Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:18]([O-:20])=[O:19])[S:9][C:6]2=[N:7][CH:8]=1.[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(N(CC)CC)C>C(#N)C>[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[S:9][C:6]2[C:5]([N:11]=1)=[CH:4][C:3]([CH2:2][N:31]1[CH2:30][CH2:29][N:28]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:33][CH2:32]1)=[CH:8][N:7]=2)([O-:20])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccccc1-c1nc2cc(CBr)cnc2s1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2cnc3sc(-c4ccccc4[N+](=O)[O-])nc3c2)CC1
Yield: 74 %

Procedure:
A solution of crude 6-(bromomethyl)-2-(2-nitrophenyl)thiazolo[5,4-b]pyridine (4.0 g), Boc-piperazine (1.99 g, 10.7 mmol), triethylamine (Et3N) (1.5 mL, 10.7 mmol) and acetonitrile (100 mL) was stirred at 50° C. (4 h) and then at room temperature (60 h). TLC demonstrated that the reaction was complete. The mixture was concentrated in vacuo and purified by silica gel chromatography (petroleum ether:ethyl acetate:Et3N=100:10:1) to afford tert-butyl 4-((2-(2-nitrophenyl)thiazolo[5,4-b]pyridin-6-yl)methyl)piperazine-1-carboxylate as a yellow solid (3.6 g, yield: 74% over 2 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[F:17][CH2:18][CH2:19]CS([O-])(=O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH2:19][CH2:18][F:17])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc(O)cc(Cl)c1
Reactant: O=S(=O)([O-])CCCF
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)cc(OCCF)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a solution of 3-chloro-5-hydroxybenzaldehyde (8.2 g, 52.5 mmol; see Preparation A(ii) above) and potassium carbonate (9.4 g, 68.2 mmol) in DMF (10 mL) under nitrogen was added a solution of (2-monofluoroethyl) methanesulfonate (9.7 g, 68.2 mmol; see step (i) above) in DMF (120 mL) dropwise at room temperature. The mixture was heated to 100° C. for 5 h and then stirred overnight at room temperature. The reaction was cooled to 0° C., poured into ice-cold 2N HCl and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The brown oil was chromatographed on silica gel eluting with Hex:EtOAc (4:1) to afford the sub-title compound (7.6 g, 71%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2]#[CH:3].C(N(CC)CC)C.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1.[Cu]Br>[CH3:20][C:19]([CH3:22])([C:18](=[O:23])[C:3]#[C:2][CH2:1][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:21]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C#CCOc1ccccc1
Agent: [Cu]Br
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)C#CCOc1ccccc1
Temperature: 80 °C
Yield: 74 %

Procedure:
13.2 g (0.1 mol) of phenyl propargyl ether are added dropwise to a mixture of 10.1 g (0.1 mol) of triethylamine and 1.43 g of copper-(I) bromide in 60 ml of toluene at 20° C., under a nitrogen atmosphere and with stirring. The mixture is subsequently stirred at 20° C. for 30 minutes. Thereafter, 12 g (0.1 mol) of pivaloyl chloride are added dropwise in the course of 15 minutes. The reaction mixture is heated to 80° C. and is stirred at this temperature for 10 hours. After cooling to room temperature, the reaction mixture is washed first with dilute aqueous hydrochloric acid and then with water. The organic phase is concentrated by stripping off the solvent and the residue which remains is distilled under a high vacuum. 16 g (75% of theory) of 2,2-dimethyl-6-phenoxyhex-4-in-3-one are obtained in this manner in the form of a liquid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1(/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:20]([C:32]([F:35])([F:34])[F:33])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:37]>C(O)C>[ClH:37].[NH2:7][C:8](/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:20]([C:32]([F:33])([F:34])[F:35])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CCCCCCCOc1ccc(/C=C/C2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1C(F)(F)F
Agent: Cl
Solvent: CCO
Product: CCCCCCCOc1ccc(/C=C/C(N)(CO)CO)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Compound 28-5 (500 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (330 mg) as a white powder.
Reaction SMILES: [O-]CC.[Na+].C(O)C.[C:8]([O:11][CH2:12][CH3:13])(=[O:10])[CH3:9].C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=O)C>C1(C)C=CC=CC=1>[CH2:12]([O:11][C:8](=[O:10])[CH2:9][C:17](=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH3:13]
Reactant: CCOC(=O)c1ccccn1
Reactant: CCOC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccccn1
Temperature: 90 °C
Yield: 91 %

Procedure:
Stir a mixture of sodium ethoxide (360 g, 5.29 mol), toluene (4 L), ethanol (18 mL, 0.265 mol), and ethyl acetate (1.04 L, 10.6 mol) in a 22 L flask equipped with a reflux condenser, nitrogen inlet, and mechanical stirrer. Stir for 1 h as the mixture warms to 26° C. Add pyridine-2-carboxylic acid ethyl ester (Fluka; 400 g, 2.65 mol) and heat the mixture to reflux (90° C.) for 18 h. Cool the mixture to room temperature, dilute with toluene (8 L), wash with water (6 L), and separate the layers. Acidify the aqueous layer to pH 5 with glacial acetic acid. Extract with ethyl acetate (2×4 L), dry the combined organic layers (sodium sulfate), filter, and concentrate in vacuo to yield 466 g (91%) the subtitled compound as a dark oil in 93% purity by HPLC analysis. MS (ES) m/z=194 (M+H).
Reaction SMILES: [C:1]([C:4]1([NH:15][S:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17])[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)(=[NH:3])[NH2:2].C[O-].[Na+].CN(C)/[CH:27]=[CH:28]/[CH:29]=O>CO>[CH3:19][C:18]([CH3:21])([S:16]([NH:15][C:4]1([C:1]2[N:2]=[CH:29][CH:28]=[CH:27][N:3]=2)[CH2:5][N:6]([C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[CH2:7]1)=[O:17])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC(NS(=O)C(C)(C)C)(C(=N)N)C1
Reactant: CN(C)/C=C/C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(NS(=O)C(C)(C)C)(c2ncccn2)C1
Temperature: 70 °C
Yield: 11.3 %

Procedure:
To the above reaction mixture of tert-butyl 3-carbamimidoyl-3-(1,1-dimethylethylsulfinamido)azetidine-1-carboxylate (assumed 4.98 mmol) in methanol (5 mL) was added sodium methoxide (0.509 g, 9.42 mmol) and (E)-3-(dimethylamino)acrylaldehyde (0.560 g, 5.65 mmol), and the resulting solution was heated at 70° C. overnight. The reaction mixture was then concentrated and the residue dissolved in ethyl acetate. The mixture was washed with water followed by saturated brine solution, and then dried over Na2SO4 and concentrated. The crude product was then purified by column chromatography (50% EtOAc in Hexane) to afford tert-butyl 3-(1,1-dimethylethylsulfinamido)-3-(pyrimidin-2-yl)azetidine-1-carboxylate Yield: 200 mg (overall 12%). 1H NMR (400 MHz, CDCl3): δ 8.78 (d, J=4.8 Hz, 2H), 7.24 (m, 1H), 4.63-4.48 (m, 2H), 4.23 (d, J=9.2 Hz, 2H), 1.47 (s, 9H), 1.29 (s, 9H). LCMS: (ES+) m/z observed=255.2 (M+H)+ of 2-methyl-N-(3-(pyrimidin-2-yl)azetidin-3-yl)propane-2-sulfinamide.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([P:16]([OH:18])[OH:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19](Cl)[CH2:20]Cl>C(O)C.C(Cl)Cl>[CH2:19]([O:18][P:16]([CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH:13]([CH3:15])[CH3:14])[OH:17])[CH3:20]
Reactant: ClCCCl
Reactant: CC(C)C(NC(=O)OCc1ccccc1)P(O)O
Solvent: CCO
Solvent: ClCCl
Product: CCOP(O)C(NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a solution of 1-(benzyloxycarbonylamino)-2-methylpropylphosphonous acid (5.8 g, 21.4 mmol) in 15 mL ethanol and 200 mL CH2Cl2 was added EDC (5.0 g, 26 mmol). The resulting reaction mixture was stirred at ambient temperature for 30 minutes. The mixture was concentrated in vacuo, and the residue was taken up into 200 mL ethyl acetate, washed with water and brine. The solvent was evaporated in vacuo to afford 1-(benzyloxycarbonylamino)-2-methylpropylphosphonous acid ethyl ester (6.2 g, 20.7 mmol, 96.8%) as white solid which was used without further purification.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:15]C(C)([O-])C.[K+].IC>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([CH3:14])(=[O:12])=[O:13])=[CH:8][CH:9]=2)[N:4]([CH3:15])[N:3]=1
Reactant: CS(=O)(=O)c1ccc2c(I)n[nH]c2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nc(I)c2ccc(S(C)(=O)=O)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
In a round-bottomed flask, 3-iodo-6-methylsulfonyl-1H-indazole (396 mg, 1.23 mmol) was dissolved in THF (4.4 ml). The orange solution was cooled to 0° C. and potassium tert-butoxide (200 mg, 1.78 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min then iodomethane (0.11 ml, 1.76 mmol) was added dropwise. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 4 h then quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with EtOAc/hexanes (gradient: 0-30% EtOAc) to give 251 mg (61%) of 3-iodo-6-methanesulfonyl-1-methyl-1H-indazole as an off-white solid. The minor regioisomer 3-iodo-6-methanesulfonyl-2-methyl-2H-indazole was also observed, but not isolated.
Reaction SMILES: [Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([O:13]CC)=[O:12])=[C:4]([O:16][CH3:17])[CH:3]=1.O[Li].O>C1COCC1.O>[Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[C:4]([O:16][CH3:17])[CH:3]=1
Reactant: CCOC(=O)CNc1cc(I)c(Cl)cc1OC
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)c(I)cc1NCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.9 %

Procedure:
To a solution of ethyl 2-(4-chloro-5-iodo-2-methoxyphenylamino)acetate (8.6 g, 22.9 mmol) in THF (50 mL) and water (50 mL), LiOH.H2O (1.96 g, 45.9 mmol) was added and the resulting mixture was stirred at room temperature for 2 h. The mixture was washed with 20% ethyl acetate/petroleum ether. The aqueous layer was acidified with aqueous HCl (1 M) to adjust PH to 3-4 and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product (5 g, 64% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][N:16](C)[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:20].[H][H]>C(O)C.[Pd]>[ClH:20].[ClH:20].[CH3:1][N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:10][CH2:9]1
Reactant: CN1CCC2(CC1)CCN(Cc1ccccc1)CC2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN1CCC2(CCNCC2)CC1

Procedure:
3-Benzyl-9-methyl-3,9-diaza-spiro[5.5]undecane (Rice, L. M. et al. J Heterocyclic Chem. 1964, 1, 3, 125.) (1.2 g, 4.65 mmol) was dissolved in ethanol (20 mL). To this solution was added hydrochloric acid (4 N in dioxane, 3 mL) and palladium (10% on charcoal, 500 mg). The reaction was shaken on a Parr shaker overnight under 60 psi of hydrogen. The reaction mixture was filtered through a pad of celite, concentrated, and the residue treated with a mixture of ethyl acetate and hexanes, to yield 670 mg (60%) as a white powder. 1H-NMR (CD3OD) δ 1.68-1.72 (m, 4H), 2.88 (s, 3H), 3.16-3.22 (m, 6H), 3.38 (m, 2H). Mass spec.: 169.12 (MH)+.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:7]([C:10]1[CH:11]=[C:12]([C:15]([NH:17][N:18]([CH2:34][C@@H:35]([OH:39])[C:36]([OH:38])=[O:37])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[F:33])=[CH:22][CH:21]=2)=[O:16])[NH:13][N:14]=1)(=[O:9])[CH3:8].C1COCC1>>[C:7]([C:10]1[CH:11]=[C:12]([C:15]([NH:17][N:18]([CH2:34][C@@H:35]([O:39][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[C:36]([OH:38])=[O:37])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[F:33])=[CH:22][CH:21]=2)=[O:16])[NH:13][N:14]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)[nH]n1
Reactant: CC(C)C(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](OC(=O)C(C)C)C(=O)O)[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.7 %

Procedure:
Isobutyryl chloride (23.4 μL, 221.1 μmol) and (R)-3-[N′-(5-acetyl-2H-pyrazole-3-carbonyl)-N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid (10.5 mg, 22.1 μmol) were combined in THF (108 μL, 1.3 mmol), and stirred overnight at room temperature. The solvent was evaporated and the residue was purified by preparative HPLC to yield the title compound (4.9 mg) as a TFA salt. MS m/z [M+H]+ calc'd for C26H26ClFN4O6, 545.15. found 545.1.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CN1CCCC1.[Cl:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>C1C=CC=CC=1>[C:1]1([O:11][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([CH2:19][Cl:18])=[CH:21][CH:22]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: Oc1cccc2ccccc12
Agent: CN1CCCC1
Solvent: c1ccccc1
Product: O=C(Oc1cccc2ccccc12)c1ccc(CCl)cc1

Procedure:
72.1 g (0.5 mole) of α-naphthol was heated to 50° C. with 150 ml of benzene and 0.5 ml of N-methylpyrrolidine, whereupon a clear solution was obtained. Following the procedure of Method C, 95 g (0.5 mole) of p-chloromethylbenzoyl chloride dissolved in 80 ml of benzene was added drop by drop over a period of about 30 minutes, and then the mixture was refluxed for 5 hours under a weak current of nitrogen gas. The benzene was then distilled from the clear, orange-colored solution. The residue crystallized upon cooling to a yellow mass amounting to 148 g (100%), M.P. 93°-96° C. The entire amount of the raw product was recrystallized from 3 liters of cyclohexane with the addition of decolorizing carbon. About 80% of the material put in was obtained in light yellow needles of a melting point of 104°-106° C. For the analysis, 20 g was again recrystallized from 400 ml of cyclohexane. 16.5 g of very pale yellow needles was obtained, M.P. 105°-106.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[CH:17][CH:16]=2)[N:10]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:33])=[C:30]([CH:32]=1)[NH2:31].C[Al](C)C>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:33])=[C:30]([NH:31][C:19](=[O:21])[C:18]2[CH:23]=[CH:24][C:15]([N:11]3[C:12](=[O:14])[NH:13][C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:10]3)=[CH:16][CH:17]=2)[CH:32]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Reactant: Cc1ccc(Cl)cc1N
Agent: C[Al](C)C
Product: Cc1ccc(Cl)cc1NC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Yield: 46.1 %

Procedure:
The title compound was prepared according to the procedure described in Example-31, by using methyl 4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate (step-2 of Intermediate-9, 0.100 g, 0.28 mmol), 5-chloro-2-methyl aniline (0.062 g, 0.43 mmol) and trimethyl aluminium (2M solution in toluene) (0.5 mL) to afford 0.059 g of desired product. 1H NMR (DMSO-d6): δ 2.23 (s, 3H), 7.23 (d, J=6.9 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.53 (m, 2H), 7.59 (m, 1H), 7.71 (m, 1H), 8.10 (br s, 4H), 9.98 (br s, 1H), 12.76 (br s, 1H); MS (m/z): 457.18 [M]+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:19]3=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][N:18]3[CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.C(O)C.[C].[Rh].[Pt](=O)=O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[C:19]3=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][N:18]3[CH2:17][CH2:16][CH2:15]2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccccc4)cc3)C2=N1
Agent: O=[Pt]=O
Agent: [Rh]
Solvent: C1CCOC1
Solvent: CCO
Product: O=S1(=O)CCN2CCCC(c3ccc(Oc4ccccc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
A mixture of 9-(4-phenoxyphenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (173 mg) and 5% rhodium-carbon (50% wet, 17 mg) in THF (50 ml) and ethanol (20 mL) was stirred under a hydrogen atmosphere at room temperature overnight. To the reaction mixture was added platinum dioxide (17 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 7 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica-bound silica gel column chromatography (ethyl acetate/methanol) to give the title compound (153 mg) as a white solid. The obtained solid was crystallized from acetonitrile and diisopropyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([OH:13])=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH3:20][N:21]([CH3:26])[S:22](Cl)(=[O:24])=[O:23].O>CN(C=O)C>[CH3:20][N:21]([CH3:26])[S:22](=[O:24])(=[O:23])[O:13][C:8]1[CH:9]=[C:10]([O:11][CH3:12])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1cc(O)c(C=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)c(OS(=O)(=O)N(C)C)cc1OC
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
Dissolve 16.2 g (0.0889 mol) of 3,4-dimethoxy-6-hydroxybenzaldehyde in 80 ml of DMF. Cool to 10° C. and add in portions 24.6 g (0.178 mol) of potassium carbonate. Allow to return to ambient temperature and stir for 30 minutes. Cool to approximately 10° C. and pour in dropwise 10.1 ml (0.093 mol) of N,N-dimethylsulphamoyl chloride. Allow to return to ambient temperature and stir for 2 h. Pour the reaction mixture into 600 g of water and ice and stir for 1 h at ambient temperature. The precipitate formed is filtered off and washed 3 times with 50 ml of water each time and then dried in vacuo. 21.3 g of title product are obtained.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:15][C:16]([F:40])([F:39])[C:17]1[N:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:60][N:61]1[C:65]([CH2:66][CH2:67]O)=[CH:64][CH:63]=[N:62]1>C1COCC1>[CH3:60][N:61]1[C:65]([CH2:66][CH2:67][O:38][C:35]2[CH:36]=[CH:37][C:32]([CH:29]3[CH2:30][CH2:31][N:26]([C:23]4[CH:24]=[CH:25][C:20]5[N:21]([C:17]([C:16]([F:15])([F:39])[F:40])=[N:18][N:19]=5)[N:22]=4)[CH2:27][CH2:28]3)=[CH:33][CH:34]=2)=[CH:64][CH:63]=[N:62]1
Reactant: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: Cn1nccc1CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1nccc1CCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
DIAD (78 μl, 0.386 mmol) was added dropwise to 4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenol (117 mg, 0.322 mmol), triphenylphosphine (101 mg, 0.386 mmol) and 2-(1-methyl-1H-pyrazol-5-yl)ethanol (obtained as described in PCT Int. Appl. WO 2007017222, Intermediate 1) (49 mg, 0.386 mmol) in THF (2 mL). The resulting mixture was stirred at ambient temperature for 16 hours and then added to a SCX column. The crude product was eluted using 2M ammonia in methanol and the product-containing fractions were evaporated. The product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 6-[4-[4-[2-(1-methyl-1H-pyrazol-5-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (79 mg, 52%) as a solid.
Reaction SMILES: [F:1][C:2]1[C:6]([F:7])=[CH:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:26]=[CH:25][CH:24]=4)=[N:15]3)=[C:10]([OH:34])[CH:9]=2)[CH:3]=1.Cl[C:36]([F:41])([F:40])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:40][CH:36]([F:41])[O:34][C:10]1[CH:9]=[C:8]([N:4]2[CH:5]=[C:6]([F:7])[C:2]([F:1])=[CH:3]2)[CH:13]=[CH:12][C:11]=1[N:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:25][CH:24]=2)=[N:15]1
Reactant: COc1cn(-c2ccc(-n3cc(F)c(F)c3)cc2O)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cn(-c2ccc(-n3cc(F)c(F)c3)cc2OC(F)F)nc(-c2ccnn2-c2ccccc2)c1=O
Yield: 75.4 %

Procedure:
A mixture of 1-[4-(3,4-difluoro-1H-pyrrol-1-yl)-2-hydroxyphenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (231 mg), sodium chlorodifluoroacetate (152 mg), potassium carbonate (104 mg), DMF (2.5 mL) and water (0.5 mL) was heated under reflux overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate), and crystallized from hexane/ethyl acetate to give the title compound (193 mg).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(=O)(OC)[O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[CH3:14]>S(=O)(=O)(O)O>[F:13][C:10]1[C:11]([N+:1]([O-:4])=[O:2])=[CH:12][C:7]([OH:6])=[C:8]([CH3:14])[CH:9]=1
Reactant: O=[N+]([O-])O
Reactant: COC(=O)Oc1ccc(F)cc1C
Agent: O=S(=O)(O)O
Product: Cc1cc(F)c([N+](=O)[O-])cc1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
A mixture of concentrated nitric acid (6 ml) and concentrated sulphuric acid (6 ml) was added slowly to a solution of 4-fluoro-2-methylphenyl methyl carbonate (11.34 g, 62 mmol) in concentrated sulphuric acid (6 ml) such that the temperature of the reaction mixture was kept below 50° C. The mixture was stirred for 2 hours, then ice/water was added and the precipitated product collected by filtration. The crude product was purified by chromatography on silica eluting with methylene chloride/hexane progressing through increasingly polar mixtures to methanol/methylene chloride (1/19) to give 4-fluoro-2-methyl-5-nitrophenol (2.5 g, 22%) as a solid. 1H NMR Spectrum: (DMSOd6; CD3COOD) 2.31(s, 3H), 7.38(d, 1H) ,7.58(d, 1H) MS-ESI: 171 [MH]+
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]=1O.P(Cl)(Cl)([Cl:19])=O>CN(C=O)C>[Cl:19][C:3]1[C:2]([Br:1])=[CH:12][C:11]([N+:13]([O-:15])=[O:14])=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cc(Br)c1O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc([N+](=O)[O-])cc(Br)c1Cl
Temperature: 90 °C
Yield: 88.9 %

Procedure:
2.38 kg (8.2 mol) of ethyl 3-bromo-5-nitrosalicylate was dissolved in 3000 ml of DMF, followed by the dropwise addition of 1.26 kg of phosphorus oxychloride at room temperature. The obtained mixture was heated to 90° C. and then maintained at that temperature under heating for 10 hours. The obtained mixture was cooled and then concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate and the obtained solution was washed with water, dehydrated and concentrated under reduced pressure to give 2.25 kg of the title compound as a colorless oil.