Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>ClCCl>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 1-(bromomethyl)-4-nitro-benzene (250 mg, 1.157 mmol) in dichloromethane (5 mL) was treated with triethylamine (200 μL, 1.39 mmol) and morpholine (110 μL, 1.27 mmol) then stirred at room temperature for 1.5 hrs. The solution was diluted with dichloromethane (20 mL) then washed with water (2×20 mL). The organic extract was dried (MgSO4), filtered and concentrated to give (i) which was used in subsequent reactions without further purification. 1H NMR (400 MHz, CDCl3) δ 8.21-8.16 (m, 2H), 7.56-7.50 (m, 2H), 3.76-3.69 (m, 4H), 3.59 (s, 2H), 2.49-2.42 (m, 4H).
Reaction SMILES: [CH3:1][Mg]Cl.[Br:4][C:5]1[C:6]([CH:12]=[O:13])=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11]>C1COCC1>[Br:4][C:5]1[C:6]([CH:12]([OH:13])[CH3:1])=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: C[Mg]Cl
Reactant: Cc1ccnc(C=O)c1Br
Solvent: C1CCOC1
Product: Cc1ccnc(C(C)O)c1Br
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 92 %

Procedure:
Methylmagnesium chloride (3.0 mol/L) in THF (0.17 mL, 0.525 mmol) was added dropwise to a solution of 3-bromo-4-methyl-pyridine-2-carbaldehyde (100 mg, 0.50 mmol) in THF (2 mL) cooled at −15° C. After 5 min, the reaction was quenched with a few drops of saturated aqueous ammonium chloride solution. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with water (5 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound as a yellow oil (100 mg, 92%), which was used in subsequent steps without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[C:21]([CH2:29][CH2:30][C:31]([CH3:34])([OH:33])[CH3:32])=[CH:20]1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C>[F:28][C:24]1[CH:23]=[C:22]2[C:27](=[CH:26][CH:25]=1)[N:19]([NH:18][C:15]([C:11]1[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=1)=[O:17])[CH:20]=[C:21]2[CH2:29][CH2:30][C:31]([OH:33])([CH3:32])[CH3:34]
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Reactant: CC(C)(O)CCc1cn(N)c2ccc(F)cc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(CCC(C)(C)O)c2cc(F)ccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (278 mg, 1.2 mmol) and 4-(1-amino-5-fluoro-1H-indol-3-yl)-2-methyl-butan-2-ol (1.2 mmol) in DMF (10 mL) is stirred at 50° C. for 1 h. The mixture is treated with DMTMM (331 mg, 1.2 mmol) and stirred at 50° C. for 1 h. The mixture is concentrated in vacuo, diluted with saturated aqueous Na2CO3 (50 mL), and extracted with EtOAc (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 50% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid [5-fluoro-3-(3-hydroxy-3-methyl-butyl)-indol-1-yl]-amide (330 mg, 61%). MS: 451 (M+H); 1H NMR (300 MHz, CD3OD): δ 9.10 (s, 1H), 8.36 (d, 1H), 8.23 (d, 1H), 7.55 (m, 1H), 7.32 (m, 3H), 7.18 (s, 1H), 7.03 (m, 1H), 3.91 (s, OH, 1H), 2.84 (s, 3H), 2.82 (m, 2H), 1.91 (m, 2H), 1.31 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:35]([F:38])([F:37])[F:36])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][C:28](=[O:30])[NH:27][CH2:26]4)=[O:24])=[C:19]([C:31]([F:34])([F:33])[F:32])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].[Na+].[F:41][C:42]([F:47])([F:46])[CH2:43][CH2:44]I.CC#N>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:35]([F:36])([F:37])[F:38])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][C:28](=[O:30])[N:27]([CH2:44][CH2:43][C:42]([F:47])([F:46])[F:41])[CH2:26]4)=[O:24])=[C:19]([C:31]([F:33])([F:34])[F:32])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: FC(F)(F)CCI
Reactant: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CN1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CN1CCC(F)(F)F
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl)carbonyl]imidazolidin-4-one (80 mg, 0.14 mmol, 1.00 equiv) in N,N-dimethylformamide (5 ml), sodium hydride (11 mg, 0.28 mmol, 2.00 equiv, 60%), 1,1,1-trifluoro-3-iodopropane (153 mg, 0.68 mmol, 5.00 equiv). The resulting solution was stirred overnight at r t. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×10 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 17.8 mg (19%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl)carbonyl]-3-(3,3,3-trifluoropropyl)imidazolidin-4-one as a light yellow solid. (ES, m/z): [M+CH3CN]+ 711.0; 1H NMR (300 MHz, CD3OD): δ8.12-8.22 (m, 2H), 7.99 (s, 1H), 7.89 (d, J=5.4 Hz, 2H), 7.71 (d, J=5.1 Hz, 1H), 5.12 (s, 1H), 4.70 (s, 1H), 4.16-4.47 (m, 3H), 3.86 (s, 1H), 3.57-3.74 (m, 2H), 2.39-2.67 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[CH2:16])[CH:5]=[CH:6][C:7]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:8]=1[C:9]#[N:10])[CH3:2].[H][H]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[CH2:16])[CH2:5][CH2:6][C:7]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:8]=1[C:9]#[N:10])[CH3:2]
Reactant: C=C(C=Cc1ccc(O)cc1C#N)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C=C(CCc1ccc(O)cc1C#N)OCC
Yield: 67.7 %

Procedure:
To a solution of 2-(3-ethoxy-buta-1,3-dienyl)-5-hydroxy-benzonitrile (600 mg) in EtOAc (50 mL) was added 5% Pd/C (0.3 g). The reaction was exposed to hydrogen gas in a Parr apparatus at 60 psi overnight at ambient temperature. The reaction mixture was filtered and concentrated to give the title compound (410 mg). MS [EI] m/z 218 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:13]1([NH2:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1>>[CH:13]1([NH:23][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)=[O:12])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: NC1CCCc2ccccc21
Reactant: O=C(O)c1ccc2c(c1)OCO2
Product: O=C(NC1CCCc2ccccc21)c1ccc2c(c1)OCO2

Procedure:
Prepared in a similar manner to example 4 using benzo[d][1,3]dioxole-5-carboxylic acid and 1,2,3,4-tetrahydronaphthalen-1-amine. MS (M+H, 296.6).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][OH:8])=[NH:6].[CH:12]1([N:15]2[C:19]([CH2:20][CH:21]([CH3:25])[C:22](O)=O)=[CH:18][N:17]=[C:16]2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:14][CH2:13]1.CCN=C=NCCCN(C)C.Cl.C1C=C2N=NN(O)C2=CC=1.O>O.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:22]([CH:21]([CH3:25])[CH2:20][C:19]3[N:15]([CH:12]4[CH2:14][CH2:13]4)[C:16]([C:26]4[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=4)=[N:17][CH:18]=3)[O:8][N:7]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: N=C(NO)c1cccc(Cl)c1
Reactant: CC(Cc1cnc(-c2ccncc2)n1C1CC1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(Cc1cnc(-c2ccncc2)n1C1CC1)c1nc(-c2cccc(Cl)c2)no1
Temperature: 120 °C
Yield: 38.4 %

Procedure:
3-chloro-N-hydroxy-benzamidine (486 mg, 2.85 mmol), 3-(3-cyclopropyl-2-pyridin-4-yl-3H-imidazol-4-yl)-2-methyl-propionic acid (702 mg, 2.59 mmol), EDCl (546 mg, 2.85 mmol) and HOBt hydrate (385 mg, 2.85 mmol) were mixed with DMF (20 ml) and stirred o.n. at r.t. The reaction was diluted with water and extracted with EA. The combined organic phase was successively washed with sat. aq. sodium bicarbonate, brine, dried (Na2SO4), filtered and concentrated in-vacuo. The residue was heated in DMF (10 ml) at 120° C. for 2 h. The reaction mixture was cooled to r.t., diluted with EA (50 ml), successively washed with water and brine, dried (Na2SO4), filtered and concentrated in-vacuo. The crude was purified via column chromatography using 2% MeOH in DCM to isolate the title compound (404 mg). 1H-NMR: 8.69 (dd, 2H), 8.09 (m, 1H), 7.96 (d, 1H), 7.67 (dd, 2H), 7.46 (m, 2H), 6.94 (s, 1H), 3.66 (m, 1H), 3.48 (m, 1H), 3.31 (m, 1H), 3.16 (m, 1H), 1.59 (d, 3H), 1.19 (m, 2H), 0.72 (m, 2H).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])(=[O:3])[CH3:2].Br[C:11]1[CH:12]=[CH:13][C:14]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:30]([CH:31]4[CH2:33][CH2:32]4)=[CH:29][C:28]([CH:34]4[CH2:36][CH2:35]4)=[CH:27][N:26]=3)[CH2:21][CH2:20]2)=[O:18])=[N:15][CH:16]=1>>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:11]2[CH:16]=[N:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[C:30]([CH:31]5[CH2:33][CH2:32]5)=[CH:29][C:28]([CH:34]5[CH2:35][CH2:36]5)=[CH:27][N:26]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)[C:5]1=[O:9])(=[O:3])[CH3:2]
Reactant: O=C(c1ccc(Br)cn1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C4CC4)CC3)nc2)C1=O
Yield: 12.8 %

Procedure:
Using 1-acetyl-2-imidazolidinone (462 mg) and (5-bromopyridin-2-yl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (1.4 g) described in Preparation Example 142 and by the reaction and treatment in the same manner as in Example 1, the title compound (199 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2I)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2[C:32]2[CH:33]=[N:34][CH:35]=[CH:36][C:31]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1I
Reactant: Cc1ccncc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccncc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 110 °C
Yield: 83 %

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-(6-chloro-4-iodo-3-pyridinyl)-N,2-dimethylpropanamide (400 mg, 0.726 mmol), 4-methylpyridine-3 boronic acid (130 mg, 0.944 mmol), sodium carbonate (0.8 mL, 2M), tetrakistriphenylphosphine palladium (7.8 mg, 0.00726 mmol) was added in dioxane (4 mL) and stirred under argon before heating in the microwave at 110° C. for 30 minutes, added more 4-methylpyridine-3 boronic acid (67.5 mg, 0.49 mmol) and tetrakistriphenylphosphinepalladium (7.8 mg, 0.00726 mmol) and heated at 110° C. for 30 minutes. therefore added more 4-methylpyridine-3 boronic acid (51 mg, 037 mmol), tetrakistriphenylphosphinepalladium (7.8 mg, 0.00726 mmol) and heated under microwave conditions at 110° C. for 30 minutes, therefore added 4-methylpyridine-3 boronic acid (47 mg, 0.34 mmol), tetrakistriphenylphosphinepalladium (7.8 mg, 0.00726 mmol) and heated at 110° C. for 30 minutes. Residue partitioned between EtOAc and Brine. Aqueous layer was extracted with EtOAc ×3. Combined extracts were dried and solvent evaporated. Residue purified on a 12+M horizon column eluting with Pet Ether to 1:1 EtOAc: Pet Ether. Unable to isolate clean fractions. Sample sent to be purified by Mass Directed Auto-Prep (MDAP) chromatography, white solid didn't dissolve was found to be desired material. This was combined with product isolated from the MDAP to afford the title compound as a white solid in an 83% yield.
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:38][OH:39].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:26])[NH:38][OH:39])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NO
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NO)cc1)n2C)c1ccccc1
Reaction time: 5 h
Yield: 39 %

Procedure:
1.44 g (3.0 mmol) of 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide, 0.625 g (9.0 mmol) of hydroxylamine hydrochloride and 0.425 g (4.0 mmol) of sodium carbonate were dissolved in 80 mL of ethanol and refluxed for 7 hours. Then a further 210 mg of hydroxylamine hydrochloride and 170 mg of sodium carbonate were added, the mixture was boiled for a further 5 hours and then evaporated down in vacuo. The residue was dissolved in about 30 mL of dichloromethane, the solution obtained was washed with 20 mL of water, the organic phase was dried and evaporated down. The crude product thus obtained was purified by column chromatography (200 g silica gel, dichloromethane +4% ethanol). Yield: 39% of theory, C28H30N6O4 (514.6); Rf value: 0.15 (silica gel; dichloromethane/ethanol=19:1); EKA mass spectrum: (M+H)+=515; (M+Na)+=537; (2M+H)+=1029; (2M+Na)+=1051.
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:20])[C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[O:18][CH3:19])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[S:22]([OH:25])(=[O:24])=[O:23]>C(Cl)(Cl)Cl>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]([O:18][CH3:19])=[C:11]([CH:16]=1)[C:10]([NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:22]([OH:25])(=[O:24])=[O:23])=[CH:5][CH:4]=1)=[O:20]
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(S(=O)(=O)O)cc1

Procedure:
N-phenethyl-5-chloro-2-methoxybenzamide (10 g.) dissolved in 25 ml. of chloroform was cooled to -10° and 19 g. of chlorosulfonic acid was added dropwise, maintaining the temperature at -10° to 0°. After the addition was complete the mixture was allowed to rise to room temperature and it was poured onto cracked ice. The crude sulfonic acid was filtered and 7.3 g. (57%) was obtained. A sample recrystallized for analysis from alcohol-acetonitrile melted at 188°-189°. Anal. Calcd. for C16H16ClNO5S: C, 51.94; H, 4.36; Cl, 9.58; N, 3.79; S, 8.67. Found: C, 50.10; H, 4.27; Cl, 9.93; N, 4.04; S, 8.84.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[ClH:5].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[C:11]([OH:13])=[O:12]>C(O)(C(F)(F)F)=O>[ClH:5].[CH3:6][O:7][C:8]1[C:16]([O:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:15][C:14]([N+:1]([O-:4])=[O:2])=[C:10]([CH:9]=1)[C:11]([OH:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(=O)O)ccc1OCCCN1CCCC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OCCCN1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
Fuming nitric acid (2.4 ml, 57.9 mmol) was added slowly at 0° C. to a solution of 3-methoxy-4-(3-(pyrrolidin-1-yl)propoxy)benzoic acid hydrochloride (12.15 g, 38.17 mmol) in TFA (40 ml). The cooling bath was removed and the reaction mixture stirred at ambient temperature for 1 hour. The TFA was removed by evaporation and ice/water was added to the residue and the solvent removed by evaporation. The solid residue was dissolved in dilute hydrochloric acid (pH2.2), poured onto a Diaion (trade mark of Mitsubishi) HP20SS resin column and eluted with methanol (gradient 0 to 50%) in water. Concentration of the fractions by evaporation gave a precipitate which was collected by filtration and dried under vacuum over phosphorus pentoxide to give 5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)benzoic acid hydrochloride (12.1 g, 90%).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[N:14]=[C:13]([SH:15])[CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:3][CH:2]=1.[OH2:17].[OH2:18].[OH2:19].O.O.O.O.O.[OH-].[Ba+2].[OH-]>O>[C:1]1([CH3:16])[CH:2]=[CH:3][C:4]([C:7]([C:9]2[N:14]=[C:13]([S:15]([OH:19])(=[O:18])=[O:17])[CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C(=O)c2cccc(S)n2)cc1
Reactant: O
Agent: [Ba+2]
Agent: [OH-]
Product: Cc1ccc(C(=O)c2cccc(S(=O)(=O)O)n2)cc1
Yield: 80.6 %

Procedure:
This thiol (9.16 g) was dissolved in a solution of barium hydroxide octahydrate (12.62 g) in water (250 ml) and the solution filtered. To the stirred and ice-cooled solution was then added dropwise 30% aqueous hydrogen peroxide (14.0 ml). After allowing to warm to room-temperature the mixture was heated on the steam bath for one hour with stirring. The resultant solution was filtered hot and then allowed to cool whereupon the barium salt of the sulphonic acid crystallised from solution. To the suspension of the barium salt was added with stirring 1.0N aqueous sulphuric acid (40 ml) and the resultant mixture heated on the steam bath for 15 minutes and then allowed to cool. The precipitate of barium sulphate was filtered off and the filtrate concentration to dryness in vacuo and the residue treated with ethanol and reconcentrated to dryness. Trituration with ethanol, filtration and washing with acetone gave 6-(4-toluoyl)pyridine-2-sulphonic acid (8.93 g) as a yellow solid. M.p.>300°.
Reaction SMILES: [OH:1][OH:2].S(=O)(=O)(O)O.[CH3:8][C:9](O)([CH2:11][CH2:12][C:13]([CH3:16])([OH:15])[CH3:14])[CH3:10]>O>[CH3:14][C:13]([O:15][O:15][C:13]([CH3:16])([CH3:14])[CH3:12])([CH2:12][CH2:11][C:9]([CH3:10])([O:1][O:2][C:9]([CH3:11])([CH3:10])[CH3:8])[CH3:8])[CH3:16]
Reactant: CC(C)(O)CCC(C)(C)O
Reactant: OO
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(C)OOC(C)(C)CCC(C)(C)OOC(C)(C)C
Reaction time: 1 h
Yield: 90 %

Procedure:
A reactor corresponding to FIG. 1 was initially charged with a mixture of 550 kg of 70% by weight hydrogen peroxide and 366 kg of 80% by weight sulphuric acid. With stirring and cooling of the reactor through the jacket, 250 kg of 2,5-dimethyl-2,5-hexanediol were metered in within 60 min, in the course of which the temperature rose from 20° C. to 30-32° C. The reaction mixture was stirred at 30° C. for another 90 min and then admixed with 200 kg of water. The stirrer was then switched off and the suspension formed was filtered within 10 min by applying reduced pressure to the filtration devices (5), in the course of which the liquid phase was sucked into the collecting vessel (7) and the precipitated 2,5-dimethylhexane-2,5-dihydroperoxide was retained in the vessel (2). The solid product retained in the reactor was washed by adding 500 kg of water, stirring the suspension for 3 min and filtering again by applying reduced pressure to the filtration devices (5). This washing operation was repeated once more. Thereafter, 481 kg of tert-butanol were added and the solid was dissolved therein by stirring and heating. 500 kg of 80% by weight sulphuric acid were metered into the resulting solution within 60 min with stirring and cooling of the reactor through the jacket, in the course of which the temperature rose to from 40 to 45° C. The reaction mixture was stirred at this temperature for a further 60 min and then admixed with 50 kg of water. The lower aqueous phase was removed and the liquid product was washed successively with 150 kg of water, 150 kg of 1% by weight sodium hydroxide solution and 150 kg of water, by stirring the phases and then removing the lower aqueous phase. After removal of residual water and volatile by-products by stripping under reduced pressure in a stripping column, 405 kg (90%) of 2,5-dimethyl-2,5-di(tert-butylperoxy)hexane were obtained.
Reaction SMILES: COC(=O)[NH:4][C:5]1[N:6]=[C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[O:22])[NH:20][CH3:21])[CH:14]=3)[CH:10]=[N:9][N:8]2[C:23]=1Br.[Cl:26][C:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[CH:29][N:28]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[NH2:4][C:5]1[N:6]=[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=3)[C:19]([NH:20][CH3:21])=[O:22])[CH:10]=[N:9][N:8]2[C:23]=1[C:31]1[CH:30]=[CH:29][N:28]=[C:27]([Cl:26])[CH:32]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CNC(=O)c1cccc(-c2cnn3c(Br)c(NC(=O)OC)nc3c2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1cccc(-c2cnn3c(-c4ccnc(Cl)c4)c(N)nc3c2)c1

Procedure:
[3-Bromo-7-(3-Methylcarbamoyl-phenyl)-imidazo-[1,2-b]-pyridazin-2-yl]-carbamic acid methyl ester (1 eq, 0.159 mmol, 65 mg) and 2-chloropyridine-4-boronic acid (1.2 eq, 0.191 mmol, 30.1 mg) are dissolved in DME (3 ml) and water (0.75 ml) and Na2CO3 (3 eq, 0.478 mmol, 50.6 mg) is added. PdCl2(PPh3)2 (0.05 eq, 0.008 mmol, 5.59 mg) is then added and the reaction mixture is heated using microwave radiation at 120° C. for 50 min. At the completion of this time the solvent is evaporated and the reaction mixture is dissolved in MeOH, filtered and the solvent is removed in vacuo to yield 3-[2-Amino-3-(2-Chloro-pyridin-4-yl)-imidazo -[1,2-b]-pyridazin-7-yl]-N-methyl benzamide as a yellow solid; [M+H]+=379