Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].ClCC(Cl)=O.[C:17]1(O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[C:1]([O:11][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: Oc1ccccc1
Reactant: CCCCCCCCC(=O)O
Agent: O=C(Cl)CCl
Solvent: CC#N
Product: CCCCCCCCC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 83 %

Procedure:
A solution of 5.00 g (31.6 mmol) of nonanoic acid, 3.93 g (34.76 mmol) of chloroacetyl chloride (CAC), 2.7 g (31.6 mmol) of phenol, and 35 ml of acetonitrile was delivered to a clean, dry, two neck 100 ml round bottom flash fitted with a mechanical stirrer and a reflux condenser. The reaction flask was flushed with nitrogen through a gas inlet at the top of the reflux condenser and placed in an 80° C. oil bath and stirred for 19 hours. The reaction mixtures was allowed to cool to room temperature and then vacuum filtered through 30 g of neutral alumina to remove chloroacetic acid. The purified product was then placed on a high vacuum line overnight to remove any residual solvent. Phenyl nonanoate (NOB) was isolated as a faint yellow liquid (6.18 g, 26.37 mmol) in 83% yield. The purity of NOB was determined to be over 97%.
Reaction SMILES: [CH3:1][CH:2]([CH3:41])[C:3]([C:17]1[N:18]=[CH:19][N:20](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:21]=1)([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:15]=[CH2:16])[CH:11]=2)[CH:6]=1)[OH:4]>C1COCC1.CO.[C].[Pd]>[CH2:15]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([C:3]([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)([OH:4])[CH:2]([CH3:41])[CH3:1])[CH:14]=[CH:13]2)[CH3:16]
Reactant: C=Cc1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 171 %

Procedure:
2-Methyl-1-(1-trityl-1H-imidazol-4-yl)-1-(6-vinylnaphthalen-2-yl)-1-propanol (1.20 g) was dissolved in THF (5 ml)-methanol (10 ml). To the solution was added 10% palladium carbon (120 mg), and the mixture was stirred at room temperature for 2 h under hydrogen atmosphere. The catalyst was filtered off and washed with THF. The filtrate was concentrated and the residue was recrystallized from isopropyl ether-hexane (1:1) to give the titled compound (1.13 g) as a colorless powder.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH3:14][C:15]1[C:19]([NH2:20])=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:17][N:16]=1>N1C=CC=CC=1>[CH3:14][C:15]1[C:19]([NH:20][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[C:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:17][N:16]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Cc1n[nH]c(-c2ccccc2)c1N
Solvent: c1ccncc1
Product: Cc1n[nH]c(-c2ccccc2)c1NC(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 16 h

Procedure:
361 mg of 4-trifluoromethylbenzoyl chloride were added dropwise to a solution of 300 mg of 3-methyl-5-phenyl-1H-pyrazol-4-ylamine in 5 ml of pyridine at room temperature. The reaction mixture was stirred for 16 h and then concentrated. The residue was extracted into dichloromethane and washed with 0.5M hydrochloric acid, at which point the title compound precipitated.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[C:24](Cl)(=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][C:24](=[O:33])[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C(=O)NC(Cc2ccc(C(F)(F)F)cc2)C(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (200 mg, 0.57 mmol) in ethyl acetate (5 ml) were added 4-anisoyl chloride (146 mg, 0.86 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to give the title compound (185 mg, 72%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([CH2:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)([CH3:11])[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[K+]>C(O)C.O>[CH2:1]([O:3][C:4](=[O:19])[C:5]([CH2:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)([CH3:11])[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C)(CCc1cccs1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)(CCc1cccs1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
2-Methyl-2-(2-thienyl)ethylmalonic acid diethylester (52.7 g, 0.19 mol) obtained in Example 1) (a) was dissolved in a mixture of ethanol (240 ml) and water (80 ml), potassium hydroxide (11.4 g, 0.20 mol) was added thereto in an ice bath, and the solution was stirred for 2 hours. And then potassium hydroxide (5.7 g, 0.1 mol) was added thereto three times, one portion every 1 hour, and the reaction solution was stirred for 6 hours in total. Water (300 ml) and ice-cold 10% hydrochloric acid (500 ml) were added to the reaction solution, and the solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuo, and the residue was purified by flash chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=2:1-0:1) to afford the title compound (28.6 g, 60% yield) as a pale yellow oil.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([N:28]5[CH2:33][CH:32]6[CH2:34][CH:29]5[CH2:30][NH:31]6)=[O:27])=[CH:22][CH:21]=4)=[CH:15][C:14]=3[Cl:35])[C:8]2=[O:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:37][C:38]([CH3:40])=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO.C(OCC)(=O)C>[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([N:28]5[CH2:33][C@@H:32]6[CH2:34][C@H:29]5[CH2:30][N:31]6[CH:38]([CH3:40])[CH3:37])=[O:27])=[CH:22][CH:21]=4)=[CH:15][C:14]=3[Cl:35])[C:8]2=[O:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)=O
Reactant: O=C(c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1)N1CC2CC1CN2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)N1C[C@@H]2C[C@H]1CN2C(=O)c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
Treat a solution of chiral 1-cyclohexyl-3-[3,5-dichloro-4′-(2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-biphenyl-4-ylmethyl]-pyrrolidin-2-one (0.096 g, 0.18 mmol) in methanol (3 mL) and acetone (0.105 g, 1.81 mmol) with sodium cyanoborohydride (0.055 g, 0.88 mmol) and then acetic acid (0.057 g, 0.94 mmol). Stir the mixture for 3 hours at room temperature under a nitrogen atmosphere, dilute with ethyl acetate and wash with saturated sodium bicarbonate then water. Dry the organic layer with sodium sulfate and purify the crude product by silica gel chromatography using a gradient of 0 to 10% methanol in dichloromethane to afford 71 mg (68%) of the title compound: MS (m/z): 568 (M+).
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.[Na].F[C:8]1[C:13]2[C:14](=[O:23])[C:15]3[CH:16]=[CH:17][N:18]=[CH:19][C:20]=3[C:21](=[O:22])[C:12]=2[C:11]([F:24])=[CH:10][CH:9]=1>C1COCC1.C(Cl)Cl>[F:24][C:11]1[C:12]2[C:21](=[O:22])[C:20]3[CH:19]=[N:18][CH:17]=[CH:16][C:15]=3[C:14](=[O:23])[C:13]=2[C:8]([O:2][CH3:1])=[CH:9][CH:10]=1
Reactant: O=C1c2ccncc2C(=O)c2c(F)ccc(F)c21
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(F)c2c1C(=O)c1ccncc1C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium methoxide, freshly prepared under nitrogen atmosphere from anhydrous methanol (97.6 ml) and sodium (2.024 g), is dropped in a time of 2 hours and 35 minutes into a solution of 6,9-difluorobenzo[g]isoquinolin-5,10-dione (19.615 g, preparation 3) in anhydrous THF (883 ml), under stirring and at room temperature. At the end of the addition, the reaction mixture is concentrated to half the starting volume, then is kept at 18° C. for 30 minutes. The separated solid is filtered and washed with 100 ml of THF, then it is suspended in water (80 ml), left overnight under stirring and filtered again to give 9.3 g of crude product, which is suspended in methylene chloride (45 ml) and refluxed for 30 minutes. After cooling at room temperature, the product is filtered and the separated solid is washed with methylene chloride (5×3 ml), then dried under vacuum at 40° C., to obtain 8.65 g of pure product, m.p. 248-250° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][C:6](=[O:10])[CH2:5]1.C(N(CC)CC)C.O1CCOCC1.Cl[C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][C:26]=1[N+:35]([O-:37])=[O:36]>O.CN(C)C(=O)C>[N+:35]([C:26]1[CH:27]=[C:28]([S:31]([NH2:34])(=[O:32])=[O:33])[CH:29]=[CH:30][C:25]=1[NH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][C:6](=[O:10])[CH2:5]1)([O-:37])=[O:36]
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCCN1CCNC(=O)C1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccc(NCCN2CCNC(=O)C2)c([N+](=O)[O-])c1
Temperature: 90 °C

Procedure:
4-(2-Amino-ethyl)-piperazin-2-one (5.51 g) and triethylamine (9.07 mL, 6.59 g) were added to 1,4-dioxane (100 mL), N,N-dimethylacetamide (20 mL), and water (10 mL) and mixed until dissolved. 4-Chloro-3-nitrobenzenesulfonamide (7.00 g) was added, and the mixture was heated to 90° C. for 16 hours. The mixture was cooled and the solvent was removed under vacuum. The crude material was purified by recrystallization from 20% methanol in dichloromethane with subsequent washing of the recrystallized solid with 10% methanol in dichloromethane followed by washing with 100% dichloromethane.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=O)[CH2:12][CH2:13][CH:14]=[CH2:15].C1COCC1.[CH:22]1([Mg]Cl)[CH:26]=[CH:25][CH:24]=[CH:23]1.Cl>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([CH2:12][CH2:13][CH:14]=[CH2:15])=[C:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1
Reactant: C=CCCC(=O)c1ccc2ccccc2c1
Reactant: Cl[Mg]C1C=CC=C1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(=C1C=CC=C1)c1ccc2ccccc2c1
Temperature: 0 °C

Procedure:
First, 6-(2-naphthyl)-6-(3-butenyl)fulvene was prepared from cyclopentadienyl Grignard reagents as follows. A 1 L round bottomed flask was charged with 1-(2-naphthyl)-4-penten-1-one, 97% (21.73 g, 100 mmol), THF (100 mL), and a stir bar, and cooled in an ice bath. Cyclopentadienyl magnesium chloride (150 mL of approximately 1 M solution in THF, 330 mmol) was added dropwise over ½ hour. The yellow solution was stirred for 2 hours in the ice bath. The yellow solution was then refluxed for 2.5 hours, during which time a red color developed. The solution was acidified by first adding 100 mLs of water, and then adding 100 mL of 1 M HCl. The product was extracted with pentane, and the pentane extracts were collected, washed with water, and dried over sodium sulfate. Elution through silica with pentane and concentration under vacuum afforded 20.25 g (73%) of the product 6-(2-naphthyl)-6-(3-butenyl)fulvene as a red oil, which was 93% pure. The major impurity was dicyclopentadiene.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])=[O:22].Br[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[O:41][C:42]([CH3:54])=[C:43]([CH2:45][CH2:46][N:47]3[CH2:51][CH2:50][C@@H:49]([CH2:52][F:53])[CH2:48]3)[N:44]=2)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(#N)C>[F:53][CH2:52][C@@H:49]1[CH2:50][CH2:51][N:47]([CH2:46][CH2:45][C:43]2[N:44]=[C:40]([C:37]3[CH:38]=[CH:39][C:34]([C:27]4[CH:28]=[CH:29][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:25][CH:26]=4)=[CH:35][CH:36]=3)[O:41][C:42]=2[CH3:54])[CH2:48]1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CC[C@@H](CF)C1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)nc1CCN1CC[C@@H](CF)C1
Yield: 36.6 %

Procedure:
Prepare using the method of Example 103 with palladium (II) acetate (0.003 g, 0.01 mmol), anhydrous acetonitrile (4 mL), triphenylphosphine (0.014 g, 0.05 mmol), distilled water (1 mL), 4-(methanesulfonyl)benzeneboronic acid (0.15 g, 0.71 mmol), 2-(4-bromophenyl)-4-{2-[(3R)-3-(fluoromethyl)pyrrolidin-1-yl]ethyl}-5-methyl-1,3-oxazole (See Example 112) (0.25 g, 0.68 mmol) and potassium carbonate (0.28 g, 2.04 mmol). Additionally triturate the resulting solid with 2:1 diethyl ether:ethyl acetate to give the title compound as a pale yellow coloured solid (0.11 g): MS (m/e): 443 (M+1).
Reaction SMILES: [C:1]([CH:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[S:6][CH2:5]1)(=[O:3])[CH3:2].[C:15](OCC)(=O)[C:16]([O:18]CC)=[O:17].[H-].[Na+]>O1CCCC1>[O:3]=[C:1]1[CH:2]=[C:15]([C:16]([OH:18])=[O:17])[O:14][C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[S:6][CH2:5][C:4]1=2
Reactant: CC(=O)C1CSc2ccccc2C1=O
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(=O)c2c(o1)-c1ccccc1SC2
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-acetyl-4-thiochromanone (6.18 g, 0.03 mole, described in Example 5) and diethyl oxalate (4.38 g, 0.03 mole) in tetrahydrofuran (25 ml) is added dropwise to a stirred suspension of 57% sodium hydride (3.79 g, 0.09 mole) in tetrahydrofuran (25 ml) under an atmosphere of nitrogen at 70°. After the addition is completed, the mixture is heated under an atmosphere of nitrogen at 70° C for 17 hr and the solvent removed by evaporation under reduced pressure. The residue is dissolved in water and washed with ether. The aqueous phase is acidified with concentrated hydrochloric acid (15 ml) in the presence of chloroform and the mixture is stirred for 1.5 hr at room temperature. The organic phase is separated and the aqueous phase is extracted with chloroform. The combined organic extracts are dried, evaporated and the resulting residue crystallized from chloroform to give the title compound; m.p. 251°-253° C, νmaxnujol 2500, 1890, 1730, 1640, 1575, 1550 and 1265 cm-1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[C:17]([CH:18]=[C:19]4[C:24]=2[CH:23]=[CH:22][CH:21]=[CH:20]4)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:25]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:25][C:18]1[C:19]2[C:24]([C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=3)=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: CC(C)(C)c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc(-c2c3ccccc3c(Br)c3ccccc23)cc1

Procedure:
5.0 g (16.0 mmol) of 9-(4-tert-butylphenyl)anthracene and 90 mL of carbon tetrachloride were put into a 500-mL three-neck flask and were stirred. A solution in which 2.8 g (18 mmol) of bromine was dissolved in 10 mL of carbon tetrachloride was dropped into the above solution through a dropping funnel. After that, the solution was stirred at the room temperature for 1 hour, and a sodium thiosulfate aqueous solution was added to the reaction solution to complete the reaction. A water layer of the reaction mixture was extracted by chloroform, and the extracted solution and an organic layer were together washed with a saturated sodium hydrogen carbonate solution and saturated saline. The organic layer was dried with magnesium sulfate, and the mixture was filtrated naturally to remove the magnesium sulfate. Then, the filtrate was condensed to obtain a solid. The obtained solid was recrystallized with ethanol, whereby 6.3 g of a yellow powdery solid, which was a target matter, was obtained with the yield of 99%.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([CH:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3([C:25]([NH:27][O:28]C4CCCCO4)=[O:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.O1CCCCC1ON.CN1CCOCC1>C(OCC)(=O)C.C(Cl)Cl>[CH2:1]([C:5]1[S:9][C:8]([CH:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3([C:25]([NH:27][OH:28])=[O:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C2CCN(S(=O)(=O)C3(C(=O)NOC4CCCCO4)CCOCC3)CC2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NOC1CCCCO1
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCc1ccc(C2CCN(S(=O)(=O)C3(C(=O)NO)CCOCC3)CC2)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Part F. Preparation of 4-{[4-(5-butylthien-2-yl)piperidin-1-yl]sulfonyl}-N-(tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-4-carboxamide. A methylene chloride solution (8.0 mL) of the ester prepared in Part E (3.27 g, 6.93 mmol) was treated with trifluoroacetic acid (8.0 mL, 104 mmol) and stirred at ambient temperature. After 4 hr, the mixture was concentrated in vacuo to approximately 8.0 mL, then treated with diethyl ether (15 mL). The resulting mixture was concentrated in vacuo to approximately 4.0 mL, then treated with diethyl ether (15 mL). The resulting precipitate was filtered, washed with diethyl ether, and dried in vacuo. The resulting white solid (2.93 g) was dissolved in N,N-dimethylformamide (14.1 mL), treated with 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (2.03 g, 10.6 mmol) and N-hydroxybenzo-triazole hydrate (1.43 g, 10.6 mmol), and stirred at ambient temperature under N2. After 1 hr, the resulting suspension was treated with O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (1.24 g, 10.6 mmol), followed by N-methylmorpholine (2.33 mL, 21.2 mmol). After 30 min, the mixture was diluted with ethyl acetate (100 mL) and partitioned with water (50 mL). The aqueous layer was separated and then extracted with ethyl acetate (25 mL). The organic layers were combined, washed with saturated NaHCO3 (25 mL), washed with 1:1 brine/water (25 mL), washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The resulting oil was purified on silica, eluting with 1:1 hexanes/ethyl acetate to produce the product in the form of a colorless glassy solid having an 11:4 mixture of desired product/impurity (3.52 g, 98.6% mass recovery). LC/MS m/z=537 [M+Na] for desired product
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1B(O)O.Cl[C:17]1[C:26]2[C:21](=[C:22]([CH3:45])[C:23]([S:27]([N:30](CC3C=CC(OC)=CC=3)[C:31]3[S:32][CH:33]=[CH:34][N:35]=3)(=[O:29])=[O:28])=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:17]1[C:26]2[C:21](=[C:22]([CH3:45])[C:23]([S:27]([NH:30][C:31]3[S:32][CH:33]=[CH:34][N:35]=3)(=[O:28])=[O:29])=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ccnc3c2C)cc1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(F)(F)F)ccc1-c1ccnc2c(C)c(S(=O)(=O)Nc3nccs3)ccc12

Procedure:
To a microwave vial charged with (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (52.6 mg, 0.239 mmol), 4-chloro-N-(4-methoxybenzyl)-8-methyl-N-(thiazol-2-yl)quinoline-7-sulfonamide (100 mg, 0.217 mmol), potassium phosphate tribasic (54.0 μl, 0.652 mmol) and 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (15.39 mg, 0.022 mmol) was added dioxane (872 μl) and water (291 μl). The mixture was irradiated at 100° C. for 30 min affording conversion to desired product according to LC-MS. The organic layer was decanted and the aqueous extracted with EtOAc. The combined organics were dried under reduced pressure. The crude material was dissolved in DCM (3.0 ml) and TFA (1.0 ml) was added. The brown solution was stirred at room temperature for 1 hr affording complete PMB cleavage according to LC-MS. The light brown solution was dried under reduced pressure and the crude material purified with a 25 g Interchim column ramping EtOAc in heptane (0-100%) affording product (elution at 100% polar eluent) 4-(2-methoxy-4-(trifluoromethyl)phenyl)-8-methyl-N-(thiazol-2-yl)quinoline-7-sulfonamide (84 mg, 0.175 mmol, 81% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ=12.81 (s, 1H), 9.08 (d, J=4.3 Hz, 1H), 8.03 (d, J=8.9 Hz, 1H), 7.62-7.45 (m, 4H), 7.43 (d, J=8.9 Hz, 1H), 7.26 (d, J=4.6 Hz, 1H), 6.81 (d, J=4.6 Hz, 1H), 3.13 (s, 3H). m/z (ESI) 480.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:28]1([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:31]2[CH2:32][CH2:33][N:28]([C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)[CH2:29][CH2:30]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 2b from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(piperazin-1-yl)-quinoline.