mixture is heated at 80°-90° C. for 6 hours, then cooled and dissolved in ethyl acetate (200 ml). The organic solution is washed with saturated sodium bicarbonate solution (100 ml), dried over magnesium sulfate, and evaporated to a yellow oil. Purification by flash chromatography on silica gel to obtain the least polar material formed in the reaction mixture affords approximately 200 mg of the title compound, a yellow glass.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[NH:6][N:5]=1)(=O)[CH3:2].BrBr.BrC(Br)C(C1C=C(C(OC)=O)NN=1)=O.[C:29]([NH2:32])(=[S:31])[CH3:30]>C(Cl)(Cl)Cl.CO>[CH3:30][C:29]1[S:31][CH:2]=[C:1]([C:4]2[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[NH:6][N:5]=2)[N:32]=1
Reactant: COC(=O)c1cc(C(C)=O)n[nH]1
Reactant: CC(N)=S
Agent: BrBr
Agent: COC(=O)c1cc(C(=O)C(Br)Br)n[nH]1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(-c2csc(C)n2)n[nH]1
Yield: 101.7 %

Procedure:
Methyl 3-acetyl-1H-pyrazole-5-carboxylate (100 mg, 0.595 mmol) was refluxed with bromine (143 mg, 0.892 mmol) in chloroform. Solvent was evaporated and thus obtained methyl 3-(2,2-dibromoacetyl)-1H-pyrazole-5-carboxylate (191 mg, 0.586 mmol) was treated with thioacetamide (44 mg, 0.586 mmol) in refluxing methanol. Solvent was evaporated and the residue was dissolved in DCM and washed with water. Organic phase was dried over Na2SO4, filtered and evaporated to give 133 mg (102%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.71 (s, 3H), 3.83 (s, 3H), 7.10 (s, 1H), 7.90 (s, 1H) 14.0 (broad s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NCc1cccs1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1cccs1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
A solution of 4-chlorobenzoyl chloride (0.114 mol) in 50 ml dry CH2Cl2 is added over 30 min to a stirred solution of 2-aminomethylthiophene (0.137 mol) and iPr2NEt (0.25 mol) in CH2Cl2 (200 ml) at 0° C. A white solid is formed and the reaction is allowed to warm to room temperature over 1 h. The mixture is diluted with 200 ml of CH2Cl2, washed twice with HCl aq. (0.1N) and dried over MgSO4. Evaporation of the solvents afforded 28 g (98%) of the title benzamide as a white solid: mp 153-54° C., 1H NMR (CDCl3) δ7.9 (d, J=8.67 Hz, 2H), 7.58 (d, J=8.67 Hz, 2H), 7.44 (dd, J=3.77, 1.13 Hz, 1H), 7.22 (d, J=5.27 Hz, 1H), 7.16 (dd, J=3.39, 5.27 Hz, 1H), 6.62 (br d, 1H), 4.98 (d, J=5.65 Hz, 2H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH3:33])[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[C:21]1[N:26]=[C:25]([CH2:27][C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH:24]=[CH:23][CH:22]=1.[CH3:34][CH2:35][O:36][CH:37]=[C:38]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:39]([O:41][CH2:42][CH3:43])=[O:40]>O1CCCC1>[CH2:35]([O:36][CH:37]([CH:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH:27]([C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([C:14]2[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=2[CH3:33])[N:26]=1)[C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH3:34]
Reactant: CCCC(=O)Cc1cccc(-c2c(C)cc(C)cc2C)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCC(=O)C(c1cccc(-c2c(C)cc(C)cc2C)n1)C(OCC)C(C(=O)OCC)C(=O)OCC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Diisopropyl amine (0.16 mL, 1.13 mmol) was dissolved in tetrahydrofuran (2 mL). n-Butyllithium (2.5M, 0.45 mL, 1.13 mmol) was added at 0° C. and the reaction stirred for 0.5 h. The solution was cooled to −78° C. and 1-(6-mesityl-pyridin-2-yl)-pentan-2-one (0.29 g, 1.0 mmol) was added. After 0.5 h, ethyl ethoxymethylene malonate (0.21 mL, 1.0 mmol) was added and the reaction was warmed to room temperature. The solution was quenched with water, extracted with ethyl acetate, dried, and concentrated. Flash chromatography (10%-20% ethyl acetate/hexanes) gave the title compound as a mixture of two isomers.
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].O[N:16]1[C:21](=[O:22])[CH2:20][CH2:19][C:17]1=[O:18].C(Cl)CCl>C1COCC1>[N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][C@H:2]1[C:3]([O:5][N:16]1[C:21](=[O:22])[CH2:20][CH2:19][C:17]1=[O:18])=[O:4]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)ON1C(=O)CCC1=O
Reaction time: 8 h
Yield: 50.7 %

Procedure:
A mixture of Boc-Aze-OH (5 g, 25 mmol) and HOSu (2.88 g, 25 mmol) in 25 ml of THF was cooled on an ice bath. EDC (4.3 ml, 25 mmol) was added and the solution was stirred overnight. It was evaporated, dissolved in ethyl acetate, washed with KHSO4 (aq, 0.3 M), Na2CO3 (aq, 10%), dried (MgSO4) and evaporated. Crystallization from ethyl acetate:petroleum ether afforded 3.78 g (51%) of sub-title compound.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:18]=[CH:17][C:11]([CH:12]=[CH:13][C:14]([OH:16])=O)=[CH:10][CH:9]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C.[NH2:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1>CN(C)C=O>[OH:1][CH:2]([C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[CH:13][C:14](=[O:16])[NH:36][CH2:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[CH:17][CH:18]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: NCc1cccnc1
Reactant: COC(=O)CC(O)c1ccc(C=CC(=O)O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CC(O)c1ccc(C=CC(=O)NCc2cccnc2)cc1

Procedure:
Finally, 82 mg of 4-[1-hydroxy-2-(methoxycarbonyl)ethyl]cinnamic acid was dissolved in 37 μl 3-(aminomethyl)pyridine and 1 ml dimethylformamide, and then treated with 55 μl diethyl cyanophosphate and 50 μl triethylamine on ice for 1 hour to give methyl 3-hydroxy-3-[4-[2-[N-(3-pyridylmethyl)carbamoyl]ethenyl]phenyl]propionate of interest (17 mg, 15%) as an amorphous solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][CH2:20][CH2:21][CH2:22][O:23][N:24]2C(=O)C3C(=CC=CC=3)C2=O)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4].[OH-].[NH4+:36]>ClC(Cl)C>[NH2:24][O:23][CH2:22][CH2:21][CH2:20][CH2:19][N:6]1[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:36])[C:8]=2[N:18]=[C:5]1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: [NH4+]
Reactant: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCCON1C(=O)c2ccccc2C1=O
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCON
Yield: 30.9 %

Procedure:
A mixture of 2-[4-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]-1H-isoindole-1,3(2H)-dione (8.92 g, 19.5 mmol) in dichloroethane (100 mL) was shaken vigorously until it became homogeneous. With vigorous stirring, ammonium hydroxide (100 mL) andp-toluenesulfonyl chloride (4.45 g, 23.4 mmol) were added sequentially. The reaction was stirred overnight at room temperature. The product was present as a white precipitate, which was isolated by filtration to provide 1.97 g of 1-[4-(aminooxy)butyl]-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:11]=[C:4]2[N:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: Clc1cc(Cl)n2nc(-c3ccccn3)cc2n1
Reactant: C1COCCN1
Solvent: O
Solvent: C1COCCO1
Product: Clc1cc(N2CCOCC2)n2nc(-c3ccccn3)cc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
There was suspended, in 1,4-dioxane (5 mL), 5,7-dichloro-2-pyridin-2-yl-pyrazolo[1,5-a]pyrimidine (348 mg. 1.31 mM), then morpholine (230 μL, 2.64 mM) was added to the suspension and the mixture was stirred at room temperature for 20 minutes. The solvent was distilled off from the reaction mixture, the residue obtained was diluted with water and then extracted with ethyl acetate. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with diethyl ether to thus give the title compound (312 mg, yield: 75%). 1H-NMR (300 MHz, CDCl3): δ 3.84-3.87 (m, 4H), 3.99-4.02 (m, 4H), 6.12 (s, 1H), 7.16 (s, 1H), 7.30 (ddd, 1H, J=1.2, 5.0, 7.7 Hz), 7.78 (dt, 1H, J=1.8, 7.7 Hz), 8.11 (d, 1H, J=7.7 Hz), 8.70 (m, 1H); MS (ESI) m/z 316 (M+H)+.
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.Cl[C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[S:37]([CH3:40])(=[O:39])=[O:38])[N:27]=[C:26]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][C@@H:42]2[CH3:47])[N:25]=1.[OH:48][CH2:49][CH2:50][NH:51][C:52]([NH:54][C:55]1[CH:60]=[CH:59][C:58](B2OC(C)(C)C(C)(C)O2)=[CH:57][CH:56]=1)=[O:53]>>[F:36][C:34]1[CH:33]=[CH:32][C:31]([S:37]([CH3:40])(=[O:39])=[O:38])=[C:30]([C:28]2[N:27]=[C:26]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][C@@H:42]3[CH3:47])[N:25]=[C:24]([C:58]3[CH:59]=[CH:60][C:55]([NH:54][C:52]([NH:51][CH2:50][CH2:49][OH:48])=[O:53])=[CH:56][CH:57]=3)[CH:29]=2)[CH:35]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCO)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1nc(Cl)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCCO)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Yield: 24 %

Procedure:
Method as described for intermediate 5 using (S)-4-(4-chloro-6-(5-fluoro-2-(methylsulfonyl)phenyl)pyrimidin-2-yl)-3-methylmorpholine (intermediate 16) and 1-(2-hydroxyethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 18). Material was purified by prep HPLC (low pH) to afford a brown solid. Further purification was achieved using flash chromatography (20-100% EtOAc in petroleum ether (40:60) to afford a light brown solid (60 mg, 24%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:20]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([CH:30]=O)[C:24]=2[N:23]=[CH:22][CH:21]=1>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:30][C:25]4[CH:26]=[CH:27][CH:28]=[C:29]5[C:24]=4[N:23]=[CH:22][CH:21]=[N:20]5)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1cccc2nccnc12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cccc5nccnc45)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with quinoxaline-5-carbaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 5-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]quinoxaline.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].[O:13]=[C:14]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN(C=O)C>[N+:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:15]([C:14](=[O:13])[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])([O-:12])=[O:11]
Reactant: COC(=O)CCC(=O)CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)C(C(=O)OC(C)(C)C)c1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 59.5 %

Procedure:
To the suspension of NaH (2.3 g, 57.5 mmol) in DMF (50 mL) was added 2-fluoro-1-nitrobenzene (4.04 g, 28.7 mmol) and 1-(1,1-dimethylethyl) 6-methyl 3-oxohexanedioate (6.6 g, 28.7 mmol). The mixture was heated at 60° C. for 12 h. After cooling to room temperature, the mixture was quenched with NH4Cl aqueous solution, and extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate, filtered, and concentrated. Purification via flash chromatography then afforded the title compound (6.0 g, 45.3% yield). LCMS: rt=4.15 min, [M+H+]=350
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][CH:10]([F:17])[C:11]1[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=1.FC(F)C1N(C)N=CC=1.O>CN(C)C=O>[Cl:1][C:15]1[C:11]([CH:10]([F:17])[F:9])=[N:12][N:13]([CH3:16])[CH:14]=1
Reactant: Cn1ccc(C(F)F)n1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cn1nccc1C(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(Cl)c(C(F)F)n1
Temperature: 60 °C
Reaction time: 12 h
Yield: 88 %

Procedure:
At 0-5° C., a solution of N-chlorosuccinimide (NCS, 12.6 g, 0.09 mol) in dimethyl-formamide (DMF, 70 ml) was added dropwise to a solution of 3-difluoromethyl-N-methylpyrazole (14.9 g, 0.09 mol, 83.7% pure according to GC analysis) comprising, as minor component, 4.1% of 5-difluoromethyl-N-methylpyrazole, based on the total amount of the isomer mixture, in DMF (30 ml). The reaction mixture was then heated at 60° C. and stirred for a further 12 h. With stirring, the reaction mixture was then poured into water (1000 ml) and extracted twice with methyl tert-butyl ether (MTBE, 150 ml). The organic phases were combined, washed with a saturated aqueous solution of NaCl, dried over magnesium sulfate, filtered and then freed from the solvent under reduced pressure. 4-Chloro-3-difluoromethyl-N-methylpyrazole was obtained as an oil (17.6 g; purity: 78.4% according to GC analysis) comprising 3.7% of unreacted 5-difluoromethyl-N-methylpyrazole. This corresponds to a yield of 88%.
Reaction SMILES: [NH2:1][C:2]([C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[C:17]([S:19]Cl)=[O:18]>>[O:18]=[C:17]1[NH:1][C:2]([C:9]([F:14])([F:15])[C:10]([F:11])([F:12])[F:13])=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[S:19]1
Reactant: O=C(Cl)SCl
Reactant: CCOC(=O)C=C(N)C(F)(F)C(F)(F)F
Product: CCOC(=O)c1sc(=O)[nH]c1C(F)(F)C(F)(F)F
Reaction time: 1 h
Yield: 46.3 %

Procedure:
To a stirred mixture of 65 g (0.4995 mole) of ethyl acetoacetate, 200 ml. of methanol and 100 ml. of saturated sodium acetate at 50° C. was introduced 100 g (0.769 mole) of pentafluoropropionitrile in 3 hours. The reaction mixture was poured into 1200 ml. of water. An oil separated from the reaction mixture. The aqueous solution was extracted with ether. The ether solution was combined with the oil, dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 40 g (37%) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate. A mixture of 21.8 g (0.0790 mole) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 75 ml. of 58% ammonium hydroxide was stirred for 66 hours. The reaction mixture was extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 16.3 g (88%) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate, nD25 =1.4011. A well stirred mixture of 54 g (0.23 mole) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 31 g (0.237 mole) of chlorocarbonylsulfenyl chloride was held at 100° C. for 1 hour. The reaction mixture was cooled and triturated with hexane. The solid precipitate was washed with water and recrystallized from hexane-ether to give 31 g (46%) of ethyl 2,3-dihydro-2-oxo-4-pentafluoroethyl-5-thiazolecarboxylate, m.p. 95°-97° C. A mixture of 10 g (0.0344 mole) of ethyl 2,3-dihydro-2-oxo-4-pentafluoroethyl-5-thiazolecarboxylate, 4 g (0.0506 mole) of pyridine and 150 ml. of phosphorus oxychloride was held at reflux for 18 hours. Excess phosphorus oxychloride was removed under reduced pressure. The residue was treated with water and extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 7.5 g (71%) of ethyl 2-chloro-4-pentafluoroethyl-5-thiazolecarboxylate, nD25 =1.4460.