Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=CC[O:4][C@H:5]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:8]([OH:13])[C@H:7]([OH:14])[C@@H:6]1[OH:15].OCCOC(=O)C=C>>[O:4]=[CH:5][C@H:6]([C@H:7]([C@@H:8]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:13])[OH:14])[OH:15]
Reactant: C=CCO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Agent: C=CC(=O)OCCO
Product: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
An 80 mol % mannose polymer was prepared as in Example A4, except that the amount of allyl-α-D-mannopyranoside was 3.54 g (16 mmol) and the amount of 2-hydroxyethylacrylate was 0.68 g (5.85 mmol).
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:44])[CH2:7][C:8]1[CH:43]=[CH:42][CH:41]=[CH:40][C:9]=1[CH2:10][CH2:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30]3)=[CH:25][CH:24]=2)[N:13]=1.CCOC(C)=O>C1COCC1.CO.O>[C:36]([O:35][C:33]([N:31]1[CH2:32][CH:29]([C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:14]3[N:13]=[C:12]([CH2:11][CH2:10][C:9]4[CH:40]=[CH:41][CH:42]=[CH:43][C:8]=4[CH2:7][C:6]([OH:44])=[O:5])[C:17]([C:18]([F:19])([F:21])[F:20])=[CH:16][N:15]=3)=[CH:28][CH:27]=2)[CH2:30]1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)O)n3)cc2)C1
Temperature: 40 °C
Reaction time: 20 h

Procedure:
LiOH.H2O (0.219 g, 9.131 mmol) was added to a solution of tert-butyl 3-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate (A80) (0.521 g, 0.913 mmol) in THF (10 mL), MeOH (1 mL) and water (1 mL) and the resulting mixture stirred at 40° C. for 20 hours. Additional LiOH.H2O (0.087 g, 3.65 mmol) was added and the mixture heated at 40° C. for a further 24 hours. The volatiles were removed in vacuo and the residue was diluted with 10% citric acid solution (20 mL). Aqueous 1 M HCl (ca 0.5 mL) was then added until a pH of 3 was obtained. EtOAc was added, the layers separated and the aqueous phase extracted with EtOAc (3×20 mL). The combined organics were washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give the title compound A81 as a viscous yellow oil (0.500 g, 98%); 1H NMR (300 MHz, d6-DMSO) δ 9.26 (brs, 1H), 8.52 (s, 1H), 7.57 (d, J=8.5 Hz, 2H), 7.32-7.24 (m, 6H), 4.31 (t, J=8.7 Hz, 2H), 3.97-3.68 (m, 5H), 3.08 (m, 4H), 1.48 (s, 9H). LCMS-B: rt 8.649 min; m/z 557 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([NH:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2(NCc3ccccc3)CC2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(C2(NCc3ccccc3)CC2)cc1
Temperature: 70 °C
Yield: 73.9 %

Procedure:
Using General Procedure D; benzyl-[1-(4-bromophenyl)-cyclopropyl]-amine (Intermediate 124, 110.0 mg, 0.36 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (10.0 mg, 0.05 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (38.0 mg, 0.05 mmol). The resulting reaction mixture was heated to 70° C. for 5 d. The title compound 85 mg (74%) was isolated by chromatography (1-10% EtOAc-hexanes).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:24][C:25]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:26]=1[CH2:27]Br>>[O:19]1[C:18]2[CH:22]=[CH:23][C:15]([N:14]([CH2:27][C:26]3[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:25]=3[F:24])[CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:16][C:17]=2[O:21][CH2:20]1
Reactant: Fc1ccc(Cl)cc1CBr
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc3c(c2)OCO3)CC1
Product: Fc1ccc(Cl)cc1CN(c1ccc2c(c1)OCO2)C1CCNCC1

Procedure:
Using general procedure H with 4-(benzo[1,3]dioxol-5-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 179) (320 mg, 1.0 mmol) and 2-fluoro-5-chlorobenzyl bromide (291 mg, 1.3 mmol) and then using general procedure C afforded benzo[1,3]dioxol-5-yl-(5-chloro-2-fluoro-benzyl)-piperidin-4-yl-amine as a white solid (323 mg, 89% over 2 steps).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[C:18]([Cl:24])[CH:17]=2)[C:11]([C:25](=[O:34])[NH:26][CH2:27][C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:10][N:9]=1.B(Br)(Br)Br.CO.C(=O)([O-])O.[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:24])[CH:17]=2)[C:11]([C:25](=[O:34])[NH:26][CH2:27][C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)=[CH:10][N:9]=1
Reactant: COc1ccc(CNc2nc(N3CCC[C@H]3CO)ncc2C(=O)NCc2ncccn2)cc1Cl
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ncccn1)c1cnc(N2CCC[C@H]2CO)nc1NCc1ccc(O)c(Cl)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 43.3 %

Procedure:
To a solution of (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidylmethyl)carbamoyl]-pyrimidine (307 mg) obtained in Example 1-(5) in methylene chloride (6 ml) is added dropwise boron bromide (300 μl) under ice-cooling. The reaction mixture is stirred at 0° C. for 4 hours, and thereto is added methanol, and then a saturated aqueous sodium hydrogen carbonate solution under ice-cooling. The mixture is extracted with a mixture of ethyl acetate and tetrahydrofuran, and the organic layer is washed successively with water and brine. The mixture is dried over sodium sulfate, and concentrated under reduced pressure to give a slightly brown amorphous (227 mg). The resultant is suspended in chloroform, and the resulting insoluble materials are removed by filtration. The filtrate is subjected to silica gel column chromatography, and further purified by NH-silica gel column chromatography to give (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-hydroxybenzylamino)-5-[N-(2-pyrimidylmethyl)carbamoyl]pyrimidine (129 mg) as a colorless foam, MS (m/z): 470 (MH+), IR (Nujol): 3279, 1632, 1593, 1569, 1518, 1463 cm−1.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH3:18][C:19]([CH3:21])=[O:20].Cl>O1CCCC1.O>[OH:20][C:19]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)([CH3:21])[CH3:18]
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CC(C)=O
Agent: CC(C)[Mg]Cl
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)c1ccc(C(=O)O)cc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a solution of 4-iodobenzoic acid (2.5 g, 10 mmol) in tetrahydrofuran (20 mL) was added lithium chloride (0.42 g, 10 mmol). Then isopropylmagnesium chloride (5 mL, 2 mol/L in tetrahydrofuran) was injected in at −40° C. under nitrogen atmosphere. The reaction mixture was stirred at −40° C. for 1 hour. Then isopropylmagnesium chloride (6 mL, 2 mol/L in tetrahydrofuran) was injected and the reaction was stirred at −40° C. for additional 1 hour. To the solution was added acetone (0.58 g, 10 mmol), and the mixture was stirred at −40° C. for 0.5 hour, then stirred at room temperature for 0.5 hour. After the reaction, the mixture was poured into water (50 mL), hydrochloric acid (3 mol/L) was added to make pH 3-4. and the product was extracted with dichloromethane (50 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (silica gel dichloromethane:methanol=15:1) to give the pure product 4-(2-hydroxypropan-2-yl)benzoic acid (1.5 g, 83%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ: 8.08 (d, J=8.7 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 1.61 (s, 6H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.O.[NH2:14][NH2:15]>C(O)C>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([NH:14][NH2:15])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1cc(NN)ccc1[N+](=O)[O-]
Yield: 74.8 %

Procedure:
To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (2.5 g, 14.60 mmol) in ethanol (25 mL) was added hydrazine hydrate (2.1 g, 43.8 mmol). The reaction mixture was refluxed for 3-4 h. The reaction mixture was concentrated to afford 2.0 g of desired product. 1H NMR (300 MHz, DMSO do): δ 3.84 (s, 3H), 4.46 (s, 2H), 6.31 (d, J=9.3 Hz, 1H), 6.50 (s, 1H), 7.83 (d, J=9.3 Hz, 1H), 8.25 (s, 1H); MS (m/z): (184.01 M)+.
Reaction SMILES: [C:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>C1C=CC=CC=1>[CH3:12][N:13]([CH:15]=[C:4]([C:1](=[O:3])[CH3:2])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:14]
Reactant: CCOC(=O)CC(C)=O
Reactant: COC(OC)N(C)C
Solvent: c1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(C)=O
Yield: 101.6 %

Procedure:
To a solution of ethyl acetylacetate (6 g, 46 mmol) in benzene (100 mL) was slowly added a solution of dimethylformamide dimethylacetal (8.2 g, 69 mmol) in benzene (100 mL) at 25° C. After the addition was complete, the reddish mixture was heated at reflux for 1 h and then evaporated to dryness to give ethyl 2-dimethylaminomethylene-3-oxobutanoate (8.66 g) as a reddish oil. This product (3.25 g, 17 mmol) was allowed to react with 4-chlorophenylhydrazine hydrochloride (3.14 g, 17 mmol) in EtOH (50 mL) at reflux for 8 h. The mixture was evaporated to dryness and the product was isolated by flash chromatography to give ethyl 1-(4-chlorophenyl)-5-methyl-1H-pyrazole-4-carboxylate as a white solid (2.07 g, 46%): mp 55°-56° C.; 1H NMR (80 MHz, CDCl3) δ (TMS) 8.02 (s, 1H, pyrazole), 7.50 (d, J=9, 2H, arom), 7.34 (d, J=9, 2H, arom), 4.33 (q, J=7, 2H, OCH2), 2.56 (s, 3H, Me-pyrazole), 1.37 (t, J=7, 3H, OCH2CH3). Analysis calculated for C13H13ClN2O2 : C 58.99; H 4.95; N 10.58. Found: C 59.03; H 5.06; N 10.58.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].[Cl:8][C:9]1[C:14]([Cl:15])=[C:13](Cl)[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:8][C:9]1[C:14]([Cl:15])=[C:13]([O:7][CH2:3][C:4]#[C:5][CH3:6])[N:12]=[CH:11][N:10]=1
Reactant: CC#CCO
Reactant: Clc1ncnc(Cl)c1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1ncnc(Cl)c1Cl
Temperature: 25 °C
Yield: 94.2 %

Procedure:
In 18 ml of tetrahydrofuran was suspended 0.56 g of sodium hydride (60% in oil), to which 2 ml of a tetrahydrofuran solution containing 0.8 g of 2-butyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes and then cooled to 0° C., to which 3 ml of a tetrahydrofuran solution containing 2 g of 4,5,6-trichloropyrimidine was slowly added dropwise, followed by further stirring at 0° C. for 2 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 2.23 g of 4,5-dichloro-6-(2-butynyloxy)pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[I-:10].[Na+].[OH-].[Na+].Cl[O-].[Na+]>CO>[Cl:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([OH:9])=[C:5]([I:10])[CH:6]=1
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: [I-]
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: CO
Product: Oc1cc(F)c(Cl)cc1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
3-Fluoro-4-chlorophenol (1.78 g, 12.1 mmol) was dissolved in methanol (40 mL). Sodium iodide (3.63 g, 24.2 mmol) and sodium hydroxide (0.97 g, 24.2 mmol) was added, and the solution was cooled to 0° C. Aqueous sodium hypochlorite (6.0% NaOCl, 24.2 mmol) was added dropwise over 75 minutes at 0-3° C. The resulting slurry was stirred for 1 h at 0-2° C. and allowed to warm up to room temperature overnight. White precipitates were observed. The mixture was adjusted to pH 7 using 1M aqueous HCl while stirring. The aqueous layer was extracted with ether for three times and the ether layer was washed with aq sodium thiosulfate, brine, the organic layers were dried with MgSO4. The solvent was removed under reduced pressure to afford the residue which was purified by flash column chromatography on silica gel (Hexanes:Ethyl acetate 1:1 to afford the desired product (1.60 g, 64% yield). 1H NMR: 6.84 (d, 1H, J=9.9 Hz), 7.67 (d, 1H, J=8.1 Hz).
Reaction SMILES: C([O:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[N:7]([C:15](=[O:17])[CH3:16])[CH:6]=1)(=O)C>S(=O)(=O)(O)O>[C:15]([N:7]1[C:8]2[C:13](=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5](=[O:4])[CH2:6]1)(=[O:17])[CH3:16]
Reactant: CC(=O)Oc1cn(C(C)=O)c2ccc(F)cc12
Agent: O=S(=O)(O)O
Product: CC(=O)N1CC(=O)c2cc(F)ccc21
Temperature: 0 °C
Yield: 88.6 %

Procedure:
2.2 g of 3-acetoxy-1-acetyl-5-fluoroindole were added to 20 ml of 90% sulfuric acid and, after stirring for three quarters of an hour, the reaction mixture was diluted with 100 ml of ice-water. The precipitate was filtered off, washed with water and dried. There were obtained 1.6 g (83%) of 1-acetyl-5-fluoroindolin-3-one as beige crystals with a m.p. of 143°-144°.
Reaction SMILES: [N:1]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:6][CH2:5][C:4]2([O:11][C:10]3[CH:12]=[C:13]([C:16]([O:18]C)=[O:17])[CH:14]=[CH:15][C:9]=3[N:8]3[CH:20]=[CH:21][CH:22]=[C:7]23)[CH2:3][CH2:2]1.[Li+].[OH-]>O1CCOCC1.C(OCC)(=O)C>[C:26]([O:25][C:23]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][C:9]=3[N:8]3[CH:20]=[CH:21][CH:22]=[C:7]23)[CH2:5][CH2:6]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)c1ccc2c(c1)OC1(CCN(C(=O)OC(C)(C)C)CC1)c1cccn1-2
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1cc(C(=O)O)ccc1-n1cccc12

Procedure:
A solution of 1′-tert-butyl 7-methyl spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′,7-dicarboxylate (3.5 g, 8.8 mmol) in LiOH (18 mL of 2.0 M, 35.1 mmol) and dioxane (18 mL) was stirred at 55° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and was washed with water. The aqueous layer was acidified with 1N HCl and the product was extracted into ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated to yield 1′-(tert-butoxycarbonyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxylic acid which was used without further purification. ESI-MS m/z calc. 384.4, found 385.3 (M+1)+. Retention time: 1.81 minutes (3 min run).
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]([CH2:12][OH:13])=[C:10]([Cl:14])[N:9]=[C:8]2[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH2:25][C:26]1[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=1>CN(C=O)C>[C:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]([CH2:12][OH:13])=[C:10]([Cl:14])[N:9]=[C:8]2[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:19][CH:20]=1)#[N:33]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(O)cc1
Reactant: N#Cc1ccccc1CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(OCc2ccccc2C#N)cc1
Reaction time: 0.25 h
Yield: 54.7 %

Procedure:
To a solution of 1.00 g of 1-(4-hydroxybenzyl)-2-butyl-4-chloro-5-hydroxymethylimidazole in 15 mL of DMF at 25° was added 0.185 g of sodium methylate, and the resulting mixture was stirred at 25° for 0.25 hours. To this mixture was then added a solution of 0.80 g of α-bromo-o-tolunitrile in 5 mL of DMF. The reaction mixture was stirred at 25° for 16 hours. The solvent was removed in vacuo, and the residue dissolved in ethyl acetate. This solution was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography on silica gel (elution: 10-25% ethyl acetate/benzene) provided 0.76 g of 1-[4-(2-cyanobenzyloxy)benzyl]-2-butyl-4-chloro-5-hydroxymethylimidazole; NMR (200 MHz, CDCl3): δ7.73-7.59 (m, 3H); 7.44 (m, 1H); 6.96 (s, 4H); 5.23 (s, 2H); 5.14 (s, 2H); 4.50 (d, 2H); 2.57 (t, 2H); 1.66 (quint., 2H); 1.33 (sext., 2H); 0.87 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=2)[N:7]=1.FC(F)(F)[C:16](O)=[O:17]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:16]=[O:17])=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=2)[N:7]=1
Reactant: Clc1ccc2nc(C3CC3)cn2n1
Reactant: O=C(O)C(F)(F)F
Product: O=Cc1c(C2CC2)nc2ccc(Cl)nn12
Yield: 45 %

Procedure:
6-chloro-2-cyclopropylimidazo[1,2-b]pyridazine x105 (1.88 g, 9.71 mmol) and hexamethyltetramine (HMTE, 13.61 g, 97.09 mmol, 10 eq) in trifluoroacetic acid (75 ml) are heated at 60° C. during 6 days. After cooling and solvent evaporation under reduced pressure, the crude product is dissolved in dichloromethane (150 ml). The organic layer is washed with water (150 ml) and the resulting aqueous layer is extracted with dichloromethane (150 ml). The cumulated organic layers are dried over MgSO4, filtered and the solvent is removed by evaporation under reduced pressure. The resulting crude compound is purified by preparative chromatography (benzine/AcOEt:80/20) affording 0.82 g of 6-chloro-2-cyclopropylimidazo[1,2-b]pyridazine-3-carbaldehyde x110.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[C:3]=1[C:15]#[N:16].C(O[CH:20](OCC)[N:21]([CH3:23])[CH3:22])C>C1(C)C=CC=CC=1>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:4]2[C:3]([C:15]#[N:16])=[C:2]([N:1]=[CH:20][N:21]([CH3:23])[CH3:22])[NH:6][N:5]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(-c2n[nH]c(N)c2C#N)cc1
Reactant: CCOC(OCC)N(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(-c2n[nH]c(N=CN(C)C)c2C#N)cc1
Temperature: 0 °C

Procedure:
Under a N2 atmosphere, a suspension of 1.87 g (8.16 mmol) of 5-amino-3-(4-methoxy-phenyl)-1H-pyrazole-4-carbonitrile (for preparation see: J. Heterocyclic Chem. 27, 647 (1990)) in 33 ml of toluene is boiled under reflux for 3.5 hours with 1.64 ml of N,N-dimethylformamide diethyl acetal (95%; 9.1 mmol). Crystallization by cooling to 0° C., filtering with suction and washing with hexane yield N'-[3-(4-methoxy-phenyl)-4-cyano-1H-pyrazol-5-yl]-N,N-dimethylformamidine; m.p. 169-171° C.; TLC: Rf =0.18 (ethyl acetate:hexane=1:1); MS: (M)+ =269.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)=[N:12][N:11]3[C:29]=2I)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:37][C:38]1[CH:43]=[C:42](B(O)O)[CH:41]=[CH:40][N:39]=1>O1CCCC1.O.C(Cl)(Cl)Cl.[Pd+2]>[Cl:37][C:38]1[CH:43]=[C:42]([C:29]2[N:11]3[N:12]=[C:13]([N:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[CH:14]=[CH:15][C:10]3=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:41]=[CH:40][N:39]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3nc(-c4ccc(F)cc4)c(I)n3n2)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3nc(-c4ccc(F)cc4)c(-c4ccnc(Cl)c4)n3n2)CC1
Yield: 78.1 %

Procedure:
To a suspension of 1.25 g (2.39 mmol) of tert-butyl 4-[2-(4-fluorophenyl)-3-iodoimidazo[1,2-b]pyridazin-6-yl]piperazine-1-carboxylate in a mixture of tetrahydrofuran and water are added 2.33 g (7.17 mmol) of cesium carbonate and 0.45 g (2.9 mmol) of 2-chloropyridine-4-boronic acid. After sparging with a stream of argon for a few moments, 0.18 g (0.21 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]dichloro)palladium(II) (PdCl2(dppf)) is added and the reaction mixture is refluxed under argon for 18 hours. The solvent is then stripped off under reduced pressure, the residue is taken up in chloroform, the organic phase obtained is washed with water, dried over sodium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The brown solid obtained is purified by chromatography on silica gel (50 g), eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5). The product obtained is crystallized from 20 ml of refluxing acetonitrile to give 0.95 g of a white powder after cooling, filtering off and drying.
Reaction SMILES: [OH2:1].Cl.[C:3](NO)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+]>O1CCOCC1>[C:3]([O:1][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ONC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: c1ccc(C(OC(c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 50 °C

Procedure:
First, to a flask charged with THI (21.20 mmol, 4.88 g) is added water (25 ml) and 1N aqueous HCl (21.2 ml, 21.2 mmol). After all solids dissolved, a solution of trityl hydroxylamine (25.44 mmol, 7.00 g) in dioxane (55 ml) was added and the reaction was maintained at 50° C. for 4 h. At completion, the reaction was cooled room temperature and the solution was adjusted to pH=7 by addition of 1N aqueous NaOH. The neutralized solution was then concentrated to a plastic mass, which was purified by flash chromatography on silica gel [10% MeOH/1% NH4OH (5% wt. solution in water) in DCM] to provide the trityl-ether as clear plastic. Treatment of the plastic mass with hexane and concentration provided a white foam, which could be dried under vacuum to a flakey solid (10.00 g, 97% yield).
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:20]=[C:19]([C:21]([NH2:23])=[O:22])[O:18][N:17]=2)=[CH:12][CH:11]=1)([F:4])[F:3].C1C=C(Cl)C=C(C(OO)=[O:36])C=1>C(Cl)Cl>[F:4][C:2]([F:1])([F:3])[S:5]([C:6]1[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:20]=[C:19]([C:21]([NH2:23])=[O:22])[O:18][N:17]=2)=[CH:12][CH:11]=1)=[O:36]
Reactant: NC(=O)c1cc(-c2ccc(OCc3ccccc3SC(F)(F)F)cc2)no1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: NC(=O)c1cc(-c2ccc(OCc3ccccc3S(=O)C(F)(F)F)cc2)no1
Temperature: 0 °C
Reaction time: 1 h
Yield: 25.8 %

Procedure:
A suspension of 3-[4-(2-trifluoromethylsulfanyl-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (which may be prepared as described in Example 1; 60 mg, 0.153 mmol) in CH2Cl2 (8 mL) was cooled to 0° C. in an ice-water bath. MCPBA (130 mg, 5 equivalents) was added and the mixture was stirred at 0° C. for 1 h and then at room temperature overnight. The reaction mixture was washed with 10% aqueous Na2SO3 and saturated aqueous NaHCO3, dried (Na2SO4), filtered, evaporated and purified by chromatography (35-45% EtOAc/hexanes) to give 3-[4-(2-trifluoromethanesulfinyl-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (16.2 mg, 26%) as a white solid. HRMS Calcd. for C18H14F3N2O4S (M+H)+, 411.0621. Found: 411.0617.