Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][CH2:25]Cl)[N:19]=[CH:18]3)[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:34][CH2:35][C@H:36]1[CH2:40][CH2:39][CH2:38][NH:37]1>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][CH2:25][N:37]2[CH2:38][CH2:39][CH2:40][C@@H:36]2[CH2:35][OH:34])[N:19]=[CH:18]3)[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@H]1CCCN1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c(cnn2CCCl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c(cnn2CCN2CCC[C@@H]2CO)c1
Temperature: 90 °C
Yield: 16.9 %

Procedure:
To a solution of 4-(benzyloxy)-1-(1-(2-chloroethyl)-1H-indazol-5-yl)pyridin-2(1H)-one (0.15 g, 0.40 mmol) in DMF (2.1 mL) was added Cs2CO3 (0.64 g, 2.0 mmol) and (R)-2-hydroxymethylpyrrolidine (0.78 mL, 7.9 mmol). The reaction mixture was heated at 90° C. for 3 h. The reaction mixture was cooled and diluted with H2O (25 mL) and was extracted with EtOAc (3×20 mL) The organic extracts were washed with brine (2×20 mL), dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (silica gel, Hexanes/EtOAc/9:1 MeOH/NH4OH, 1:1:0 to 9:9:2) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×21.2 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) gave the title compound (30 mg, 17%) as a clear film. 1H NMR (500 MHz, CDCl3) δ 8.05 (s, 1H), 7.67 (s, 1H), 7.49-7.46 (m, 1H), 7.42-7.36 (m, 6H), 7.30-7.26 (m, 1H), 6.09-6.08 (m, 2H), 5.06 (s, 2H), 4.50-4.49 (m, 2H), 3.47-3.45 (m, 1H), 3.39-3.37 (m, 1H), 3.28-3.19 (m, 2H), 2.88-2.86 (m, 1H) 2.69 (br s, 1H), 2.60-2.45 (br s, 1H), 2.39-2.38 (m, 1H), 1.86-1.70 (m, 4H); ESI MS m/z 445 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[C:15]([O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=1>C1COCC1.[OH-].[Na+]>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][CH2:2][C@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]2)(=[O:21])=[O:20])=[C:15]([O:23][C:24]([F:26])([F:25])[F:27])[CH:14]=1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CC[C@H](CNS(=O)(=O)c2ccc(Br)cc2OC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of trans-4-aminomethyl-cyclohexanecarboxylic acid (3.14 g, 20 mmol) in THF (20 mL) and 1 M aqueous sodium hydroxide (42 mL) was added a solution of 4-bromo-2-trifluoromethoxy benzenesulfonyl chloride (6.9 g, 20.4 mmol) in THF (20 mL) and the mixture was stirred for 2 hr at ambient temperature. The resulting mixture was concentrated and 1 M aqueous HCl (45 mL) was added. The resulting precipitate was filtered, washed with water and hexanes to give trans-4-[(4-bromo-2-trifluoromethoxy-benzenesulfonylamino)-methyl]-cyclohexanecarboxylic acid (7.18 g, 78%) as a white powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][CH:2]=1.[CH3:7][C:8]([CH3:12])([CH3:11])[CH:9]=[O:10]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[CH3:7]
Reactant: c1cnccn1
Reactant: CC(C)(C)C=O
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1cnccn1
Yield: 11 %

Procedure:
The reaction of pyrazine and trimethylacetaldehyde is conducted in the manner described in Example I on the same molar scale. Preparative thick layer chromatography (2000μ silica gel GF, developed with methylene chloride) of the crude reaction product provides an 11% yield of 1-pyrazinyl-2,2-dimethyl-1-propanone.
Reaction SMILES: [C:1]1([C:7](=[N:17][OH:18])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](OC(=O)C)(=O)[CH3:20]>>[CH3:19][C:20]1[O:18][N:17]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=1
Reactant: CSc1ccc(CC(=NO)c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Product: CSc1ccc(-c2c(-c3ccccc3)noc2C)cc1
Yield: 48 %

Procedure:
5-Methyl-4-[4-(methylthio)phenyl]-3-phenylisoxazole was prepared in 48% yield from the reaction of 1-phenyl-2-[4-(methylthio)phenyl]-ethan-1-one oxime (Step 2) and acetic anhydride according to the procedure outlined in Example 4, Step 1: Mass Spectrum: MH+=282. High resolution mass spectrum Calc'd. for C17H15NOS: 281.0874. Found: 281.0875. Anal. Calc'd. for C17H15NOS: C, 72.57; H, 5.37; N. 4.98; S, 11.39. Found: C, 72.56; H, 5.41; N, 5.00; S, 11.34.
Reaction SMILES: I[C:2]1[C:3]([CH3:14])=[C:4]([C:9]([S:12][CH3:13])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:15][N:16](C)C=O>O.Cl>[C:15]([C:2]1[C:3]([CH3:14])=[C:4]([C:9]([S:12][CH3:13])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])#[N:16]
Reactant: COC(=O)c1c(SC)ccc(I)c1C
Reactant: CN(C)C=O
Agent: Cl
Solvent: O
Product: COC(=O)c1c(SC)ccc(C#N)c1C
Temperature: 150 °C

Procedure:
A mixture of methyl 3-iodo-2-methyl-6-methylsulphenyl-benzoate (16.6 g) and cuprous cyanide (4.4 g) in dimethyl formamide (50 ml) was stirred and heated at 150° C. for 1 hour. The mixture was cooled to 90° C. and a solution of ferric chloride (18 g) in water (28 ml) and concentrated hydrochloric acid (5 ml) was added. The mixture was stirred and heated at 90° C. for 1 hour. The cooled mixture was filtered and the solid was washed with ether. The layers in the filtrate were separated and the aqueous layer was extracted with ether (100 ml). The combined organic layers were washed with water (2×100 ml), aqueous sodium sulphate solution (10%, 2×100 ml), water (2×100 ml), aqueous sodium hydroxide solution (2×100 ml), water (3×100 ml), dried (anhydrous MgSO4) and filtered. The filtrate was evaporated to dryness to give methyl 3-cyano-2-methyl-6-methylsulphenylbenzoate (10.0 g) as a brown oil NMR (CDCl3) 2.5(s,6H), 3.9(s,3H), 7.05(d,1H), 7.45(d,1H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:38]([NH:42][C:43]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)=[O:44])([CH3:41])([CH3:40])[CH3:39].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:48]2[CH:49]=[CH:50][C:45]([C:43]([NH:42][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:44])=[CH:46][CH:47]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)NC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 79.1 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (1.5 g, 2.78 mmol), [4-(tert-butylaminocarbonyl)phenyl]boronic acid (1.3 g, 5.56 mmol) and dichlorobis(triphenylphosphine)palladium (II) (195 mg, 0.28 mmol) in dioxane (8 mL) was added an aqueous sodium carbonate solution (2 M, 3.5 mL, 7 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (250 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 20% ethyl acetate/hexanes) afforded 4-[1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-N-tert-butyl-benzamide (1.2 g, 79.5%) as a light yellow solid: LC/MS m/e calcd for C31H32FN3O3S [M+H]+ 546.69, observed 546.1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([Cl:30])[N:18]=[C:17]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OO)(=[O:39])C>C(O)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([Cl:30])[N:18]=[C:17]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N+:32]=3[O-:39])[N:16]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccccn2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: CC(=O)OO
Solvent: CC(=O)O
Product: COc1ccccc1Oc1c(Cl)nc(-c2cccc[n+]2[O-])nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
A suspension of 525 mg of 4-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(pyridin-2-yl)-pyrimidin-4-yl]benzenesulfonamide in 1 ml of glacial acetic acid was treated with 2.5 ml of 40% peracetic acid and slowly heated to reflux. After 2 minutes the mixture was cooled, evaporated under reduced pressure and the residue was recrystallized from ethyl acetate. There was obtained 2-[4-(4-tert-butyl-phenylsulphonylamino)-6-chloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine 1-oxide of m.p. 201°-202° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.Cl.[CH3:34][NH:35][C:36](=[O:44])[CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:41]3[CH2:40][CH2:39][N:38]([CH2:37][C:36](=[O:44])[NH:35][CH3:34])[CH2:43][CH2:42]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: CNC(=O)CN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)CN1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (150 mg, 0.32 mmol) in DMF (10 mL) was added N-methyl-2-(piperazin-1-yl)acetamide hydrochloride (125 mg, 0.65 mmol), HATU (185 mg, 0.49 mmol), DIEA (126 mg, 0.97 mmol). The resulting solution was stirred at room temperature for 12 h and concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 8% MeOH in DCM. The crude product (180 mg) was purified by Prep-HPLC with the following conditions (3#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 10 mM NH4CO3 and MeCN (26.0% MeCN up to 40.0% in 8 min); Detector, 254/220. This resulted in 73.9 mg (38%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(methylcarbamoyl)methyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. LCMS (Method 20) [M+H]+=602.2, RT=3.66 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.69-8.68 (m, 2H), 8.32 (s, 1H), 7.75 (q, 1H, J=4.8 Hz), 7.63 (dd, 1H, J=2.6, 8.6 Hz), 7.56 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.4, 7.2 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.24 (s, 2H), 3.54 (t, 4H, J=5.0 Hz), 2.95 (s, 2H), 2.63 (d, 3H, J=4.8 Hz), 2.48-2.45 (m, 2H), 2.44-2.41 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([O:16]C)=[O:15])[S:13][C:6]=12.[OH-].[K+]>C1COCC1>[F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([OH:16])=[O:15])[S:13][C:6]=12
Reactant: COC(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Yield: 95.8 %

Procedure:
To a stirred solution of 38 (2.5 g, 7.18 mmol) in THF (50 ml) was added KOH (14.3 ml, 1.0 N in H2O, 14.3 mmol). After 4 hours the reaction mixture was concentrated and the resultant residue was dissolved in H2O (50 ml). The aqueous layer was then washed with ethyl acetate and acidified with 1N HCl (pH=1). The precipitate that formed upon acidification was collected by filtration, washed with water and dried under high vacuum to afford title compound 39 (2.3 g, 96% yield) as a white solid 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.68 (d, J=5.2 Hz, 1H), 8.47 (dd, J=2.8 and 10.4 Hz, 1H), 8.20 (m, 1H), 8.17 (s, 1H), 7.76 (dd, J=8.0 and 8.8 Hz, 1H), 7.04 (d, J=5.2 Hz, 1H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9](Cl)[N:8]=[C:7]([NH2:12])[N:6]=2)[CH2:3][CH2:2]1.[NH3:13]>O1CCOCC1>[CH:1]1([NH:4][C:5]2[N:10]=[C:9]([NH2:13])[N:8]=[C:7]([NH2:12])[N:6]=2)[CH2:3][CH2:2]1
Reactant: Nc1nc(Cl)nc(NC2CC2)n1
Reactant: N
Solvent: C1COCCO1
Product: Nc1nc(N)nc(NC2CC2)n1
Temperature: 140 °C
Yield: 55.8 %

Procedure:
A mixture of 100 g of 2-cyclopropylamino-4-chloro-6-amino-s-triazine, 51 g of anhydrous ammonia and 500 ml of dioxane is heated for 24 hours in an autoclave at 140° C. After cooling to room temperature the solvent is removed by water jet vacuum distillation. 300 ml of water are added to the residue. After stirring, the residue product is filtered off and recrystallised from boiling ethanol. 50 g of 2-cyclopropylamino-4,6-diamino-s-triazine are obtained. Melting point: 219°-222° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CS[C:12]1[N:17]=[C:16]([OH:18])[C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][N:13]=1>C(O)C>[OH:18][C:16]1[C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][N:13]=[C:12]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)[N:17]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: CCOC(=O)c1cnc(SC)nc1O
Solvent: CCO
Product: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1O
Temperature: 25 °C
Yield: 77.1 %

Procedure:
To a solution of indoline (3.58 g, 30 mmol) in ethanol (50 mL) was added ethyl 2-methylthio-4-hydroxypyrimidine-5-carboxylate (5.35 g, 25 mmol) and the mixture was heated under reflux for 18 h. The reaction mixture was allowed to cool to room temperature and the precipitated crystals were collected by filtration. The crystals were washed several times with cold ethanol and dried to give the title compound (5.5 g, 77%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(-n2ccnc2)c(Cl)c1

Procedure:
1.0 g (5.21 mmol) of 3,4-dichloronitrobenzene (Fluka, Buchs, Switzerland), 532 mg (7.81 mmol) imidazole (Aldrich, Buchs, Switzerland) and 1.35 g (10.4 mmol) Hünig's base in 4 ml of DMA are heated in a microwave oven at 180° C. for 1 h 40 min. The reaction mixture is quenched with sat. aqueous NaHCO3 and extracted with EtOAc (2×). The organic layers is washed with sat. aqueous NaHCO3 (3×), with brine, dried over MgSO4, filtered and evaporated. The residue is purified by flash chromatography on silica gel (CH2Cl2-MeOH 1:0 to 93:7) to provide the title compound as an oil. ES-MS: 224 (M+H)+; analytical HPLC: tret=2.11 minutes (Grad 1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[N:10]=2)[N:7]=1>CN(C=O)C.C1COCC1.[Pd]>[N:10]1[C:9]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:7]2
Reactant: N#Cc1cccc(-c2cn3nc(Cl)ccc3n2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2cn3ncccc3n2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.5 %

Procedure:
A mixture of 3-(6-chloroimidazo[1,2-b]pyridazin-2-yl)benzonitrile (1 mmol) and Pd/C (20 mg) in DMF/THF (10 ml/10 ml) was stirred at r.t. for 6 h equipped with a H2 balloon. Then the solvent was removed under reduced pressure and 3-(imidazo[1,2-b]pyridazin-2-yl)benzonitrile was obtained with a yield of 88.5%.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:23][O:24][C:25]1[C:34]([O:35][CH3:36])=[N:33][C:32]2[C:31]([CH:37]=[O:38])=[CH:30][CH:29]=[CH:28][C:27]=2[N:26]=1.[OH-].[Na+]>FC(F)(F)C(O)=O>[CH3:23][O:24][C:25]1[C:34]([O:35][CH3:36])=[N:33][C:32]2[C:31]([CH:37]=[O:38])=[CH:30][C:29]([N+:1]([O-:4])=[O:2])=[CH:28][C:27]=2[N:26]=1
Reactant: COc1nc2cccc(C=O)c2nc1OC
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2cc([N+](=O)[O-])cc(C=O)c2nc1OC
Temperature: 0 °C

Procedure:
44 ml of 100% nitric acid, 44 ml of 97% sulfuric acid and 44 ml of trifluoroacetic anhydride are added in succession to a solution, cooled to 0° C., of 22 g (100.8 mmol) of 2,3-dimethoxy-quinoxaline-5-carbaldehyde in 88 ml of trifluoroacetic acid. The mixture is maintained at 0° C. for 2 hours and is then carefully poured onto a mixture of 4N NaOH and ice. The temperature should not exceed 20° C. The mixture is extracted with ethyl acetate. The organic phase is washed with an aqueous 1 N NaOH solution, water and brine and dried over sodium sulfate. Crystallization of the crude product yields the title compound in the form of light-yellow crystals. M.p.: 147-149° C.; TLC (EtOAc/hexane 1:3): Rf =0.25.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([Br:10])[C:3]=1[O:11][C:12](=[O:16])[O:13][CH2:14]I.[C:17]([OH:20])(=[O:19])[CH3:18]>C([O-])(=O)C.[Ag+]>[Br:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([Br:10])[C:3]=1[O:11][C:12]([O:13][CH2:14][O:20][C:17](=[O:19])[CH3:18])=[O:16]
Reactant: CC(=O)O
Reactant: N#Cc1cc(Br)c(OC(=O)OCI)c(Br)c1
Agent: [Ag+]
Agent: CC(=O)[O-]
Product: CC(=O)OCOC(=O)Oc1c(Br)cc(C#N)cc1Br
Reaction time: 3 h

Procedure:
A solution of carbonic acid iodomethyl ester 2,6-dibromo-4-cyanophenyl ester (0.30 g, 0.65 mmol) in acetic acid (6.5 mL) was added silver acetate (0.33 g, 1.95 mmol). The mixture was stirred for 3 h. The slurry was concentrated to solids and washed with ether. The ether was concentrated to afford the desired product as white solids (240 mg). 1H-NMR (300 MHz, CDCl3) δ (ppm): 2.19 (s, 3H), 5.90 (s, 2H), 7.89 (s, 2H).). 13C-NMR (300 MHz, CDCl3) δ (ppm): 21.0, 83.3, 113.7, 115.7, 119.1, 136.4, 149.9, 169.4, 183.7. Mp=84-86° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[F:13][C:14]1[CH:15]=[C:16]([N:24]=[C:25]=[O:26])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1>C1COCC1>[F:13][C:14]1[CH:15]=[C:16]([NH:24][C:25]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Br:1])=[C:3]([C:9]([F:10])([F:11])[F:12])[CH:4]=2)=[O:26])[CH:17]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:19]=1
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Reactant: O=C=Nc1cc(F)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: O=C(Nc1cc(F)cc(C(F)(F)F)c1)Nc1ccc(Br)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a solution of 4-Bromo-3-(trifluoromethyl)-aniline (132 mg, 0.55 mmol, 1.1 eq.) in dry THF (5 ml) was added 3-Fluoro-5-(trifluoromethyl)-phenylisocyanate (72 μl, 0.5 mmol). After stirring overnight at rt the mixture was diluted with cHexane (20 ml), washed twice with 2 N HCl, once with sat. NaHCO3 and brine (20 ml each) and adsorbed on Celite in vacuo. Flash chromatography on silica with cHexane/TBME (4:1 to 2:1) yielded 111 mg product (50%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][Br:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2c(Br)c(C)ccc2s1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1nc2c(Br)c(CBr)ccc2s1
Yield: 74 %

Procedure:
A mixture of 4-bromo-2,5-dimethyl-1,3-benzothiazole (5.8 g, 24 mmol), N-bromosuccinimide (5.12 g, 28.7 mmol), and benzoyl peroxide (0.580 g, 2.40 mmol) in carbon tetrachloride (100 mL) was heated at reflux overnight. The mixture was diluted with dichloromethane, washed with 1 N NaOH, brine and dried over sodium sulfate, then concentrated under reduced pressure. The residue was purified on silica gel, eluting with 0% to 50% EtOAc in hexane, to give the desired product (5.70 g, 74%). LCMS calculated for C9H8Br2NS(M+H)÷: m/z=319.9; found: 319.8.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([C:16]2[C:20]([Cl:21])=[C:19]([S:22][CH:23]([F:25])[F:24])[N:18]([CH3:26])[N:17]=2)=[CH:11][C:10]=1[OH:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(C(C)=O)C>[Cl:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([C:16]2[C:20]([Cl:21])=[C:19]([S:22][CH:23]([F:25])[F:24])[N:18]([CH3:26])[N:17]=2)=[CH:11][C:10]=1[O:27][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cn1nc(-c2cc(O)c(Cl)cc2F)c(Cl)c1SC(F)F
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: Cn1nc(-c2cc(Oc3ncccn3)c(Cl)cc2F)c(Cl)c1SC(F)F
Temperature: 25 °C
Yield: 78.7 %

Procedure:
A mixture of 2-chloropyrimidine (150 mg), 2-chloro-5-[4-chloro-5-[(difluoromethyl)-thio]-1-methyl-1H-pyrazol-3-yl]-4-fluorophenol (0.3 g) and potassium carbonate (0.18 g) in N,N-dimethylformamide and methyl ethyl ketone (1:4, 20 ml) was heated at reflux overnight. The resulting mixture was allowed to cool to room temperature and partitioned between ethyl acetate and brine. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The organic solution was concentrated in vacuo and the residue purified by column chromatography on silica gel (eluent, ethyl acetate:hexane, 2:3) to give 2-[2-chloro-5-[4-chloro-5-[(difluoromethyl)thio)-1-methyl-1H-pyrazol-3-yl]-4-fluorophenoxy]pyrimidine, (0.29 g).