Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:6]2=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[CH:9][CH:10]=[CH:11][C:5]2=[CH:4][CH:3]=[CH:2]1.[N:16]1C=CC=C[CH:17]=1>C(Cl)Cl>[CH2:15]1[C:7]2=[C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]3=[CH:11][CH:10]=[CH:9][C:8]2=[C:12]([C:17]#[N:16])[CH:13]=[CH:14]1
Reactant: c1ccncc1
Reactant: C1=CCC2=c3ccccc3=CC=CC2=C1
Solvent: ClCCl
Product: N#CC1=C2C=CC=c3ccccc3=C2CC=C1

Procedure:
Under a dry nitrogen atmosphere a stirred mixture of 8-chloro-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-5-one (2.6 grams, 0.011 mole), 85% hydrazine hydrate (5 ml, 0.1 mole), potassium hydroxide (4 grams, 0.071 mole) and ethylene glycol (30 ml) was heated at reflux for 1.5 hours. Sufficient volatiles were removed by distillation to increase the pot temperature to 200° while maintaining reflux. The two-phase reaction mixture was refluxed at that temperature for three hours. The mixture was cooled, poured into ice water, and the resultant mixture extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure to give a yellow oil. The oil was purified by distillation to give 4-chloro-6,7-dihydro-5H-dibenzo[a,c]cycloheptene (bp 119°-126°/0.15 mm). Under a dry nitrogen atmosphere a mixture of 4-chloro-6,7-dihydro-5e,uns/H/ -dibenzo[a,c]cycloheptene (1.6 grams, 0.007 mole), cuprous cyanide (0.95 gram, 0.011 mole), and pyridine (0.8 gram, 0.01 mole) was stirred and heated at 195° for approximately 16 hours. The mixture was cooled, dissolved in methylene chloride (150 ml), and the resultant solution was washed with three 70 ml portions of concentrated ammonium hydroxide. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to give a brown solid. Recrystallization from n-hexane gave 6,7-dihydro-5e,uns/H/ -dibenzo[a,c]cycloheptene-4-carbonitrile (mp 109°-111°).
Reaction SMILES: [O:1]=[C:2]1[CH:5]([NH:6][C:7](=[O:16])[CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]([S:17]NC2C=CC=CC=2)[N:3]1[CH:25]([C:30]([CH3:32])=[CH2:31])[C:26]([O:28][CH3:29])=[O:27].[ClH:33]>C(Cl)Cl>[Cl:33][CH2:31][C:30]1([CH3:32])[CH:25]([C:26]([O:28][CH3:29])=[O:27])[N:3]2[C:2](=[O:1])[CH:5]([NH:6][C:7](=[O:16])[CH2:8][O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C@H:4]2[S:17]1
Reactant: Cl
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)COc2ccccc2)C1SNc1ccccc1
Solvent: ClCCl
Product: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1(C)CCl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of methyl 2-oxo-3-(2-phenoxy-acetamido)-4-anilinothio-α-isopropenyl-1-azetidineacetate (0.12 g), in dried methylene chloride (5 ml) was added 5% methanolic hydrochloric acid (0.8 ml) and the mixture was stirred for 10 hours at room temperature. After the reaction, methylene chloride was distilled off under reduced pressure from the reaction mixture. The residue was extracted with ethyl acetate and the extract was washed with water and dried. The solvent was distilled off to give oily methyl 2-chloromethyl-2-methyl-6-(2-phenoxyacetamido)-penam-3-carboxylate (0.085 g).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:9]1[CH2:14][CH:13]=[CH:12][CH2:11][CH:10]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]>CO.[Pt]=O>[C:1]([NH:4][C@H:5]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](C(=O)O)C1=CCC=CC1
Agent: O=[Pt]
Solvent: CO
Product: CC(=O)N[C@@H](C(=O)O)C1CCCCC1
Reaction time: 4 h
Yield: 74.5 %

Procedure:
To a solution of 15 g of (R)-(acetylamino) (1,4-cyclohexadiene-1-yl)acetic acid in 500 mL of methanol was added 500 mg of platinum oxide, and the mixture was stirred for 4 hours under hydrogen gas atmosphere. Then, the reaction mixture was filtrated and the filtrate was condensed. The residue was recrystallized from ethanol to give 11.4 g (75%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5](N)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[BrH:13].N([O-])=O.[Na+].[OH-].[Na+]>O.Br.O.C(OCC)(=O)C>[Br:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH2:3][N:2]([CH3:1])[CH2:11][CH2:10]2
Reactant: CN1CCc2cccc(N)c2C1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCc2cccc(Br)c2C1
Temperature: 0 °C

Procedure:
Into a 50 mL 3-necked round bottom flask (named A), was placed 2-methyl-1,2,3,4-tetrahydroisoquinolin-8-amine (500 mg, 3.08 mmol). This was followed by the addition of a solution of HBr (5 mL) in H2O (5 mL), which was added dropwise with stirring, while cooling to a temperature of 0° C. To the above was added NaNO2 (230 mg, 3.33 mmol) in several batches, while cooling to a temperature of 0° C. and the mixture was stirred for 30 mins at that temperature. Then into another 50 mL 3-necked round bottom flask (named B), was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of CuBr (550 mg, 3.83 mmol) in HBr/H2O (3 mol/L) (10 mL), while cooling to a temperature of 0° C. The mixture was stirred for 10 minutes. Then was followed by the addition of the reaction solution of flask A with dropwise while the temperature was maintained at 0° C. The resulting solution was allowed to react, with stirring, for 30 minutes while the temperature was maintained at 0° C. The resulting solution was allowed to react, with stirring, for an additional 2 hours at room temperature. The reaction progress was monitored by TLC(ethyl acetate:petroleum ether=1:1). Adjustment of the pH to 9 was accomplished by the addition of NaOH (10%). The resulting solution was extracted three times with 50 mL of CH2Cl2 and the organic layers combined and dried over K2CO3. A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The residue was purified by eluting through a column with a 1:1 ethyl acetate; petroleum ether solvent system. This resulted in 0.45 g (65%) of 8-bromo-2-methyl-1,2,3,4-tetrahydroisoquinoline as light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:15](O)[CH3:16]>OS(O)(=O)=O>[CH2:15]([O:13][C:12](=[O:14])[CH2:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH2:1])[S:3][C:4]=2[CH:10]=1)[CH3:16]
Reactant: CCO
Reactant: Nc1nc2ccc(CC(=O)O)cc2s1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc2nc(N)sc2c1

Procedure:
A solution of (2-amino-benzothiazol-6-yl)-acetic acid (0.61 mmol, as prepared by Meyer et al. in J. Med. Chem. 1997, 40, 1060) in absolute ethanol (10 mL) was treated with 3 drops of concentrated H2SO4 and ca. 1 g of dry 4A molecular sieves, and heated to reflux for 3 d. The reaction was concentrated to dryness in vacuo, partitioned between CH2Cl2 and saturated aqueous NaHCO3, filtered, and phases separated. The aqueous layer was extracted with CH2Cl2, and the combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and the filtrate concentrated in vacuo giving the title compound as a yellow solid. 1H NMR (CDCl3) δ 7.50 (1H, m), 7.41 (1H, d, J=8.3 Hz), 7.20 (1H, dd, J=8.2 Hz, 1.9 Hz), 4.15 (2H, q, J=7.2 Hz), 3.65 (2H, s), 3.42 (4H, s [NH2+H2O]), 1.26 (3H, t, J=7.1 Hz). ESI-MS (m/z): Calcd for C11H12N2O2S: 236.1; found 237.1 (M+H).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][CH2:16][C:17]([OH:19])=[O:18]>CN(C)C=O>[SH:7][C:4]1[S:3][C:2]([S:1][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[N:6][N:5]=1
Reactant: O=C(O)CCBr
Reactant: Sc1nnc(S)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CCSc1nnc(S)s1
Temperature: 0 °C
Yield: 34.2 %

Procedure:
To a mixture of 1.5 g of 2,5-dimercapto-1,3,4-thiadiazole, 1.3 g of anhydrous potassium carbonate, and 20 ml of N,N-dimethylformamide was added 1.6 g of 3-bromopropionic acid, whereby the red color of the reaction mixture began to gradually fade and the reaction mixture became yellow. Then, the reaction mixture was poured into 100 ml of ice water and extracted with 30 ml of ethyl acetate three times. The extract thus obtained was washed with water and extracted with 20 ml of an aqueous solution of 5% sodium hydrogen carbonate two times. The extract was washed with ethyl acetate, acidified with diluted hydrochloric acid, and extracted with 30 ml of ethyl acetate three times and the extract thus obtained was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide 0.76 g of 3-[(5-mercapto-1,3,4-thiadiazol-2-yl)thio]propionic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])[CH2:16][CH2:15][CH:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:32]I>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])[CH2:16][CH2:15][CH:14]([N:17]([CH3:32])[S:18]([CH3:21])(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)NC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1)S(C)(=O)=O
Temperature: 50 °C

Procedure:
The product of Example 1 (52 mg, 0.11 mmol) in tetrahydrofuran (3 ml), cooled to 0° C. was treated with sodium hydride (11 mg, 0.28 mmol) After 10 minutes methyl iodide was added (70 μL, 1.1 mmol) and the reaction heated to 50° C. for 4 hours, then extracted into ethyl acetate and washed with H2O, dried (MgSO4) and evaporated. Product was purified by chromatography (25% ethyl acetate/hexane). 1H NMR (400 MHz, CDCl3) δ 7.36-7.26 (4H, m), 7.04-7.01 (2H, m), 6.79-6.71 (1H, m), 3.91-3.84 (1H, m), 3.24-3.19 (2H, d, broad), 2.91 (3H, s), 2.86 (3H, s), 2.64-2.57 (2H, dd, J=12.5, J=3.8), 2.06-2.01 (2H, m), 1.85-1.76(2H, m). m/z=500, 502 [MNa]+
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:24][C:25]1[CH:26]=[C:27](O)[C:28](=[CH:30][CH:31]=1)[OH:29].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[F:24][C:25]1[CH:26]=[CH:27][C:28]2[O:29][C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[O:23][C:30]=2[CH:31]=1
Reactant: Oc1ccc(F)cc1O
Reactant: COc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: COc1ccc(C2(C3CCNCC3)Oc3ccc(F)cc3O2)cc1
Yield: 33.4 %

Procedure:
A solution of 4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 284) (638 mg, 2.00 mmol), 4-fluorocatechol (512 mg, 4.00 mmol) and p-TsOH.H2O (760 mg, 4.00 mmol) in xylene (20 mL) was heated at reflux using a Dean-Stark apparatus to remove water for 52 hours. Standard work-up and purification gave 4-[5-fluoro-2-(4-methoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine as a pale yellow oil (220 mg, 33%).
Reaction SMILES: [CH2:1]([CH:8]([C:14](=O)[CH3:15])[C:9]([O:11]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:18](=[NH:23])([NH2:22])[CH2:19][CH2:20][CH3:21].C[O-].[Na+].CO.C(OCC)(=O)C>CO.O>[CH2:1]([C:8]1[C:9](=[O:11])[NH:23][C:18]([CH2:19][CH2:20][CH3:21])=[N:22][C:14]=1[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Reactant: CCCC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CCCc1nc(C)c(Cc2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl 2-benzyl-3-oxobutanoate (2.13 mL) and butanimidamide hydrochloride (2.05 g) in methanol (50 mL) was added 28% sodium methoxide-methanol solution (5.8 g), and the mixture was stirred at room temperature for 24 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.61 g, 66%).
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:14]=[O:15])C1C=CC=CC=1.[CH2:16]([O:18][C:19]([C:21]1[N:22]([CH2:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)[C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([F:30])=[CH:25][CH:24]=2)=[O:20])[CH3:17].C([O-])(=O)C.[Na+]>ClCCCl>[CH2:16]([O:18][C:19]([C:21]1[N:22]([CH2:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)[C:23]2[C:28]([C:29]=1[CH:14]=[O:15])=[CH:27][C:26]([F:30])=[CH:25][CH:24]=2)=[O:20])[CH3:17]
Reactant: CCOC(=O)c1cc2cc(F)ccc2n1Cc1cccc2ccccc12
Reactant: CN(C=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(C=O)c2cc(F)ccc2n1Cc1cccc2ccccc12
Temperature: 22 °C
Reaction time: 0.17 h

Procedure:
A mixture of POCl3 (0.79 ml) and N-methylformanilide (1.07 ml) was stirred at 22° C. for 10 min. To the solid formed was added a solution of 5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (2.00 g from Example 15) in 1,2-dichloroethane (25 ml) and the solution was stirred at reflux temperature for 5 h. The solution was poured into a solution of ice-cold water (40 ml) containing sodium acetate (4.6 g) and stirring was continued at 22° for 2 h. The layers were separated, the aqueous layer extracted with dichloromethane, the combined extracts were dried, evaporated and the residue was chromatographed on silica using n-heptane/AcOEt (10:1) to give 5-fluoro-3-formyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester as a colorless solid. MS: 376.4 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-:3])=[O:2].[Na+].[Cl-].C(O)(=[O:18])C>OO>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N+:9]2[O-:18])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2ncccc12
Reactant: CC(=O)O
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Product: O=[N+]([O-])c1cccc2c1ccc[n+]2[O-]

Procedure:
A solution of 25.5 g (146 mmol) of 5-nitroquinoline in 544 ml of acetic acid and 272 ml of 30% aqueous H2O2 solution are heated for 100 minutes to 62-69° C. The reaction mixture is poured onto saturated NaCl solution and extracted with ethyl acetate. The combined extracts are concentrated by evaporation to about 50 ml with the addition of toluene. Column chromatography on silica gel with ethyl acetate-MeOH yields 12.3 g of the product as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:26][CH2:25][CH2:24][C:23]4[N:19]([N:20]=[C:21]([C:27]5[N:28]([CH2:32][C:33]([F:36])([F:35])[F:34])[N:29]=[CH:30][N:31]=5)[CH:22]=4)[C:18]=3[CH:37]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)C>[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:26][CH2:25][CH2:24][C:23]4[N:19]([N:20]=[C:21]([C:27]5[N:28]([CH2:32][C:33]([F:35])([F:34])[F:36])[N:29]=[CH:30][N:31]=5)[CH:22]=4)[C:18]=3[CH:37]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)-n2nc(-c4ncnn4CC(F)(F)F)cc2CCO3)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Product: FC(F)(F)Cn1ncnc1-c1cc2n(n1)-c1cc(C3CCNCC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
A solution of 4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert butyl ester (232 mg, 0.41 mmol) in IMS (10 mL) was treated with a slurry of Pd/C (170 mg, 10% wt Pd on carbon, 50% water) in IMS. The mixture was degassed then the atmosphere evacuated and back-filled with hydrogen and then stirred at RT for 18 h. The reaction mixture was filtered through Ceilte® with ethyl acetate washings and the filtrate concentrated in vacuo. The resultant residue was dissolved in methanol (5 mL), treated with 1M HCl in diethyl ether (2 mL, 2 mmol) and the mixture stirred at RT for 18 h. Solvent was removed in vacuo and residue triturated in diethyl ether to give 130 as a pale yellow solid (127 mg, 74%). 1H NMR (DMSO-d6, 400 MHz): δ 9.08-8.97 (br m, 1H); 8.96-8.81 (br m, 1H); 8.22 (s, 1H); 7.69 (s, 1H); 7.31-7.23 (m, 2H); 6.99 (s, 1H); 5.72 (q, J=8.8 Hz, 2H); 4.51 (t, J=6.1 Hz, 2H); 3.42-3.32 (m, 2H); 3.22-3.15 (m, 2H); 3.08-2.88 (m, 3H); 2.04-1.95 (m, 2H); 1.94-1.80 (m, 2H). LCMS: RT=6.75 min, M+H+=419.2
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][C:12]([C:14]([CH3:20])([CH3:19])[C:15]([O:17][CH3:18])=[O:16])=[N:11][C:10]=1[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[C:23]([OH:30])[N:22]=1.[H][H]>[Pd].CO>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:10]2[N:11]=[C:12]([C:14]([CH3:20])([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[NH:13][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[N:22][C:23]=1[OH:30]
Reactant: COC(=O)C(C)(C)c1nc(-c2ccc([N+](=O)[O-])c(O)n2)c(-c2ccc(F)cc2F)[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)(C)c1nc(-c2ccc(N)c(O)n2)c(-c2ccc(F)cc2F)[nH]1
Temperature: 55 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
Methyl 2-[5-(2,4-difluorophenyl)-4-(6-hydroxy-5-nitro-2-pyridyl)-1H-imidazol-2-yl]-2-methyl-propanoate (90.0 g, 0.22 mol), wet 10% Pd/C (4.5 g), and methanol (1.77 L) are combined at 15-25° C. The reaction is stirred under 20-25 psig hydrogen atmosphere for 3-6 h. The reaction mixture is filtered over diatomaceous earth, and the filter aid is washed with methanol (227 mL). The filtrate is concentrated under reduced pressure below 40° C., and methyl tert-butyl ether (729.3 mL) is added. The MTBE is removed under reduced pressure below 40° C., and more methyl tert-butyl ether (729.3 mL) is added. The MTBE is removed under reduced pressure below 40° C. Methyl tert-butyl ether (182 mL) and methanol (46 mL) are added and the mixture heated to 50-60° C. for 1-2 h. The mixture is cooled to 10-15° C., and stirred for 2-4 h. The solids are collected by filtration and the filtercake washed with methyl tert-butyl ether (61 mL). The solids are dried under vacuum below 50° C. to furnish the title compound as a yellow solid (75.0 g, 88%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:15])([F:14])[F:13])[C:6]=1[F:16])=[N+]=[N-].C(OC(=O)C)C.[ClH:23]>[Pd].CO>[ClH:23].[F:16][C:6]1[C:7]([O:11][C:12]([F:14])([F:15])[F:13])=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][NH2:1]
Reactant: [N-]=[N+]=NCc1cccc(OC(F)(F)F)c1F
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: NCc1cccc(OC(F)(F)F)c1F
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture of 1-(azidomethyl)-2-fluoro-3-(trifluoromethoxy)benzene (0.81 g, 3.46 mmol, Step-3), palladium 10% on carbon (0.20 g), 4M hydrochloric acid ethyl acetate solution (4 mL), and methanol (20 mL) is stirred at room temperature under hydrogen atmosphere (1 atm). After filtration through a pad of celite, the filtrate is concentrated under reduced pressure. The residue is crystallized from ether and diisopropyl ether to give 0.85 g (>99% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9](Cl)[CH3:10].[SH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=1[O-:19].[Na]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]([S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=1[O-:19])[CH3:10]
Reactant: Cc1ccc(C)c(C(C)Cl)c1
Reactant: [O-][n+]1ccccc1S
Agent: [Na]
Product: Cc1ccc(C)c(C(C)Sc2cccc[n+]2[O-])c1
Yield: 83 %

Procedure:
The intermediate 2-(1-[2,5-dimethylphenyl]ethylthio)pyridine N-oxide is prepared from 1-(2,5-dimethylphenyl)ethyl chloride and 2-mercaptopyridine N-oxide, sodium salt by the procedure described in Example 2. Melting point 118° - 120° C. Structure confirmed by IR and NMR.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)=[CH:10][N:4]2[N:3]=1.[B:25]1(B2OC(C)(C)C(C)(C)O2)[O:29]C(C)(C)C(C)(C)[O:26]1.C([O-])(=O)C.[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:24][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[N:8]=[C:5]3[CH:6]=[CH:7][C:2]([B:25]([OH:29])[OH:26])=[N:3][N:4]3[CH:10]=2)=[CH:16][C:15]=1[NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Cc1ccc(-c2cn3nc(Cl)ccc3n2)cc1NC(=O)C(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: Cc1ccc(-c2cn3nc(B(O)O)ccc3n2)cc1NC(=O)C(C)(C)C
Temperature: 90 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A suspension of N-[5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-methyl-phenyl]-2,2-dimethyl-propanamide (15.43 g 0.045 mol), bis(pinacolato)diboron (17.14 g, 0.0675 mol), potassium acetate (8.833 g, 0.09 mol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.305 g, 3.15 mmol) in dioxane (153 mL) is heated at 90° C. for 16 hours. The reaction mixture is cooled, concentrated, added to an aqueous NaOH solution (150 mL, 3 M). The mixture is stirred for 1 hour then extracted with EtOAc (300 mL). Organic layers are washed with the NaOH solution (150 mL, 3 M). The aqueous portions are combined, washed twice with ether, and the aqueous pH is lowered to 5 with an aqueous HCl solution (6 M) to cause solid formation. This heterogeneous solution is cooled in the freezer for 2 hours, the solids are collected by filtration to give the desired product (8.56 g). The resulting aqueous solution is back extracted with EtOAc, combined with earlier organic portions and filtered through celite. The combined organic layer is dried, concentrated and taken up into an aqueous HCl solution (0.5 M). The solid product formed is collected by filtration and combined with the earlier batch, to afford a total 10.16 g of the desired title compound. LCMS (m/z)=353.5 [M+H]+, tR=2.04 min.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=2)[N:14]=1.CCN(C(C)C)C(C)C.CCOCC>CN(C=O)C>[F:20][C:18]([F:19])([F:21])[C:15]1[N:13]2[N:14]=[C:9]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)[CH:10]=[CH:11][C:12]2=[N:17][N:16]=1
Reactant: OC1CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: OC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 125 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
4-Hydroxypiperidine (10.91 g, 107.84 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (20 g, 89.87 mmol) and DIPEA (23.48 mL, 134.80 mmol) in DMF (200 mL). The resulting solution was stirred at 125° C. for 2 hours. The reaction mixture was evaporated to dryness, redissolved in DCM and purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to give a beige solid which was stirred with ether then filtered to afford 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (22.64 g, 88%) as a solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[C:9]([NH:14]C(=O)C(C)(C)C)=[N:10][CH:11]=[CH:12][CH:13]=2)[O:5][N:4]=1.CO.[OH-].[Na+]>C(O)(=O)C>[NH2:14][C:9]1[C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][OH:1])[CH:7]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)C(=O)Nc1ncccc1-c1cc(CO)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ncccc1-c1cc(CO)no1
Temperature: 58.5 °C
Reaction time: 14 h
Yield: 73.4 %

Procedure:
To a mixture of N-{3-[3-(hydroxymethyl)isoxazol-5-yl]pyridin-2-yl}-2,2 dimethylpropanamide (82.8 g) obtained in Reference Example 9 and methanol (350 mL) was added 5N aqueous sodium hydroxide (350 mL) at room temperature, which was stirred at 57 to 60° C. for 14 hours. To the reaction mixture was added acetic acid (100 mL) and the precipitated solid was filtered to obtain the title compound (42.2 g) as a grayish white solid.