Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[N:20]1([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCOC(C)=O>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:30][C:29]2[CH:28]=[CH:27][C:26]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:32][CH:31]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1ccc(N2CCCCC2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)N1C(=O)C(Nc2ccc(N3CCCCC3)cc2)=C(c2ccccc2)S1(=O)=O
Yield: 50 %

Procedure:
A solution of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150 g, 0.50 mmol) and 4-piperidinoaniline (0.176 g, 1.00 mmol) in DMF (2 mL) was heated at 120° C. for 15 mins in a microwave reactor. EtOAc was then added and the resulting mixture was washed with brine and evaporated. The residue was purified by silica gel column chromatography using a 9:1 mixture of petroleum ether and EtOAc as eluant, to give the title compound (0.110 g, 50%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.22-7.18 (m, 1H), 7.16-7.05 (m, 5H), 6.58 (d, 2H), 6.54 (d, 2H), 3.02 (t, 4H), 1.80 (s, 9H), 1.70-1.62 (m, 4H), 1.58-1.54 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 160.3, 149.9, 131.3, 129.6, 128.8, 128.1, 127.8, 125.3, 123.5, 116.3, 109.4, 61.9, 51.1, 27.9, 25.7, 24.4; Mass Spectrum: M+H+ 440.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][O:16][C:17]2=[O:18].C[O-].[Na+]>C(OCC)(=O)C.CO>[CH3:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15](=[O:16])[CH:4]([C:3]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:10])[C:17]2=[O:18]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: COc1cccc2c1COC2=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cccc2c1C(=O)C(c1c(Cl)cccc1Cl)C2=O
Yield: 82.4 %

Procedure:
A solution of 2,6-dichlorobenzaldehyde (5.98 grams, 0.034 mole) and 4-methoxyphthalide (5.6 grams, 0.34 mole) in 20.5 milliliters of ethyl acetate was added to a solution of sodium methoxide in methanol (prepared from 2.36 grams of sodium metal and 34 milliliters of methanol). The mixture was then heated under reflux for 1 hour. The bulk of the ethyl acetate and methanol was removed under reduced pressure. The residue was dissolved in water and the solution filtered from insoluble material. Acidification of the filtered alkaline solution afforded 9.0 grams of a yellow solid which was recrystallized from ethanol to give 6.5 grams (59.3%) of the title compound, melting point 163°-165°C. Calc'd: C, 59.83, H, 3.14; Found: C, 59.55, H, 3.19.
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[C:6]([C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)[CH:7]=[CH:8][CH:9]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:47]([O:53][CH2:54][CH3:55])(=[O:52])[CH2:48]C(C)=O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:54]([O:53][C:47](=[O:52])[CH2:48][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)[CH:5]=1)[CH3:55]
Reactant: CC1(c2cccc(Br)c2)OCCO1
Reactant: CCOC(=O)CC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)Cc1cccc(C2(C)OCCO2)c1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 2-(3-bromo-phenyl)-2-methyl-[1,3]dioxolane (3.620 g, 14.89 mmol), 2-di-t-butylphosphino-2′-methylbiphenyl (931 mg, 2.98 mmol), tri-potassiumphosphate monohydrate (11.063 g, 52.12 mmol) and palladium(II)acetate (334 mg, 1.49 mmol) in toluene (74 mL) was treated with ethyl acetoacetate (2.45 mL, 19.36 mmol). The reaction mixture was heated at 90° C. for 2 h followed by 4 h at 100° C. The reaction mixture was cooled to rt, water (100 mL) was added and the mixture was stirred for 30 min at rt. The org. layers was separated and washed twice with 5% aq. NaCl (50 mL), brine (50 mL) dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (4:1 hept-EA) gave the title compound as an orange oil. TLC: rf (4:1 hept-EA)=0.37. LC-MS-conditions 02: tR=0.96 min, [M+H]+=251.21.
Reaction SMILES: [CH2:1]([Sn:9](=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13]CCCC)[CH2:2][CH2:3][CH2:4]CCCC.[CH3:19][CH:20]([CH3:24])[CH2:21][CH2:22][OH:23]>>[CH2:10]([Sn:9]([CH2:1][CH2:2][CH2:3][CH3:4])([O:18][CH2:22][CH2:21][CH:20]([CH3:24])[CH3:19])[O:18][Sn:9]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:1][CH2:2][CH2:3][CH3:4])[O:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH3:19])[CH2:11][CH2:12][CH3:13]
Reactant: CC(C)CCO
Reactant: CCCCCCCC[Sn](=O)CCCCCCCC
Product: CCCC[Sn](CCCC)(OCCC(C)C)O[Sn](CCCC)(CCCC)OCCC(C)C
Temperature: 25 °C
Yield: 99 %

Procedure:
972 g (2.7 mol) of di-n-octyl tin oxide (Sankyo Organic Chemicals Co., Ltd., Japan) and 2100 g (23.9 mol) of 3-methyl-1-butanol were placed in a 5000 mL volumetric pear-shaped flask. The flask was connected to an evaporator to which was connected an oil bath equipped with a temperature controller, a vacuum pump and a vacuum controller. The purge valve outlet of the evaporator was connected to a line containing nitrogen gas flowing at normal pressure. After closing the purge valve of the evaporator to reduce pressure inside the system, the purge valve was opened gradually to allow nitrogen to flow into the system and return to normal pressure. The oil bath temperature was set to about 145° C., the flask was immersed in the oil bath and rotation of the evaporator was started. After heating for about 40 minutes in the presence of atmospheric pressure nitrogen with the purge valve of the evaporator left open, distillation of 3-methyl-1-butanol containing water began. After maintaining in this state for 7 hours, the purge valve was closed, pressure inside the system was gradually reduced, and excess 3-methyl-1-butanol was distilled with the pressure inside the system at from 74 to 35 kPa. After the fraction no longer appeared, the flask was taken out of the oil bath. After allowing the flask to cool to the vicinity of room temperature (25° C.), the purge valve was opened gradually and the pressure inside the system was returned to atmospheric pressure. 1176 g of reaction liquid were obtained in the flask. Based on the results of 119Sn-, 1H- and 13C-NMR analyses, 1,1,3,3-tetra-n-butyl-1,3-bis(3-methylbutyloxy) distannoxane was confirmed to have been obtained at a yield of 99% based on the di-n-octyl tin oxide. The same procedure was then repeated 12 times to obtain a total of 14120 g of 1,1,3,3-tetra-n-octyl-1,3-bis(3-methylbutyloxy) distannoxane.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[C:13]1[N:14]([CH2:17][CH:18](O)[CH3:19])[CH:15]=[CH:16][C:12]=1[CH2:11]2.C(N(CC)CC)C.[N-:33]=[N+:34]=[N-:35].[Na+]>ClCCl.CN(C)C=O.O>[N:33]([CH:18]([CH3:19])[CH2:17][N:14]1[CH:15]=[CH:16][C:12]2[CH2:11][C:10]3[C:21]([C:13]1=2)=[CH:22][C:23]([O:24][CH3:25])=[C:8]([O:7][CH3:6])[CH:9]=3)=[N+:34]=[N-:35]
Reactant: COc1cc2c(cc1OC)-c1c(ccn1CC(C)O)C2
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)-c1c(ccn1CC(C)N=[N+]=[N-])C2
Yield: 40.3 %

Procedure:
0.52 ml of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 0.91 g of (RS)-1-(1,4-dihydro-6,7-dimethoxy-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 1.86 ml of triethylamine in 25 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 140 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 40 ml of anhydrous dimethylformamide, treated with 0.43 g of sodium azide and the reaction mixture was heated to 60° for 15 hours while stirring. After cooling, the solution was poured into 140 ml of water and extracted twice with 140 ml of ethyl acetate each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene/ethyl acetate 4:1). 400 mg (40%) of (RS)-1-(2-azido-propyl)-1,4-dihydro-6,7-dimethoxy-indeno[1,2-b]pyrrole were obtained as an oil which was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]2[N:12](COCC[Si](C)(C)C)[N:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[N:29][C:28]=23)=[O:23])[CH:7]=1.Cl>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[N:29][C:28]=23)=[O:23])[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1c(NC(=O)c2cnn3cccnc23)cnn1COCC[Si](C)(C)C
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(Cl)cc1-c1[nH]ncc1NC(=O)c1cnn2cccnc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
To a solution of N-(5-(5-chloro-2-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (2.75 g, 5.51 mmol) in 105 mL ethanol was added HCl (8.0 mL of a 5 M solution in water, 40 mmol). The reaction mixture was then stirred at 70° C. for 2 hours. After cooling to room temperature, the product was filtered as a light yellow solid, rinsing with methanol and diethyl ether. The filtrate was reduced in volume, and more solid product filtered. The combined collected solids were dried under vacuum to yield 1.81 g (89%) of N-(5-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=369.2; 1H NMR (400 MHz, DMSO-d6) δ: 9.66 (s, 1H), 9.33 (dd, J=7.0, 1.6, 1H), 8.78 (dd, J=4.2, 1.6, 1H), 8.65 (s, 1H), 8.20 (s, 1H), 7.50 (dd, J=8.8, 2.7, 1H), 7.44 (d, J=2.7, 1H), 7.29 (dd, J=7.8, 4.8, 2H), 3.86 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:12][CH3:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1cc2cncnc2cc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2cncnc2cc1OCCCCl
Temperature: 40 °C
Yield: 85.7 %

Procedure:
A mixture of 44-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (957 mg, 3 mmol), (prepared as described for the starting material in Example 2), 1-bromo-3-chloropropane (2.36 g, 15 mmol) and potassium carbonate (2.1 g, 15 mmol) in DMF (20 ml) was heated at 40° C. for 1.5 hours. The mixture was allowed to cool, was diluted with water and extracted with ethyl acetate (3×50 ml). The organic extracts were combined, washed with water and brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was triturated with hexane/ethyl acetate, collected by filtration and dried under vacuum to give 4-chloro-2-fluoroanilino)-7-(3-chloropropoxy)6-methoxyquinazoline (650 mg, 55%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:26]I>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])[CH3:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Br)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)C1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-(2-Bromo-phenylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (0.50 g, 1.30 mmol) was dissolved in dry N,N-dimethylformamide (5.0 mL). To the reaction mixture was then added at 0° C. sodium hydride (60% in mineral oil, 62.6 mg, 1.56 mmol) under nitrogen atmosphere and the reaction mixture was stirred at 0° C. for one hour. To the reaction mixture was then added at 0° C. methyl iodide (0.241 g, 1.70 mmol). The reaction mixture was stirred at 0° C. for one hour, then at room temperature under nitrogen atmosphere for 3 hours. The reaction mixture was then added into an excess of water-ice and a gum formed. The gum was filtered by suction, washed with water and dried to yield a crude solid. The crude solid was purified via flash chromatography (25% ethyl acetate/hexanes) to yield the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:28]1[N:29]=[C:30]([NH:33]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:31][CH:32]=1)[C:5]([NH:7][CH:8]1[C:26](=[O:27])[N:10]2[C:11]([C:23]([OH:25])=[O:24])=[C:12]([CH:15]=[CH:16][C:17]3[S:21][CH:20]=[N:19][C:18]=3[CH3:22])[CH2:13][S:14][C@H:9]12)=[O:6].FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C1(OC)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][N:3]=[C:4]([C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1)[C:5]([NH:7][CH:8]1[C:26](=[O:27])[N:10]2[C:11]([C:23]([OH:25])=[O:24])=[C:12]([CH:15]=[CH:16][C:17]3[S:21][CH:20]=[N:19][C:18]=3[CH3:22])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=Cc3scnc3C)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=Cc3scnc3C)CS[C@H]12)c1csc(N)n1
Reaction time: 0.5 h

Procedure:
7-[2-Methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid (syn-isomer) pivaloyloxymethyl ester (0.160 g) was dissolved in anisole (0.5 ml). The resultant solution was admixed with trifluoroacetic acid (1.15 ml) under ice-cooling, followed by stirring for 30 minutes again under ice-cooling. The reaction solution was mixed with isopropyl ether (30 ml), and the powder substance deposited was recovered by filtration and washed with isopropyl ether. The solid obtained was dissolved in ethyl acetate (20 ml), washed with ice-coole aqueous saturated sodium hydrogen carbonate solution (10 ml). The organic phase was separated from the aqueous phase, dried over anhydrous sodium sulfate and concentrated under reduced pressure. 7-[2-Methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid (syn-isomer) pivaloyloxymethyl ester (0.083 ) was thus obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([F:14])=[C:8]([N+:11]([O-])=O)[CH:9]=2)[NH:4][N:3]=1.Cl[Sn]Cl>CCO.CCOC(C)=O.[OH-].[Na+]>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([F:14])=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)n[nH]c2cc1F
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc2c(Cl)n[nH]c2cc1F
Temperature: 70 °C
Yield: 50.5 %

Procedure:
The product from Step 1 (575 mg, 2.667 mmol, 1.0 equiv) was dissolved in 15 mL EtOH and SnCl2 (2.5 g, 13.337 mmol, 5.0 equiv) was added. The reaction mixture was heated to 70° C. for 4 hours. The reaction mixture was diluted with EtOAc and 6N NaOH, filtered through a pad of celite and washed with EtOAc and water. The phases of the filtrate were separated, and the organic phase was washed once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (20-100% EtOAc in Hexanes) to provide 250 mg (51%) of the title compound as a yellow solid. MS (ES+) m/e 186 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[C:9](OCC)=[O:10])=[C:4]([O:16][CH3:17])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[CH2:9][OH:10])=[C:4]([O:16][CH3:17])[CH:3]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(Br)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Br)ccc1C(C)(C)CO
Temperature: 0 °C
Reaction time: 4 h
Yield: 91.1 %

Procedure:
To a stirred solution of ethyl 2-(4-bromo-2-methoxyphenyl)-2-methylpropanoate (110 mg, 0.36 mmol) in THF (4 mL) was added 1M solution of lithium aluminum hydride in THF (0.4 mL, 0.4 mmol) at −60° C. and the reaction mixture was warmed up to 0° C. in 40 min (the starting material is still present by TLC) and then allowed to stir at room temperature for 4 hours—now the starting material is consumed (TLC). A solution of sodium hydroxide (105 mg) in water (0.2 mL) was added and the mixture was stirred at room temperature for 30 min. Then 3 mL of methylene chloride (3 mL), silica gel (1 g), and anhydrous magnesium sulfate (1 g) were added and the mixture was stirred for 2 hours. Solids were filtered off and mother liquor was concentrated to give the title compound (85 mg). By GCMS, this is a mixture of the target primary alcohol and de-brominated primary alcohol (40% of the desired product by GCMS). This mixture was used for the next step without purification. GCMS (ES+) 258 (M+).
Reaction SMILES: [I-].[OH:2][C:3]([CH3:30])([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[C:36]([O:39][C@H:40]1[CH2:44][CH2:43][C@H:42]([CH:45]=O)[C@H:41]1[CH2:47][CH2:48][S:49][C:50]1[S:51][CH:52]=[C:53]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[N:54]=1)(=[O:38])[CH3:37]>O1CCCC1>[C:36]([O:39][C@H:40]1[CH2:44][CH2:43][C@H:42](/[CH:45]=[CH:5]/[CH2:4][C:3]([OH:2])([CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C@H:41]1[CH2:47][CH2:48][S:49][C:50]1[S:51][CH:52]=[C:53]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[N:54]=1)(=[O:38])[CH3:37]
Reactant: CCCCCC(C)(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1csc(SCC[C@H]2[C@@H](OC(C)=O)CC[C@@H]2C=O)n1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCC(C)(O)C/C=C/[C@H]1CC[C@H](OC(C)=O)[C@@H]1CCSc1nc(C(=O)OCC)cs1
Temperature: 0 °C
Yield: 38.1 %

Procedure:
To a solution of (3-hydroxy-3-methyloctyl)(triphenyl)phosphonium iodide (800 mg) in anhydrous tetrahydrofuran (9.00 mL) was added n-butyllithium (1.60M in hexane, 1.90 mL) at room temperature and the solution was stirred for 1 Hour. To the solution was added a solution of the compound 49 (349 mg) in anhydrous tetrahydrofuran (6.00 mL) was slowly added at −78° C. and the solution was stirred for 2 Hours. The solution temperature was risen to room temperature. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed water and brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (178 mg) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:6][N:5]=[C:4]2[S:15][CH:16]=[CH:17][C:3]=12.[Cl:18][C:19]1[CH:20]=[C:21]([C:26]2([C:29](Cl)=[O:30])[CH2:28][CH2:27]2)[CH:22]=[CH:23][C:24]=1[Cl:25]>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:29]([C:26]3([C:21]4[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=4)[CH2:28][CH2:27]3)=[O:30])=[CH:12][CH:13]=2)[CH2:6][N:5]=[C:4]2[S:15][CH:16]=[CH:17][C:3]=12
Reactant: O=C(Cl)C1(c2ccc(Cl)c(Cl)c2)CC1
Reactant: NC1=c2ccsc2=NCN1c1ccc(N)cc1
Solvent: c1ccncc1
Product: NC1=c2ccsc2=NCN1c1ccc(NC(=O)C2(c3ccc(Cl)c(Cl)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-Amino-3-(4-aminophenyl)thieno[2,3-d]pyrimidine (0.3 mL of a 0.324 M solution, 0.1 mmol) 1-(3,4-Dichloro-phenyl)-cyclopropanecarbonyl chloride (0.2 mL of a 1 M solution in pyridine, 0.2 mmol) was added in one portion. After the mixture was stirred at room temperature for 3 d, the reaction was purified by hplc to afford the title compound as a beige solid. MS(ES) m/e 455 [M+H].
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([O:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[Cl:34])(=[O:26])=[O:25])=[CH:18][C:17]=1[Cl:35])=[CH:8]2)=[O:4].[OH-].[Na+].Cl>C1COCC1.CO>[Cl:22][C:21]1[CH:20]=[C:19]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])(=[O:26])=[O:25])[CH:18]=[C:17]([Cl:35])[C:16]=1[O:15][C:9]1[CH:10]=[N:11][C:12]2[C:7]([CH:8]=1)=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:14][CH:13]=2
Reactant: COC(=O)c1ccc2ncc(Oc3c(Cl)cc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3Cl)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2ncc(Oc3c(Cl)cc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3Cl)cc2c1
Temperature: 25 °C
Yield: 78.3 %

Procedure:
To a solution of 3-[2,6-Dichloro-4-(2,4-dichloro-benzenesulfonylamino)-phenoxy]-quinoline-6-carboxylic acid methyl ester (181) (200 mg, 0.35 mmol) in THF/MeOH(2 ml/2 ml) was added 4N NaOH (0.1 ml, 0.4 mmol). This mixture was refluxed for 2.5 hr. The reaction mixture was cooled to room temperature and was neutralized with 2N HCl, and then concentrated. The residue was extracted twice with AcOEt. Organic layer was washed by Brine, dried over anhydrous MgSO4, and concentrated to give a solid. Crude product was recrystallized by Hexane/AcOEt to afford compound 183 (153 mg, 78%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=1.[NH2:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[C:17]([Cl:22])[N:16]=1>>[NH2:13][C:9]1[N:8]=[C:7]([NH:6][CH2:5][CH2:4][NH:3][C:19]2[CH:18]=[C:17]([Cl:22])[N:16]=[C:15]([NH2:14])[N:20]=2)[CH:12]=[CH:11][N:10]=1
Reactant: NCCNc1ccnc(N)n1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Product: Nc1nccc(NCCNc2cc(Cl)nc(N)n2)n1

Procedure:
The product of Example 1E (250 mg, 1.11 mmol) and 2-amino-4,6-dichloropyrimidine (201 mg, 1.23 mmol) were treated under the conditions described in Example 1F to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.31-3.41 (m, 4H) 5.72 (d, J=5.95 Hz, 1H) 5.75 (s, 1H) 5.85 (s, 2H) 6.40 (s, 2H) 6.85 (s, 1H) 7.21 (s, 1H) 7.61 (d, J=5.55 Hz, 1H); MS (ESI+) m/z 280.9 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([C:14]([OH:16])=O)[O:7][N:6]=1)[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1.[F:23]C1N=C(F)N=C(F)N=1>ClCCl>[CH2:1]([C:5]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([C:14]([F:23])=[O:16])[O:7][N:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1noc(C(=O)O)c1C(F)(F)F
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)Cc1noc(C(=O)F)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 70.8 %

Procedure:
To a mixture of 3-isobutyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (0.070 g, 0.295 mmol) and pyridine (0.029 mL, 0.354 mmol) in dichloromethane (2.5 mL) at room temperature was added 2,4,6-trifluoro-1,3,5-triazine (cyanuric fluoride) (0.030 mL, 0.354 mmol). The reaction mixture was stirred at room temperature for 5.5 h. The heterogeneous reaction was complete by HPLC and was diluted with dichloromethane, washed with an ice-cold solution of 0.5N aqueous hydrochloric acid (2×), and the organic layer was collected. The aqueous layer was back-extracted with dichloromethane, and the combined organic layers were dried with anhydrous sodium sulfate and concentrated to afford 3-isobutyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride (0.050 g, 0.209 mmol, 70.8% yield) as a yellow solid. The product had an HPLC ret. time=2.52 min (methyl ester)-Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA.