Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3](=[O:16])[CH2:4][C:5]([CH3:15])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][CH3:14])[CH3:6].[OH2:19].I([O-])(=O)(=O)=[O:21].[Na+]>C(#N)C.C(OCC)C.[Ru](Cl)(Cl)Cl>[F:18][C:2]([F:1])([F:17])[C:3](=[O:16])[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([CH3:14])(=[O:21])=[O:19])([CH3:6])[CH3:15]
Reactant: CSc1ccccc1C(C)(C)CC(=O)C(F)(F)F
Reactant: O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)(CC(=O)C(F)(F)F)c1ccccc1S(C)(=O)=O
Reaction time: 18 h
Yield: 90 %

Procedure:
1,1,1-Trifluoro-4-methyl-4-(2-methylsulfanylphenyl)pentan-2-one (21.0 g, 60.8 mmol) was dissolved in 240 mL of acetonitrile. 80 mL of water was added followed by sodium metaperiodate (44.9 g, 210 mmol) and ruthenium (III) chloride (0.622 g, 3.0 mmol). The resulting reaction was stirred for 18 hours. The reaction mixture was diluted with 500 mL of diethyl ether (Et2O) and the layers were mixed and separated. The aqueous was washed with 500 mL of diethyl ether and the organics were combined, dried over sodium sulfate (Na2SO4), decanted, and concentrated in vacuo to a thick orange oil. The crude material was separated by flash column chromatography with 0-35% EtOAc/hexanes as the eluent. 1,1,1-Trifluoro-4-(2-methanesulfonylphenyl)-4-methylpentan-2-one (16.9 g, 90%) was obtained as a colorless oil.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:15][CH2:16][NH:17][C:18]3[CH:28]=[CH:27]C=C[C:19]=3[C:20](OCC)=O)=[C:11]([CH3:14])[CH:12]=2)[C:7]([CH3:30])([CH3:29])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[OH-:31].[K+].[CH2:33]([OH:35])[CH3:34]>>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:15][CH2:16][NH:17][C:18]3[CH:28]=[CH:27][C:34]([C:33]([OH:31])=[O:35])=[CH:20][CH:19]=3)=[C:11]([CH3:14])[CH:12]=2)[C:7]([CH3:30])([CH3:29])[CH2:6][CH2:5]1)([CH3:2])[CH3:3]
Reactant: [OH-]
Reactant: CCOC(=O)c1ccccc1NCCc1cc2c(cc1C)N(C(C)C)CCC2(C)C
Reactant: CCO
Agent: [K+]
Product: Cc1cc2c(cc1CCNc1ccc(C(=O)O)cc1)C(C)(C)CCN2C(C)C
Temperature: 40 °C
Reaction time: 20 h

Procedure:
Ethyl [(1-isopropyl-4,4,7-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl)ethylamino]benzoate (Compound 23, 0.16 g, 0.39 mmol) was dissolved in ethanol (4.0 mL) and the solution treated with 2.3 M KOH (1.0 mL). The solution was heated to 40° C. and stirred for 20 hours. The solution was cooled and concentrated under reduced pressure. The residue was diluted with water, acidified with 10% HCl, sat. ammonium chloride, and extracted with ether (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. Purification by recrystallization in ethanol gave (115 mg, 77%) as light yellow crystals.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Cl[C:13]1[C:18]([C:19](N)=O)=[CH:17][N:16]=[C:15](Cl)[CH:14]=1.[CH2:23](N(CC)CC)C>C(#N)C>[CH2:17]([NH:16][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])[C:18]1[CH:13]=[CH:14][CH:15]=[CH:23][CH:19]=1
Reactant: NC(=O)c1cnc(Cl)cc1Cl
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: CCN(CC)CC
Solvent: CC#N
Product: NC(=O)c1ccc(Cl)nc1NCc1ccccc1
Temperature: 60 °C
Yield: 53.6 %

Procedure:
To a solution of 2,6-dichloro-nicotinamide (1) (2.3 g, 12.2 mmol) in acetonitrile (anhydrous, 100 mL) were added 2-benzylamine (2) (1.3 g, 12.2 mmol) and triethylamine (1.7 mL, 12.2 mmol). The reaction was heated at 60° C. for 4 hours. The solution was cooled to room temperature and filtered. The filtrate was evaporated in vacuo. Purification was achieved by Biotage silica gel chromatography with 5%-50% EtOAc/hexanes gradient to afford 1.71 g (54% yield) of the title compound.
Reaction SMILES: Br[CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[OH-:7].[Na+].OC[NH:11][C:12]([O:14][CH2:15]C)=[O:13].Cl>O>[C:12]([NH:11][O:7][CH:2]([CH3:6])[C:3]([OH:5])=[O:4])([O:14][CH3:15])=[O:13]
Reactant: CC(Br)C(=O)O
Reactant: CCOC(=O)NCO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)NOC(C)C(=O)O
Temperature: 25 °C

Procedure:
A 500 ml single necked round bottomed flask was equipped with a stirring bar. The flask was charged with 2-bromopropionic acid (28.6 gm, 0.187 mole), water (100 ml) and sodium hydroxide (14.9 gm, 50% aqueous 0.187 mole). N-hydroxymethyl urethane (17.0 gm, 0.187 mole) was added in one portion, followed by another equivalent of 50% aqueous sodium hydroxide (14.9 gm). The resulting solution was warmed on a steam bath for about 4 hours. This solution was cooled to room temperature and adjusted to pH 4 with concentrated hydrochloric acid. The resulting mixture was extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate then taken to residue in vacuo to leave N-carbomethoxy-alpha-aminooxypropionic acid as a clear oil. This was crystallized from diethyl ether to give 15.1 gm of the compound as a white solid having a melting point of 85°-92° C. This compound was stirred with concentrated hydrochloric acid (30 ml) in a 50 ml Erlenmeyer flask for about five hours. Water and acid were removed in vacuo to leave N-carbomethoxy-alpha-aminooxypropionic acid hydrochloride (6.9 gm) having a melting point of 144°-48° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([N:20]1[CH2:25][CH2:24][O:23][CH:22]([CH2:26][N:27]2[C:32](=[O:33])[C:31]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]4[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=4)=[CH:37][CH:36]=3)=[C:30]([CH2:49][CH2:50][CH2:51][CH3:52])[N:29]=[C:28]2[CH3:53])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[CH2:13]([N:20]1[CH2:25][CH2:24][O:23][CH:22]([CH2:26][N:27]2[C:32](=[O:33])[C:31]([CH2:34][C:35]3[CH:36]=[CH:37][C:38]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:47]4[NH:3][C:4](=[O:7])[O:5][N:48]=4)=[CH:39][CH:40]=3)=[C:30]([CH2:49][CH2:50][CH2:51][CH3:52])[N:29]=[C:28]2[CH3:53])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(CC2CN(Cc3ccccc3)CCO2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC2CN(Cc3ccccc3)CCO2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
A mixture of hydroxylammonium chloride (1.23 g), sodium hydrogen carbonate (0.76 g) and dimethyl sulfoxide (7 mL) was stirred at 40° C. for 30 min, 4′-({1-[(4-benzylmorpholin-2-yl)methyl]-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.62 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), N,N′-carbonyldiimidazole (0.30 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.11 g, 15%).
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:7])[CH:4]=[CH:5][CH:6]=1.O.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12](S(O)(=O)=O)=[CH:11][CH:10]=1.CO.[OH-].[Na+].[OH:24]P([O-])(O)=O.[K+]>O>[OH:24][C:12]1[CH:13]=[CH:14][C:9]([C:19]2[CH:5]([CH3:6])[CH2:4][C:3](=[O:7])[NH:2][N:1]=2)=[CH:10][CH:11]=1
Reactant: O=c1cccn[nH]1
Reactant: O=P([O-])(O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1CC(=O)NN=C1c1ccc(O)cc1
Reaction time: 24 h
Yield: 80 %

Procedure:
A 25 ml round-bottomed flask equipped with a stir bar and reflux condenser was charged with 0.10 g (0.49 mmol) of (-)-enriched-4,5-dihydro-6-(4'-hydroxyphenyl)-5-methyl-3(2H-pyridazinone (45% ee by chiral HPLC), 0.45 g (0.24 mmol) of p-toluenesulfonic acid monohydrate and methanol (15 ml). The solution was stirred under an atmosphere of nitrogen at reflux and epimerization of C-5 ° f the starting material was monitored by chiral HPLC (Cyclobond I, 75% pH 7 NaOH/KH2PO4 buffer, 25% methanol, 0.5 ml/min, lamba=280 nm). After 24 hrs, the starting material was nearly racemized. The solution was poured into water (30 ml) and extracted with EtOAc (3x35 ml). The combined EtOAc extracts were washed with saturated aqueous sodium chloride (50 ml), dried over anhydrous magnesium sulfate (5 g), filtered and concentrated in vacuo to provide 0.08 g (80%) of (±)-4,5-dihydro-6-(4'-hydroxyphenyl)-5-methyl-3(2H)-pyridazinone, m.p. 268°-273° C.; [α]D -9.8° (c 0.24, methanol); 2.5% optical purity.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4](NS(C1C=CC=CC=1)(=O)=O)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].F[P-](F)(F)(F)(F)F.[N:29]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.CC#N>C(OCC)(=O)C>[C:8]([O:7][C:5](=[O:6])[CH2:4][CH2:3][NH:2][NH2:29])([CH3:11])([CH3:10])[CH3:9]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCNN

Procedure:
A solution of acid 2-7 (380 mg, 1.19 mmole), amine 1-4 (362 mg, 1.19 mmole), BOP (789 mg, 1.79 mmole), NMM (521 μl, 4.76 mmole) and CH3CN (6 ml) was stirred at ambient temperature for 20 h. The reaction was diluted with ethyl acetate and then washed with H2O, sat. NaHCO3, 10% KHSO4, brine, dried (MgSO4) and concentrated. Flash chromotography (silica, EtOAc) gave the ester 2-8 as a white solid.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[O:3][C:4]1[CH:31]=[CH:30][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][NH:16][CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:11])=[CH:6][CH:5]=1.Cl[C:35]1[S:36][C:37]2[C:42]([Cl:43])=[N:41][C:40]([CH:44]3[CH2:46][CH2:45]3)=[N:39][C:38]=2[N:47]=1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[F:33][C:2]([F:1])([F:32])[O:3][C:4]1[CH:31]=[CH:30][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:35]3[S:36][C:37]4[C:42]([Cl:43])=[N:41][C:40]([CH:44]5[CH2:45][CH2:46]5)=[N:39][C:38]=4[N:47]=3)[CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:28][CH2:29]3)=[CH:23][CH:22]=2)(=[O:19])=[O:20])=[O:11])=[CH:6][CH:5]=1
Reactant: Clc1nc2nc(C3CC3)nc(Cl)c2s1
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CNCCN1S(=O)(=O)c1ccc(C2CC2)cc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3nc(C4CC4)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a mixture of (R)-1-(4-cyclopropyl-benzenesulfonyl)-piperazine-2-carboxylic acid 4-trifluoromethoxy-benzylamide (39 mg) obtained in Example 1100, Step 4 and 2,7-dichloro-5-cyclopropyl-thiazolo [4,5-d]pyrimidine (20 mg) in chloroform (1.0 ml) was added N,N-diisopropylethylamine (20 μl) at room temperature. After stirring overnight at room temperature, the reaction mixture was diluted with ethyl acetate, and the mixture was partitioned by adding water. The organic layer was dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1) to give the title compound (54 mg).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[C:34]2[CH:43]=[CH:42][C:37]3[O:38][C:39]([CH3:41])=[CH:40][C:36]=3[CH:35]=2)=[CH:18]/[CH2:19][O:20][C:21]2[CH:32]=[CH:31][C:24]([O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[C:23]([CH3:33])[CH:22]=2)=[CH:13][CH:12]=1>O1CCCC1.C(N(CC)CC)C.C1C=CC=CC=1.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>[CH3:33][C:23]1[CH:22]=[C:21]([O:20][CH2:19]/[CH:18]=[C:17](/[C:34]2[CH:43]=[CH:42][C:37]3[O:38][C:39]([CH3:41])=[CH:40][C:36]=3[CH:35]=2)\[C:14]2[CH:15]=[CH:16][C:11]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)=[CH:12][CH:13]=2)[CH:32]=[CH:31][C:24]=1[O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: C#CCN1CCOCC1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(I)cc2)c2ccc3oc(C)cc3c2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2ccc3oc(C)cc3c2)cc1C
Temperature: 0 °C
Reaction time: 96 h

Procedure:
N-Propargylmorpholine (270 mg, 2.16 mmol) was added under nitrogen atmosphere to a degassed solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-(2-methylbenzo[b]furan-5-yl)allyloxy]-2-methylphenoxy]acetate (400 mg, 0.68 mmol; prepared as described in example 25) in a mixture of tetrahydrofuran (6 mL) and triethylamine (6 mL) The solution was cooled to 0° C., tetrakis(triphenylphosphine)palladium (71 mg, 0.061 mmol) and copper(I) iodide (21 mg, 0.11 mmol) were added. The reaction mixture was stirred at ambient temperature for 96 h, diluted with benzene (100 mL), decanted and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene/ethyl acetate 1:0-0:1) yielding methyl (E)-[2-methyl-4-[3-(2-methyl benzo[b]furan-5-yl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-allyloxy]phenoxy]acetate.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]=[CH:17][C:18]([C:21]([NH:23][C:24]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:25]=3[C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=3)=[O:27])=[O:22])=[N:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C1(OC)C=CC=CC=1>[F:40][C:37]1[CH:38]=[CH:39][C:24]([NH:23][C:21]([C:18]2[CH:17]=[N:16][C:15]([N:11]3[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]3)=[CH:20][N:19]=2)=[O:22])=[C:25]([CH:36]=1)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cnc(C(=O)Nc3ccc(F)cc3C(=O)Nc3ccc(Cl)cn3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: O=C(Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1)c1cnc(N2CCCNCC2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-[5-(4-t-butoxycarbonylhexahydro-1,4-diazepin-1-yl)pyrazin-2-ylcarbonylamino]-5-fluoro-N-(5-chloropyridin-2-yl)benzamide (Example P1, 11.4 g) in methylene chloride (30 mL) and anisole (10 mL) was added trifluoroacetic acid (30 mL) dropwise. The mixture was stirred overnight at room temperature before the solvent was evaporated. The residue was purified by using an SCX column. Yield 8.1 g.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11]>C(O)C.[Pd]>[CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(N)cccc1O
Yield: 100.1 %

Procedure:
2-methyl-3-nitrophenol (25 g, 0.163 mol) was dissolved in 170 ml of absolute ethanol in a 11 Parr hydrogenation flask. The flask was purged with nitrogen. 10% palladium on charcoal (1.73 g, 1.6 mmol) was added and the mixture was hydrogenated (40 psi H2) for 1.5 hr in a Parr apparatus. The flask was evacuated and purged with nitrogen. The catalyst was removed by filtration through a Whatman GF/F filter. After removal of the ethanol at reduced pressure, 20.1 g (100% yield) of 2-methyl-3-aminophenol was obtained as a lightly brown solid.
Reaction SMILES: [NH3:1].[N:2]1[N:3]=[CH:4][N:5]2[C:10]=1[CH:9]=[CH:8][C:7]([C:11]1[CH:12]=[C:13]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[C@@H:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:27]([CH3:36])([CH3:35])[O:26][C:25]4=[O:37])=[CH:20][CH:19]=3)[CH:14]=[N:15][C:16]=1F)=[N:6]2>CS(C)=O>[N:2]1[N:3]=[CH:4][N:5]2[C:10]=1[CH:9]=[CH:8][C:7]([C:11]1[CH:12]=[C:13]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[C@@H:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:27]([CH3:36])([CH3:35])[O:26][C:25]4=[O:37])=[CH:20][CH:19]=3)[CH:14]=[N:15][C:16]=1[NH2:1])=[N:6]2
Reactant: CC1(C)OC(=O)N(c2ccc(-c3cnc(F)c(-c4ccc5nncn5n4)c3)cc2)[C@H]1c1ccccc1
Reactant: N
Solvent: CS(C)=O
Product: CC1(C)OC(=O)N(c2ccc(-c3cnc(N)c(-c4ccc5nncn5n4)c3)cc2)[C@H]1c1ccccc1
Temperature: 120 °C

Procedure:
A 2-mL glass microwave reaction vessel was charged with ammonia (2 M solution in 2-propanol) (63.2 μL, 2.91 mmol) (commercially available from Sigma-Aldrich, Milwaukee, Wis.) and (S)-3-(4-(5-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-6-fluoropyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (14 mg, 0.029 mmol) in DMSO (291 μL). The reaction mixture was stirred and heated at 120° C. overnight. LC-MS indicated clean and complete conversion to desired product. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with water (2×) and brine and dried over MgSO4. The solution was filtered and concentrated under reduced pressire. The residue was purified by reverse-phase preparative HPLC using 0.1% TFA in ACN/H2O, gradient 15% to 90% over 20 minutes to provide (S)-3-(4-(5-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-6-aminopyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one as yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.44 (d, J=2.24 Hz, 1H), 8.39 (d, J=9.72 Hz, 1H), 8.27 (d, J=2.56 Hz, 1H), 8.03 (d, J=9.94 Hz, 1H), 7.67 (d, J=8.76 Hz, 2H), 7.55 (d, J=8.87 Hz, 2H), 7.35-7.41 (m, 2H), 7.27-7.34 (m, 3H), 7.23 (s, 2H), 5.47-5.53 (m, 1H), 1.66 (s, 3H), 0.92 (s, 3H). m/z (ESI) 478.2 (M+H)+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][CH:10]([CH3:20])[C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1CCCCC1.O>C1C=CC=CC=1>[C:2]1([CH:1]=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11](=[O:19])[CH:10]([CH3:20])[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)C(=O)Cc1ccccc1
Solvent: C1CCNCC1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)C(=O)C(=Cc1ccccc1)c1ccccc1

Procedure:
A solution of benzaldehyde (6.5g, 0.0617 mole), 3-methyl-1-phenyl-2-butanone (10 g, 0.0617 mole) and piperidine (0.2 g) in benzene (50 ml) was heated to reflux for 20 hours. Water formed during the reaction was removed (azeotrope) by the use of a Dean-Stark trap. The reaction was concentrated to an oil, and the product was purified by silica gel chromatography.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](C)=[CH:4][C:3]=1[N+:9]([O-])=O.N[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([O-])(=O)C.[Na+]>>[CH3:19][C:13]1[CH:18]=[CH:17][C:16]([NH:9][C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:15][CH:14]=1
Reactant: CC(=O)[O-]
Reactant: Nc1ccccc1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Product: Cc1ccc(Nc2ccccc2)cc1

Procedure:
A mixture of 4-chloro-3-nitrotoluene (II: R′=4-Me, halogen=Cl) (1.00 mL, 7.56 mmol), aniline (III: R1′=H) (6.89 mL, 0.075 mmol) and sodium acetate (1.24 g, 0.015 mol) was refluxed under nitrogen for 18 hours. The cooled product was partitioned between EtOAc and water, and the organic portion was washed with 2N HCl, then brine, and worked up to give an oil which was chromatographed on silica gel. Elution with petroleum ether gave the 4-methyldiphenylamine (VI:R′=4-Me, R1′=H) as an orange oil (1.01 g, 58%) which was used directly. A solution of this (1.01 g, 4.42 mmol) in 1:1 MeOH/EtOAc (60 mL) was hydrogenated over 5% Pd-C for 3 hours. After removal of the catalyst and concentration to dryness under reduced pressure, the residue was dissolved in 2-methoxyethanol (100 mL) containing formamidine acetate (0.92 g, 8.84 mmol) and the solution refluxed for 3 hours. After removal of the solvent under reduced pressure, the residue was partitioned between EtOAc and water. The organic portion was worked up to give an oil which was chromatographed on silica gel. Elution with EtOAc/petroleum ether (1:5) gave foreruns, while EtOAc/petroleum ether (1:1) gave Example 12 (0.91 g, 98%). HCl salt: mp (MeOH/Et2O) 196-200° C.
Reaction SMILES: N[C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(#N)C.[BrH:15].N([O-])=O.[Na+]>O>[Br:15][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1c(F)cccc1C(=O)O
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1cccc(F)c1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 78 %

Procedure:
In a 1 L, three necked, round-bottomed flask fitted with a dropping funnel and a thermometer, were charged 20 g (0.13 mol) of 2-amino-3-fluoro-benzoic acid and 160 mL of acetonitrile. After cooling to 0° C., 160 mL of hydrobromic acid (47%) was added dropwise over 10 min. To the resulting solution, 10 g of NaNO2 (0.145 mol) in water (20 mL) was added dropwise over 1 hour. After addition, the reaction mixture was stirred at 0° C. for 5 min, and 21.8 g of Cu(I) Br (0.15 mol) was added portionwise over 30 min. Stirring was continued at 70° C. in an oil bath for 1 hour. After cooling to 0° C., 700 mL of H2O was added and the precipitate was filtered, washed with cold water and dried under vacuum to give an orange solid corresponding to 2-bromo-3-fluoro-benzoic acid (22 g, 78%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:14][C:15]1[C:20]([F:21])=[CH:19][C:18]([NH2:22])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1.O.[OH-].[Li+].C(OCC)(=O)C>CS(C)=O>[F:14][C:15]1[C:20]([F:21])=[CH:19][C:18]([NH:22][C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[C:4]#[N:5])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1cc(C(F)(F)F)ccc1Nc1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
Heat a solution of 2-fluoro-5-trifluoromethyl-benzonitrile (1.0 g, 5.74 mmol) with 4,5-difluoro-2-nitro-phenylamine (1.09 g, 5.74 mmol) and lithium hydroxide monohydrate (0.48 g, 11.49 mmol) in DMSO (12 ml) to 55° C. for 16 hours. Cool the reaction to ambient temperature and then add approximately 150 ml of ice water and stir the mixture for one hour. Extract with three 200 ml portions of dichloromethane. Combine organic layers, dry over sodium sulfate and evaporate solvent. Purify the residue via flash chromatography eluting with a linear gradient starting with 100% hexanes and going to 70% hexanes: 30% ethyl acetate to obtain 0.995 g (2.90 mmol, 50% yield) of the title compound as a yellow amorphous solid: Mass Spectrum (m/e): 344 (M+1).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](Cl)=[O:13])=[CH:7][CH:6]=1>C(Cl)Cl>[CH3:1][N:2]([C:12](=[O:13])[CH2:11][C:8]1[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=1)[NH2:3]
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CNN
Solvent: ClCCl
Product: CN(N)C(=O)Cc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a −78° C. stirred solution of methyl hydrazine (11 mL, 208.5 mmol) in CH2Cl2 (100 mL) is added dropwise a solution of commercially available 4-fluorophenyl-acetyl chloride (12 g, 69.5 mmol) in CH2Cl2 (200 mL). The reaction mixture is stirred for 2 hours at −78° C. and is then slowly warmed to room temperature. The reaction mixture is filtered and the filtrate concentrated under reduced pressure to give a pale yellow oil. Purification over silica (EtOAc) affords 7.6 g (61% yield) of the desired product: 1H NMR (300 MHz, CDCl3) δ 7.28-7.23 (m, 2H), 6.99-6.92 (m, 2H), 3.87 (s, 2H), 3.190 (s, 2H), 3.11 (s, 3H); ESI/MS: 183.1 (M+H).