Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[F:35][C:36]1[CH:37]=[CH:38][C:39]([O:45][CH3:46])=[C:40](B(O)O)[CH:41]=1>C(OCC)(=O)C>[F:35][C:36]1[CH:41]=[CH:40][C:39]([O:45][CH3:46])=[C:38]([C:2]2[C:3]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:37]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)ncnc21
Reactant: COc1ccc(F)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: COCCOC
Product: COc1ccc(F)cc1-c1ncnc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 100 °C

Procedure:
To a suspension of Example 3A (5 g, 14.79 mmol) in 2:1 1,2-dimethyoxyethane/ethanol (150 mL) was added 2M aqueous sodium carbonate (29.6 mL, 59.1 mmol), (5-fluoro-2-methoxyphenyl)boronic acid (3.02 g, 17.74 mmol) and dichlorobis(triphenylphosphine) palladium(II) (1.038 g, 1.479 mmol). The mixture was heated at 100° C. for 1.5 hours, cooled and diluted with 100 mL ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, water, and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was triturated with dichloromethane, filtered, and dried under vacuum. The filtrate was concentrated to ⅓ volume, and the solid filtered and rinsed with dichloromethane. The remainder of the filtrate was purified by flash chromatography on silica (Analogix 280) eluting with a gradient of 15 to 70% ethyl acetate/hexane. This was combined with the triturated material and dried over vacuum to give the title compound. MS (ESI+) m/z 383.5 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:33]=[CH:32][C:27]5[O:28][CH2:29][CH2:30][O:31][C:26]=5[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:34][N:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[C:40](Cl)=[O:41]>C1COCC1.C(Cl)Cl>[O:28]1[C:27]2[CH:32]=[CH:33][C:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[C:8]([C:4]5[CH:3]=[C:2]([NH:1][C:40]([C:36]6[N:35]([CH3:34])[CH:39]=[CH:38][CH:37]=6)=[O:41])[CH:7]=[CH:6][CH:5]=5)=[N:9][N:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=45)[CH:22]=[CH:21][N:20]=3)=[CH:25][C:26]=2[O:31][CH2:30][CH2:29]1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: Cn1cccc1C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1cccc1C(=O)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)OCCO4)n2)c1
Yield: 91.2 %

Procedure:
To a solution of {4-[2-(3-amino-phenyl)-pyrazolo[1,5-a]pyridin-3-yl]-pyrimidin-2-yl}-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amine (105 mg, 0.24 mmol) in 5 mL THF was added N-methylpyrrole carbonyl chloride (37 mg, 0.26 mmol). When TLC showed the reaction to be complete, the solution was diluted with DCM and washed with a solution of saturated NaHCO3 and with brine. The organic phase was dried over MgSO4 and concentrated. The residue was triturated with diethyl ether to give the title compound as a yellow solid (119 mg, 92%). 1H NMR (400 MHz, d6-DMSO) δ 9.90 (s, 1H), 9.80 (s, 1H), 8.87 (d, J=6.8 Hz, 1H), 8.50 (s, 1H), 8.14 (d, J=6.0 Hz, 1H), 8.05 (s, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.51 (m, 1H), 7.43 (m, 1H), 7.27-7.22 (m, 2H), 7.17 (t, J=6.8 Hz, 1H), 7.05-7.04 (m, 2H), 7.00 (s, 1H), 6.81 (d, J=8.4 Hz, 1H), 6.47 (d, J=6.0 Hz, 1H), 6.08-6.07 (m, 1H), 4.22 (m, 4H), 3.85 (s, 3H) ppm. HRMS calculated C31H25N7O3 [M+H]+ 544.2097 found 544.2101.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6](=O)[CH2:5][C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH3:9])[O:3]1.C(O)C.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:30][OH:31]>O.CC(C)=O>[CH3:1][C:2]1([CH3:19])[C:6](=[N:30][OH:31])[CH2:5][C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH3:9])[O:3]1
Reactant: CCC1(COCc2ccccc2)CC(=O)C(C)(C)O1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)=O
Solvent: O
Product: CCC1(COCc2ccccc2)CC(=NO)C(C)(C)O1
Yield: 94.6 %

Procedure:
The ketone of Example 6 (1 g), ethanol (20 ml) hydroxylamine hydrochloride (280 mg) and potassium carbonate (330 mg) were refluxed together for 2 hours. Thin layer chromatography, using 15% acetone in petrol as eluant, showed partial conversion. Additional quantities of hydroxylamine hydrochloride (280 mg) and potassium carbonate (330 mg) were added three times, with refluxing for 2 hours after each addition. Water was then added, and the mixture was extracted with diethyl ether. The ether extract was dried over magnesium sulphate and evaporated and the residue was purified on a silica gel column using 5% acetone in petrol as eluant to give 1 g (94%) of the desired product.
Reaction SMILES: Cl.C([NH:5][CH2:6][CH2:7][N:8]([CH2:21][CH2:22][C:23]12[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[CH2:24]1)[CH2:30]2)[C:9]([NH:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)=[O:10])(=O)C.[OH-].[Na+].C(Cl)(Cl)Cl>CO.O>[C:23]12([CH2:22][CH2:21][N:8]([CH2:7][CH2:6][NH2:5])[C:9]([NH:11][CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[O:10])[CH2:30][CH:29]3[CH2:28][CH:27]([CH2:26][CH:25]([CH2:31]3)[CH2:24]1)[CH2:32]2
Reactant: CC(=O)NCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCCc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: NCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCCc1ccncc1
Reaction time: 72 h
Yield: 21.7 %

Procedure:
Under ice-cooling, 6 N hydrochloric acid (15 ml) was added to a solution of 1-[2-(acetylamino)ethyl]-1-[2-(1-adamantyl)ethyl]-3-[3-(4-pyridyl)propyl]urea (Compound No. 1-103) (1.02 g, 2.39 mmol) in methanol (10 ml), and the mixture was heated at 90° C. with stirring for three days. The reaction mixture was neutralized with a 1 N aqueous sodium hydroxide solution (10 ml), chloroform (50 ml) and water (10 ml) were added thereto, and layers were separated. The organic layer was washed with a saturated aqueous sodium chloride solution (50 ml) and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 200 mg (21.7%) of the titled compound as an oily matter.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][NH:8][CH:7]=1)=[O:5])[CH3:2].Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([F:14])([F:12])[F:13])=[CH:9][N:8]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][N:17]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: Clc1nccc2ccccc12
Reactant: CCOC(=O)c1c[nH]cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cn(-c2nccc3ccccc23)cc1C(F)(F)F
Temperature: 110 °C
Reaction time: 17 h
Yield: 87.3 %

Procedure:
1.04 g (5 mmol) of 3-ethoxycarbonyl-4-trifluoromethyl-1H-pyrrole and 0.818 g (5 mmol) of 1-chloroisoquinoline are added to 1.73 g (12.5 mmol) of potassium carbonate suspended in 10 mL of dimethyl sulphoxide at a temperature in the region of 20° C. under an argon atmosphere. After stirring for 17 hours at a temperature in the region of 110° C., the reaction mixture is cooled and then diluted with 30 mL of water. The solid formed is filtered off and washed with water and then oven-dried under reduced pressure (2.7 kPa), giving 1.46 g of 3-ethoxycarbonyl-4-trifluoromethyl-1-(isoquinolin-1-yl)-1H-pyrrole in the form of cream-colored crystals. IR spectrum (KBr), 3159; 2983; 2937; 1721; 1628; 1555; 1534; 1502; 1405; 1343; 1290; 1272; 1215; 1179; 1151; 1135; 1120; 1035; 831; 809; 755; 679 and 674 cm−1. Mass spectrum (EI) m/e 334 (M+.), m/e 289.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O.C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>ClCCl>[Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:10]
Reactant: Nc1ccccc1
Reactant: O=C(O)CCCOc1ccc(Cl)cc1Cl
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCOc1ccc(Cl)cc1Cl)Nc1ccccc1
Temperature: -30 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
To a solution of the 4-(2,4-dichloro-phenoxy)-butyric acid (9.8 g, 40 mmol) and triethylamine (6.0 ml, 40 mmol) in dichloromethane (150 mL) was added dropwise isobutyl chlorocarbonate (6 mL, 40 mol) at −30° C. After stirring at −30° C. for 3 h, aniline (4 mL 40 mol) was added dropwise. The reaction mixture was stirred for 3 h at −30° C. and then allowed to warm up to RT. Aqueous HCl (5%, 100 mL) was added and stirring was continued for 0.5 h. The phases were separated, the aqueous layer was extracted with dichloromethane (2×200 mL). The combined organic extracts were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the product (10 g, 77.5%). 1H-NMR (CDCl3): δ 7.49 (d, 2H, J=8.0 Hz), 7.38 (d, 1H, J=2.4 Hz), 7.31 (t, 2H, J=8.0 Hz), 7.18 (dd, 1H, J1=8.8 Hz, J2=2.4 Hz) 7.12 (t, 1H, J=8.0), 6.87 (d, 1H, J=8.8 Hz), 4.12 (t, 2H, J=6.4 Hz), 2.64 (t, 2H, J=6.4 Hz), 2.25 (p, 2H, J=6.4 Hz).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:19]=[C:13]3[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][N:12]3[N:11]=2)[C:5](=[O:8])[NH:6][N:7]=1.[F:20][C:21]1[C:26]([NH:27][C:28]([C:30]2[S:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[CH:31]=2)=[O:29])=[C:25]([CH3:39])[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C(OCC)(=O)C>[F:20][C:21]1[C:26]([NH:27][C:28]([C:30]2[S:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[CH:31]=2)=[O:29])=[C:25]([CH3:39])[C:24]([C:2]2[CH:3]=[C:4]([NH:9][C:10]3[CH:19]=[C:13]4[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][N:12]4[N:11]=3)[C:5](=[O:8])[NH:6][N:7]=2)=[CH:23][CH:22]=1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc(F)c1NC(=O)c1cc2ccccc2s1
Reactant: CN1CCn2nc(Nc3cc(Cl)n[nH]c3=O)cc2C1
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: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Cc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4)c(=O)[nH]n2)ccc(F)c1NC(=O)c1cc2ccccc2s1
Yield: 49.8 %

Procedure:
A microwave tube equipped with a magnetic stirrer was charged with 6-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one (225 mg, 0.80 mmol), N-(6-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzo[b]thiophene-2-carboxamide (463 mg, 1.13 mmol), DME (5 mL) and 1M aqueous sodium carbonate (2 mL). After bubbling Argon while sonicating for 30 sec, Pd(PPh3)4 (65 mg, 0.06 mmol) was added. The mixture was subjected to microwave irradiation at 150° C. for 20 min. After this time, ethyl acetate (10 mL) and water (10 mL) were added. The separated aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organics were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford the title compound N-{6-fluoro-2-methyl-3-[5-({5-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-6-oxo-1,6-dihydropyridazin-3-yl]phenyl}-1-benzothiophene-2-carboxamide (211 mg) in 50% yield.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([CH3:11])([C:7]([F:10])([F:9])[F:8])[C:4](Cl)=[O:5].[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:4](=[O:5])[C:3]([CH3:11])([C:7]([F:10])([F:9])[F:8])[C:2]([F:13])([F:12])[F:1])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: CC(C(=O)Cl)(C(F)(F)F)C(F)(F)F
Product: CC(C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1)(C(F)(F)F)C(F)(F)F

Procedure:
Following the procedure of Example 3, making variations only as required to use (3,3,3-trifluoro-2-methyl-2-trifluoromethylpropionyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (35% yield). 1H NMR (300 MHz, CDCl3) δ 8.02, 7.96, 6.80, 3.91-3.75, 3.58, 1.58-1.48, 0.78-0.63, 0.48-0.43, 0.11-0.04. MS (ES+) m/z 468.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[H][H].Cl[C:21]1[C:30]([CH3:31])=[N:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:21]2[C:30]([CH3:31])=[N:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Reactant: Cc1nc2ccccc2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2nc1Oc1ccc(OCc2ccccc2)cc1
Temperature: 125 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
In a nitrogen atmosphere, a solution of 28.0 g (0.14 mole) 4-benzyloxyphenol in 50 cc dimethylformamide was added dropwise at about 15° C. to 6.0 g (0.14 mole) 57% sodium hydride in 25 cc dimethylformamide. When the evolution of hydrogen ceased, 25.0 g (0.14 mole) 2-chloro-3-methylquinoxaline was added and the reaction mixture was heated at 125° C. for about 2 hours. After standing overnight at room temperature, the reaction mixture was poured into ice-water (~500 cc). The solid product was filtered and crystallized from methanol or acetonitrile to give 36.3 g of the title compound, m.p. 99°-102° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>>[CH3:20][N:21](/[CH:23]=[N:1]/[C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2)[CH3:22]
Reactant: COC(=O)c1cc2ccc(OC)cc2cc1N
Reactant: COC(OC)N(C)C
Product: COC(=O)c1cc2ccc(OC)cc2cc1/N=C/N(C)C
Yield: 64.6 %

Procedure:
According to the procedure of example 97, the reaction mixture of 1.05 g (4.54 mmol) of methyl 3-amino-6-methoxy-2-naphthoate in 20 mL of dimethylformamide dimethylacetal is refluxed for 2.5 hours to give 840.5 mg (64.6%) of methyl 3-{[(E)-(dimethylamino)methylidene]amino}-6-methoxy-2-naphthoate as a beige solid, mp 122–124° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:17][I:18]>>[I-:18].[CH3:17][N+:10]1[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=[C:2]([CH3:1])[C:11]=1[CH3:12]
Reactant: COc1cc2nc(C)c(C)nc2cc1OC
Reactant: CI
Product: COc1cc2nc(C)c(C)[n+](C)c2cc1OC
Product: [I-]
Temperature: 100 °C

Procedure:
5.5 g (0.025 mol) of 2,3-dimethyl-6,7-dimethoxyquinoxaline are dissolved in 30 ml of methyl iodide, in a 100 ml stirred autoclave. This solution is warmed to 100° C over the course of 24 hours. whilst stirring, the pressure rising to about 7 atmospheres gauge. After cooling to room temperature, the yellow precipitate is filtered off, rinsed with a little dry acetone and dried. Yield about 6.5 g, corresponding to 72% of theory. Melting point 210° to 212° C (decomposition). The IR (KBr) and NMR (DMSO-d6) spectra are in agreement with the postulated structure.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([C:13]([F:24])([F:23])[F:12])[CH:19]=3)=[CH:3][N:4]=2)[N:7]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1cccc(-c2cnc3ccc(Cl)nn23)c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 8.6 %

Procedure:
To a solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (2 g, 8.6 mmol) and 3-(trifluoromethyl)phenylboronic acid (1.63 g, 8.6 mmol) in dioxane/H2O (100 mL, 4:1) was added K2CO3 (2.4 g, 17.2 mmol) and Pd(PPh3) 4 (0.497 g, 0.430 mmol), the mixture was stirred at 110° C. for 3 h. The solution was concentrated, partitioned in EtOAc/H2O. The aqueous layer was washed with EtOAc (50 mL) for 3 times. The collected organic layers were dried over Na2SO4, concentrated and purified by column chromatography to give compound 6-chloro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine (0.22 g, 0.739 mmol, yield 9%) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([CH:17]=1)[C:7]([O:9]CC1C=CC=CC=1)=[O:8].[OH-].[Li+].O>O1CCCC1>[Br:1][C:2]1[C:3]([CH2:26][N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:6]([CH:17]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(OCc1ccccc1)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccccc1

Procedure:
To a solution of phenylmethyl 5-bromo-4-(4-morpholinylmethyl)-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 6; 379 mg, 0.76 mmol) in tetrahydrofuran (6 ml) was added lithium hydroxide (110 mg, 4.58 mmol) followed by water (1.5 ml). The reaction was stirred over the weekend, the solvent removed in vacuo and purified by MDAP to yield the title compound as a solid. 249 mg.
Reaction SMILES: [N+]([O-])([O-])=O.[Na+].N[C:7]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[BrH:17]>O.[Cu](Br)Br>[Br:17][C:7]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: Br
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: Br[Cu]Br
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
An aqueous solution of sodium nitrate (2.21 g) in water (15 mL) is added dropwise to a stirred, ice-cooled mixture of 2-amino-4-chlorobenzoic acid (5.00 g, 29.1 mmol) and 48% hydrobromic acid (150 mL) in water (150 mL). The resultant mixture is stirred for 2 hr at 0° C. Then it is treated dropwise with an aqueous solution of copper bromide (7.81 g) in water (20 mL). Upon the completion of the addition, the reaction mixture is allowed to warm to ambient temperature where it is stirred overnight. After extraction with ethyl acetate/hexanes (3:1; 2×400 mL), the combined organic layers are washed with brine (200 mL), dried, concentrated, and chromatographed on silica (1% methyl alcohol and 0.5% acetic acid in chloroform) to give the title compound (4.04 g, 59% yield). mp 154–155° C.; ES(−)MS m/z 233, (M−H)− consistent with 1 Br an 1 Cl.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=2[Cl:16])=[CH:5][CH:4]=1.C([Mg]Cl)(C)C.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C.Cl>C1COCC1.CCCCC>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:14]=[C:13]([B:24]([OH:29])[OH:25])[CH:12]=[CH:11][C:10]=2[Cl:16])=[CH:5][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(COc2cc(I)ccc2Cl)cc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc(COc2cc(B(O)O)ccc2Cl)cc1
Temperature: -50 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a solution of 145 g (387 mmol) of 2-[(4-methoxybenzyl)oxy]-1-chloro-4-iodobenzene in 1.2 L of anhydrous THF, placed under argon and stirred at −50° C., are added dropwise 220 mL (440 mmol) of a 2N solution of iPrMgCl in THF, while maintaining the temperature between −40 and −50° C. The reaction mixture is allowed to warm to −10° C. and stirring is continued for 1 hour. 94 mL (406 mmol) of triisopropyl borate are then added and the reaction mixture is then allowed to warm slowly to 0° C. After stirring for 2 hours, the mixture is treated with 500 mL of aqueous 5N HCl solution and then extracted with ether (2×600 mL). The organic phase is washed with 2×1 L of water, dried over Na2SO4 and then concentrated under reduced pressure. The residue obtained is solidified in 300 mL of pentane, filtered off on a sinter funnel and washed with 200 mL of pentane. 96 g of [3[(4-methoxybenzyl)oxy]-4-chlorophenyl]boronic acid are thus obtained in the form of a white solid.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Br[C@H:7]([CH3:11])[C:8]([OH:10])=[O:9]>C(#N)C>[C:1]([S:3][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])(=[O:4])[CH3:2]
Reactant: C[C@@H](Br)C(=O)O
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC#N
Product: CC(=O)S[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
To a light green solution of potassium thioacetate (3.94 g, 34.5 mmol) in acetonitrile (150 ml) was added a solution of (R)-2-bromopropanoic acid (4.8 g, 31 mmol) in acetonitrile (12 ml) at room temperature under an argon atomosphere. The resulting white slurry was stirred at room temperature for 2 hours then filtered. The filtrate was concentrated in vacuo. The residue was diluted in ethyl acetate (100 ml), washed with a 10% aqueous solution of potassium bisulfate (50 ml) and brine, dried (sodium sulfate), and concentrated in vacuo. The crude product (4.61 g) was purified by flash chromatography (60 g-Merck silica gel, 1:45:54 acetic acid/ethyl acetate/hexane) to afford 3.7 g of the title product as a light yellow oil; [α]D =-114° (c=0.50, methanol).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH2:17][CH2:18][F:19])=[O:16])=[C:11]([F:20])[CH:10]=2)[CH2:4]1.[C:21](SCC)(=[S:23])[CH3:22]>CN(C=O)C>[C:21]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH2:17][CH2:18][F:19])=[O:16])=[C:11]([F:20])[CH:10]=2)[CH2:4]1)(=[S:23])[CH3:22]
Reactant: CCSC(C)=S
Reactant: NC[C@H]1CN(c2ccc(S(=O)CCF)c(F)c2)C(=O)O1
Solvent: CN(C)C=O
Product: CC(=S)NC[C@H]1CN(c2ccc(S(=O)CCF)c(F)c2)C(=O)O1

Procedure:
Prepared analogously to the Method A of General Methods of Preparation of 5-(S)-Thioamidomethyloxazolidinones (Example 1) from 5-(S)-aminomethyl-3-[4′-(2″-fluoroethyl)sulfinyl-3′-fluorophenyl]oxazolidine-2-one (0.100 g, 0.329 mmol) and ethyl dithioacetate. Reaction was performed in DMF overnight. Yield 0.114 g (96%). M.p. 161° C. MS (m/z): [M+H]+=363.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1.[C:20]1([N:26]=[C:27]=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][CH2:9][N:6]2[CH2:5][CH2:4][CH:3]([N:2]([CH3:1])[C:27]([NH:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[S:28])[CH2:8][CH2:7]2)=[CH:12]1
Reactant: CNC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: S=C=Nc1ccccc1
Solvent: c1ccccc1
Product: CN(C(=S)Nc1ccccc1)C1CCN(CCc2c[nH]c3ccccc23)CC1
Reaction time: 24 h

Procedure:
3-[2-(4-Methylaminopiperidyl)ethyl]indole (1.28g, 0.005 mole) was stirred in dry benzene (75 ml) and treated with phenyl isothiocyanate (0.74g, 0.0055 mole). Stirring was continued for 24 hr. and the mixture evaporated to give the title compound, which was converted to the hydrochloride by addition of hydrogen chloride in ethanol and precipitation with ether. Yield, 0.95g, m.p. 193.7°.