Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH2:16][C:17]1[S:18][C:19]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[C:20]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:16][C:17]2[S:18][C:19]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[C:20]([C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: Nc1nc(-c2ccco2)c(N2CCOCC2)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
4-Bromomethylbenzoic acid (2.24 g, 10.4 mmol) was dissolved in toluene (80 mL), and thionyl chloride (7.59 mL, 104 mmol) was added thereto, followed by stirring under heating and reflux for 6 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in THF (50 mL), and 2-amino-4-(2-furyl)-5-morpholinothiazole (2.00 g, 7.97 mmol) obtained in Step 1 of Example 29, triethylamine (1.67 mL, 12.0 mmol) and N,N-dimethylaminopyridine (97.6 mg, 0.800 mmol) were added thereto, followed by stirring under heating and reflux for 1 hour. The reaction mixture was allowed to cool down to room temperature, and then a 10% aqueous solution of sodium carbonate was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:ethyl acetate=9:1) to afford the entitled Compound 59 (3.29 g, 92%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])/[C:5](/[O:29][CH2:30][CH3:31])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][C:8]=1[CH3:28])[CH3:2]>CO.C1COCC1.CC(O)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([O:29][CH2:30][CH3:31])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][C:8]=1[CH3:28])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1C)OCC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1C)OCC
Yield: 94.6 %

Procedure:
A suspension of 400 mg of 2Z-ethoxy-3-{2-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-acrylic acid ethyl ester and 98 mg of Pd/C (10%) in 8 ml of MeOH, 2 ml of THF and 0.5 ml of AcOH was hydrogenated at 22° C./1 bar overnight. The suspension was filtered, the filtrate evaporated and dried to give 380 mg (95%) of the title compound as colourless oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB(C2C=CC=CC=2C(NC2SC=CN=2)=O)O1.[CH3:37][C:38]1[CH:51]=[CH:50][C:41]([C:42]([NH:44][C:45]2[S:46][CH:47]=[CH:48][N:49]=2)=[O:43])=[CH:40][C:39]=1B1OC(C)(C)C(C)(C)O1>CC(O)C>[S:46]1[CH:47]=[CH:48][N:49]=[C:45]1[NH:44][C:42]([C:41]1[CH:40]=[C:39]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)=[CH:4][CH:3]=2)[C:38]([CH3:37])=[CH:51][CH:50]=1)=[O:43]
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nnc(-c2ccc(I)cc2)o1
Agent: CC1(C)OB(c2ccccc2C(=O)Nc2nccs2)OC1(C)C
Solvent: CC(C)O
Product: Cc1nnc(-c2ccc(-c3cc(C(=O)Nc4nccs4)ccc3C)cc2)o1

Procedure:
Example 38 was prepared using 2-(4-iodophenyl)-5-methyl-[1,3,4]oxadiazole (Intermediate 15) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-N-(thiazol-2-yl)-benzamide (Intermediate 22) with propan-2-ol as the solvent.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16].[Br:21][C:22]1[C:23]([F:33])=[C:24]([F:32])[C:25](F)=[C:26]([CH:30]=1)[C:27]([OH:29])=[O:28]>C1COCC1>[Br:21][C:22]1[C:23]([F:33])=[C:24]([F:32])[C:25]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[Cl:13])=[C:26]([CH:30]=1)[C:27]([OH:29])=[O:28]
Reactant: Nc1ccccc1Cl
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
To a solution of i-Pr2NH (25.0 mL, 178 mmol) in THF (200 mL) at 0° C. was added n-BuLi (71.0 mL, 178 mmol, 2.5 M solution in hexanes). After stirring for 15 minutes, this solution was cooled to −78° C. 2-Chloroaniline (12.7 mL, 118 mmol) was added. After vigorous stirring for 10 minutes, a solution of 5-bromo-2,3,4-trifluorobenzoic acid (14.95 g, 58.63 mmol) in THF (30 mL) was added. The dry-ice bath was removed, and the reaction mixture was stirred for 2 hours at room temperature. The mixture was concentrated, treated with 10% aqueous HCl (120 mL), extracted with EtOAc, dried over MgSO4, filtered, and concentrated to give the crude solid which was triturated with boiling CH2Cl2 (125 mL). The yellow solids were filtered, and dried in vacuo to give the desired product (17.4 g, 82%).
Reaction SMILES: [CH2:1]([C@@:3]1([CH2:10][S:11](Cl)(=[O:13])=[O:12])[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4]1)[CH3:2].Cl.[F:16][C:17]([F:34])([F:33])[CH2:18][O:19][C:20]1[CH:32]=[CH:31][C:23]([O:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([C@:3]1([CH2:10][S:11]([N:28]2[CH2:29][CH2:30][CH:25]([O:24][C:23]3[CH:22]=[CH:21][C:20]([O:19][CH2:18][C:17]([F:16])([F:33])[F:34])=[CH:32][CH:31]=3)[CH2:26][CH2:27]2)(=[O:13])=[O:12])[NH:4][C:5](=[O:9])[NH:6][C:7]1=[O:8])[CH3:2]
Reactant: CC[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Reactant: FC(F)(F)COc1ccc(OC2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@]1(CS(=O)(=O)N2CCC(Oc3ccc(OCC(F)(F)F)cc3)CC2)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
[(4S)-4-ethyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (WO 2004/024698) (869 mg) was added to a stirred solution of 4-[4-(2,2,2-trifluoroethoxy)phenoxy]piperidine hydrochloride (750 mg) and triethylamine (1.68 ml) in dichloromethane (50 ml) and the reaction stirred at ambient temperature for 2 hours. The solvents were removed in vacuo and the residue stirred in water for 2 hours. The resulting solid was filtered off, washed with water then ether and dried to give the title compound (1.13 g); NMR Spectrum: (DMSOd6) 0.78 (t, 3H), 1.25 (m, 2H), 1.66 (m, 4H), 1.94 (m, 2H), 3.11 (m, 2H), 3.49 (d, 1H), 3.58 (m, 1H), 4.41 (m, 1H), 4.64 (q, 2H), 6.97 (m, 4H), 8.5 (s, 1H), 10.71 (s, 1H); Mass Spectrum: M−H− 478.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=2[S:22][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[S:22]1[CH:23]=[C:19]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[CH:10][C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)[C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][C:21]1=2.[O:4]1[C:5]2[CH:12]=[CH:11][C:10]([OH:15])=[CH:9][C:6]=2[CH:7]=[CH:8][CH2:3]1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: Brc1csc2ccccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C)c2c(c1C)OC(C)(C#Cc1csc3ccccc13)CC2
Product: Oc1ccc2c(c1)C=CCO2
Reaction time: 96 h
Yield: 66.7 %

Procedure:
A mixture of 4.6 g (20 mmol) of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 6.4 g (30 mmol) of 3-bromobenzo[b]thiophene 0.4 g of triphenylphosphine, 95 mg of cuprous iodide, 6 ml of triethylamine and 150 ml of acetonitrile was degassed with argon for 15 minutes. Palladium acetate, 110 mg, was then added and stirring at room-temperature was continued for 4 days. The solvent was evaporated under reduced pressure and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and evaporated. The residue was chromatographed over 200 g of silica gel using methylene chloride/hexane 1:1(v/v) for elution. Crystallization of the combined clean fractions from ether/hexane yielded 3.3 g (45.5%) of colorless crystals with m.p. 123°-124° C. A lower melting modification with m.p. 88°-91° C. was also observed.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([CH3:17])[C:5]([NH:7][C:8]1[S:12][N:11]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=1)=[O:6].[OH-].[K+].O>C(O)C.C(O)C.O>[CH3:14][C:13]([C:10]1[CH:9]=[C:8]([N:7]2[CH2:2][CH2:3][CH:4]([CH3:17])[C:5]2=[O:6])[S:12][N:11]=1)([CH3:16])[CH3:15]
Reactant: CC(CCCl)C(=O)Nc1cc(C(C)(C)C)ns1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1CCN(c2cc(C(C)(C)C)ns2)C1=O
Temperature: 25 °C
Yield: 46.1 %

Procedure:
To a stirred solution of 0.5 g of 4-chloro-N-[3-(1,1-dimethylethyl)-5-isothiazolyl]-2-methylbutanamide dissolved in 30 ml ethanol was slowly added 0.112 g of potassium hydroxide dissolved in ethanol/water. The mixture was stirred at room temperature for about one-half hour and poured into water. The solution was extracted with diethyl ether, and the organic phase was washed with water, filtered, dried, filtered again, and finally evaporated to dryness under reduced pressure. The product crystallized from Skellysolve B to provide about 0.2 g of 1-[3-(1,1-dimethylethyl)-5-isothiazolyl]-3-methyl-2-pyrrolidinone. Yield 46%. mp 111°-113° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][CH2:16]Cl)[CH2:9][C:10]1[CH:14]=[CH:13][O:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[OH-].[Na+]>O1CCCC1.CCCCCC>[CH2:1]([N:8]1[CH2:15][CH2:16][C:11]2[O:12][CH:13]=[CH:14][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCN(Cc1ccccc1)Cc1ccoc1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1ccc(CN2CCc3occc3C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.209 g (0.837 mmol) of N-benzyl-N-(3-furylmethyl)-2-chloroethylamine in 50 ml of tetrahydrofuran, 1.05 ml (1.67 mmol) of 1.6 M n-butyl lithium in hexane was added under ice-cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to yield 5-benzyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine.
Reaction SMILES: [ClH:1].[C:2]([O:10][C@@H:11]1[C@@H:15]([CH2:16][OH:17])[CH2:14][C@@H:13]([NH:18]C(OC(C)(C)C)=O)[C@@H:12]1[O:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CCOCC.CO>[ClH:1].[C:2]([O:10][C@@H:11]1[C@@H:15]([CH2:16][OH:17])[CH2:14][C@@H:13]([NH2:18])[C@@H:12]1[O:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 N solution of HCl in ether (15 ml) was added in stirring solution of compound 5 (10.0 g, 21.9 mmol) in methanol at 0° C. The mixture was allowed to warm to room temperature gradually and continue stirred for 2 hr. Solvent was evaporated under reduced pressure, and the residue was treated with anhydrous ether (120 mL) to precipitate the product 6. The precipitated product was washed with ether (50 mL×2) afforded the titled compound as white solid. [α]D25-28.190; 1H NMR (500 MHz, DMSO-d6): δ 8.40 (bs, 2H, D2O exchange, NH2), 7.88 (m, 4H), 7.64 (m, 2H), 7.45 (m, 4H), 5.48 (m, 2H), 5.07 (m, 1H), 3.96 (m, 1H), 3.61 (m, 1H), 3.52 (m, 1H), 2.47 and 2.39 (m, 1H), 1.63 (m, 1H); HR-MS Calcd. For (C20H21NO5)+ 355.1420. found 335.1293.
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:10]=[N:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH2:2][CH3:3].Br[CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=2)[C:14]1=O.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:24][O:23][C:18]1[CH:17]=[CH:16][C:15]2[C:14]3[N:11]=[C:8]4[N:9]([C:13]=3[CH2:22][CH2:21][C:20]=2[CH:19]=1)[N:10]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:6]=[CH:7]4
Reactant: CCCOc1ccc(N)nn1
Reactant: COc1ccc2c(c1)CCC(Br)C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCOc1ccc2nc3c(n2n1)CCc1cc(OC)ccc1-3
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A stirred mixture of 6-propoxypyridazin-3-amine (120 mg, 0.78 mmol), 2-bromo-6-methoxy-3,4-dihydronaphthalen-1 (2H)-one (200 mg, 0.78 mmol) in ethanol was heated under reflux for 0.5 hours. The mixture was cooled and sodium bicarbonate (66 mg, 0.78 mmol) added. The mixture was stirred at room temperature for 3 days and evaporated. The residue was extracted with chloroform and the extract washed with saturated, aqueous, sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel. Elution with 1-2% methanol in dichloromethane afforded Compound 121 (30 mg) as a white solid. 1H n.m.r. (CDCl3) δ 1.05, t, J=7.4 Hz, 3H; 1.74-1.94, m, 2H; 3.14, s, 4H; 3.82, s, 3H; 4.28, t, J=6.8 Hz, 2H; 6.60, d, J=9.9 Hz, 1H; 6.78-6.89, m, 2H; 7.77, d, J=9.6 Hz, 1H; 7.87, d, J=7.9 Hz, 1H.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[N:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=2)[CH2:2]1.C(N(CC)CC)C.Cl[C:21]1[N:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:22]=1[C:23]([OH:25])=[O:24]>CO.O1CCCC1>[F:12][C:9]1[CH:10]=[N:11][C:6]([O:5][CH:3]2[CH2:2][N:1]([C:21]3[N:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][C:22]=3[C:23]([OH:25])=[O:24])[CH2:4]2)=[N:7][CH:8]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1Cl
Reactant: Fc1cnc(OC2CNC2)nc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2ncc(F)cn2)C1
Temperature: 80 °C
Yield: 23.1 %

Procedure:
To a mixture of 2-(azetidin-3-yloxy)-5-fluoropyrimidine (D51) (108 mg, 0.638 mmol) and triethylamine (0.11 ml, 0.798 mmol) in methanol (1 ml) and tetrahydrofuran (2 ml), 2-chloro-5-(trifluoromethyl)nicotinic acid (120 mg, 0.532 mmol) was added and the mixture was heated 2 h at 80° C. After solvent evaporation the residue was purified by SPE-Si cartridge (25 g) eluting with a mixture dichloromethane/methanol from 95/5 to 80/20. Collected fraction after solvent evaporation afforded the title compound (D131) (44 mg)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](F)[CH:9]=1)[C:5]#[N:6].Br[C:12]1C=CC=C(Br)C=1C.CN(C=O)C.[Cu]C#N>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: Cc1c(Br)cccc1Br
Reactant: N#Cc1cc(F)cc(Br)c1
Agent: N#C[Cu]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1c(Br)cccc1C#N
Yield: 35 %

Procedure:
This compound was prepared in a manner similar to that described for 3-bromo-5-fluorobenzonitrile from commercially available 2,6-dibromotoluene (1.80 g, 7.20 mmol), DMF (11 mL), pyridine (1.1 mL), and copper (I) cyanide (0.52 g, 5.76 mmol). The crude product was purified by flash column chromatography (100 mL silica, hexane) to afford 50 mg (35%) of 3-bromo-2-methylbenzonitrile. Data for 3-bromo-2-methylbenzonitrile: 1H NMR (400 MHz, acetone-d6) 7.88 (d, J=8.0, 1H), 7.73 (d, J=8.0, 1H), 7.32 (t, J=15.8, 7.9, 1H), 2.58 (s, 3H).
Reaction SMILES: Cl.[O:2]=[C:3]1[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:6][C:5]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:4]1.[Br:23][C:24]1[CH:29]=[C:28]([CH2:30]Br)[C:27]([Cl:32])=[CH:26][C:25]=1[Cl:33]>>[Br:23][C:24]1[C:25]([Cl:33])=[CH:26][C:27]([Cl:32])=[C:28]([CH:29]=1)[CH2:30][N:20]1[CH2:21][CH2:22][C:5]2([O:4][C:3](=[O:2])[N:7]([C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)[CH2:6]2)[CH2:18][CH2:19]1
Reactant: COC(=O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1
Reactant: Clc1cc(Cl)c(CBr)cc1Br
Agent: Cl
Product: COC(=O)c1ccc(N2CC3(CCN(Cc4cc(Br)c(Cl)cc4Cl)CC3)OC2=O)cc1

Procedure:
The title compound was prepared methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate hydrochloride salt (80 mg, 0.245 mmol; Example 1, Step 2) and 1-bromo-5-(bromomethyl)-2,4-dichlorobenzene (86 mg, 0.269 mmol) following essentially the same procedure described in Step 1 of Example 7-9. The title compound was obtained as an off-white solid (129 mg) and was used without further purification.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)N1CCCC=N[NH:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1.B(F)(F)F.[C:38]([O-:41])([O-])=O.[Na+].[Na+].[C:44]([OH:47])(=O)[CH3:45]>O>[O:47]=[C:44]1[C:45]2[C:30](=[CH:29][CH:28]=[CH:33][CH:32]=2)[C:38](=[O:41])[N:17]1[CH2:18][CH2:19][C:20]1[C:19]2[C:18](=[CH:23][CH:22]=[C:21]([S:24]([NH:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)(=[O:25])=[O:26])[CH:20]=2)[NH:17][CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)O
Reactant: O=C1c2ccccc2C(=O)N1CCCC=NNc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Agent: FB(F)F
Agent: [Na+]
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(S(=O)(=O)Nc3ccccc3)cc12

Procedure:
A solution of the product of stage (i) (5.08 g) in glacial acetic acid (40 ml) containing boron trifluride, etherate (6.7 ml) was heated on a steam bath for 15 min, cooled, diluted with water (200 ml) basified (Na2CO3) and extracted with ethyl acetate (2×200 ml). The combined organic extracts were dried (MgSO4) and evaporated in vacuo to give crude 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N-phenyl-1H-indole-5-sulphonamide as a foam (4.8 g). The foam was suspended in ethanol (100 ml) containing hydrazine hydrate (5 ml), heated at reflux for 2 h, cooled, the ethanol removed in vacuo and the residue partitioned between sodium carbonate (2 N, 150 ml) and ethyl acetate (2×150 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give a foam which was purified by flash chromatography eluted with dichloromethane:ethanol:ammonium hydroxide (20:5:0.2) to give the title compound free base (0.57 g) as a solid. The free base was dissolved in a solution of maleic acid (0.21 g) in methanol (10 ml), and the salt precipitated by the addiion of ethyl acetate (100 ml) and dry ether (300 ml). The salt was filtered off and dried in vacuo to give the title compound as a solid. (0.55 g) m.p. 145°-147°.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.C(N(CC)CC)C.[C:19]([C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:37])[C:29]2[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=2[F:36])[CH:24]=[CH:25][CH:26]=1)#[CH:20]>CN(C=O)C.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.[Cu]I>[NH2:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([C:20]#[C:19][C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:37])[C:29]4[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=4[F:36])[CH:24]=[CH:25][CH:26]=3)=[N:7][N:6]2[CH:8]=1
Reactant: Nc1cn2nc(I)ccc2n1
Reactant: C#Cc1cccc(NC(=O)c2cc(C)ccc2F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(F)c(C(=O)Nc2cccc(C#Cc3ccc4nc(N)cn4n3)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the nitrogen bubbled solution of 6-iodo-imidazo[1,2-b]pyridazin-2-ylamine (52 mg, 0.2 mmol, 1 eq) in anhydrous DMF (2 mL) was added triethylamine (0.11 mL, 4 eq), bis(triphenylphosphine)palladium(II) dichloride (14 mg, 0.1 eq), copper(I) iodide (7.6 mg, 0.2 eq), and N-(3-ethynylphenyl)-2-fluoro-5-methylbenzamide (76 mg, 1.5 eq). after the mixture was stirred at room temperature for 30 minutes, it was diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine, and lastly dried with anhydrous sodium sulfate. The upper solution was decanted, concentrated, and the solid residue was subject to a gradient column chromatography [EtOAc-Hex 1:2 to 3:1 (with 1% v/v MeOH added)]. The product fractions were collected, concentrated, the residue was further triturated with ethyl acetate to give N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)ethynyl]phenyl}-2-fluoro-5-methylbenzamide as a yellow solid in amount of 23 mg.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O.O>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=1)=[O:11])([CH3:4])[CH3:5])#[N:2]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Reactant: Nc1cccc(O)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(O)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.8 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)benzoic acid (10 g, 52.8 mmol) produced in Example A7(ii) in tetrahydrofuran (100 mL) were added N,N-dimethylformamide (4 drops) and oxalyl chloride (6.28 mL, 72.0 mmol), and the mixture was stirred at room temperature for 1.5 hr. The solvent was evaporated under reduced pressure to give a residue. To a solution of 3-aminophenol (5.24 g, 48.0 mmol) in tetrahydrofuran (40 mL) was added a suspension of sodium hydrogencarbonate (6.05 g, 72.0 mmol) in water (60 mL), and the mixture was stirred vigorously at room temperature. To this mixture was added dropwise a solution of the residue obtained above in tetrahydrofuran (60 mL) under ice-cooling, and the mixture was stirred at room temperature for 5 hr. The aqueous layer of the reaction mixture was separated, and the organic layer was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and decolorized with activated carbon. The insoluble material was filtered off through a pad filled with two layers of silica gel and celite. The solvent was evaporated under reduced pressure, and the obtained solid was washed with ethyl acetate-hexane mixture to give the title compound (13.03 g, 96%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4](Cl)[N:3]=1.[OH2:9].[CH3:10]CCCCC>O1CCCC1.C[O-].[Na+].CO>[Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:9][CH3:10])[N:3]=1
Reactant: O
Reactant: Clc1cncc(Cl)n1
Reactant: CCCCCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cncc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
After dissolving 7.99 g of 2,6-dichloropyrazine in 100 ml of tetrahydrofuran, 11.3 ml of a 28% sodium methoxide-methanol solution was added dropwise while stirring at room temperature, and stirring was continued overnight. Water was added to the reaction solution, and extraction was performed with n-hexane. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain the title compound (6.96 g, 90% yield).
Reaction SMILES: CO[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH:9]([NH2:15])[CH2:8][C:7]=2[CH:6]=1)=[O:4].[CH2:16]([S:20](Cl)(=[O:22])=[O:21])[CH2:17][CH2:18][CH3:19].[OH:24][NH2:25].[OH-].[K+]>ClCCl>[OH:24][NH:25][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH:9]([NH:15][S:20]([CH2:16][CH2:17][CH2:18][CH3:19])(=[O:22])=[O:21])[CH2:8][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)CC(N)CC2
Reactant: NO
Reactant: CCCCS(=O)(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCS(=O)(=O)NC1CCc2ccc(C(=O)NO)cc2C1

Procedure:
The title compound was prepared in two steps according to Scheme 6 by (1) treating amine VII with n-butylsulfonyl chloride and TEA in dichloromethane, and (2) treating the ester intermediate with aqueous HONH2 and KOH. MS: calc'd (MH+) 327, exp (MH+) 327.4. 1H NMR (CD3OD, 400 MHz), 7.50 (d, 1H, J=7.6 Hz), 7.49 (s, 1H), 7.19 (d, 1H, J=8.0 Hz), 3.68 (m, 1H), 3.14 (m, 3H), 2.79-3.00 (m, 3H), 2.16 (m, 1H), 1.82 (m, 3H), 1.50 (m, 2H), 0.99 (m, 3H).