Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([CH3:22])[C:6]([C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[CH:16]=1)[C:11]([OH:13])=O)=[O:7])[CH2:2][CH2:3][CH3:4].[CH:23](N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:58][C@@H:59]([CH2:75][C:76]1[CH:81]=[C:80]([F:82])[CH:79]=[C:78]([F:83])[CH:77]=1)[C@H:60]([OH:74])[CH2:61][NH:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[C:66]([C:70](F)(F)F)[CH:65]=1>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:1]([N:5]([CH3:22])[C:6](=[O:7])[C:8]1[CH:16]=[C:15]([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[CH:14]=[C:10]([C:11]([NH:58][C@@H:59]([CH2:75][C:76]2[CH:81]=[C:80]([F:82])[CH:79]=[C:78]([F:83])[CH:77]=2)[C@H:60]([OH:74])[CH2:61][NH:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][CH3:23])[CH:65]=2)=[O:13])[CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCN(C(C)C)C(C)C
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNCc1cccc(C(F)(F)F)c1
Reactant: CCCCN(C)C(=O)c1cc(C(=O)O)cc(-c2nccs2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCN(C)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(-c2nccs2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-{[Butyl(methyl)amino]carbonyl}-5-(1,3-thiazol-2-yl)benzoic acid (125 mg, 0.39 mmol) is dissolved in DMF (3 mL), and diisopropylethylamine (271 μL, 1.6 mmol), HATU (178 mg, 0.47 mmol), (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[3-(trifluoromethyl)benzyl]amino}butan-2-ol dihydrochloride (176 mg, 0.43 mmol) are added. The reaction stirred at room temperature 4 h. The reaction mixture is diluted with chloroform, washed with water, saturated sodium bicarbonate, saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/methylene chloride) provides the title compound as the free base. The residue is dissolved in diethyl ether (3 mL) and 1N hydrochloric acid in diethyl ether (2 mL) is added. The mixture is concentrated under reduced pressure to yield the title compound. ESI MS m/z 635.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][CH:17]([CH2:21][OH:22])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][O:22][S:24]([CH3:23])(=[O:26])=[O:25])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1cccc(F)c1)c1ccc2c(c1)OC(CO)CC2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Temperature: -10 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a solution of [7-(3-fluoro-benzenesulfonyl)-chroman-2-yl]-methanol (10.0 g, 0.032 mol) in 200 mL of methylene chloride at −10° C. was added methanesulfonyl chloride (2.76 mL, 0.036 mol) and triethylamine (4.95 mL, 0.036 mol). The reaction mixture was stirred for one hour at −10° C. and was then quenched by addition of 10% aqueous NaHCO3. The organic layer was separated, washed with water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes:EtOAc 85:15) to give 11.35 g (92%) of methanesulfonic acid (R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-ylmethyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:30]=[CH:29][N:28]=2)[CH2:23][CH2:22]1>C(OCC)(=O)C.CCCCCC>[Cl:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][CH:5]1[C:4]2[C:9](=[N:10][CH:11]=[C:2]([C:31]3[CH:30]=[CH:29][N:28]=[C:27]([N:24]4[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]4)[CH:32]=3)[CH:3]=2)[NH:8][CH2:7][CH2:6]1
Reactant: Clc1cccc(OC2CCNc3ncc(Br)cc32)c1
Reactant: CN1CCN(c2cc(B3OC(C)(C)C(C)(C)O3)ccn2)CC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CN1CCN(c2cc(-c3cnc4c(c3)C(Oc3cccc(Cl)c3)CCN4)ccn2)CC1
Yield: 36 %

Procedure:
6-Bromo-4-(3-chlorophenoxy)-1,2,3,4-tetrahydro-[1,8]naphthyridine (20 mg) was reacted with 1-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine (25 mg) as in General Procedure 13. Silica gel chromatography using a gradient of 0-100% ethyl acetate/hexane as the eluting solvent gave the title compound as a white foam (36% yield). LCMS: m/z=436.06 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.0-2.11 (m, 1H), 2.24-2.40 (m, 1H), 2.35 (s, 3H), 2.54 (t, J=4.9 Hz, 4H), 3.4-3.51 (m, 1H), 3.57-3.68 (m, 5H), 5.27 (bs, 1H), 5.38 (t, J=3.4 Hz, 1H), 6.64 (s, 1H), 6.73 (dd, J=1.0 and 5.2 Hz, 1H), 6.90 (dd, J=2.2 and 8.3 Hz, 1H), 6.95-7.03 (m, 1H), 7.04-7.08 (m, 1H), 7.22-7.28 (m, 1H), 7.57 (d, J=1.9 Hz, 1H), 8.17 (d, J=5.2 Hz, 1H), 8.31 (d, J=2.2 Hz).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:19]=[C:18]2[C:9]([C:10](=[O:21])[C:11]3[C:16]([C:17]2=[O:20])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:8]2[CH2:22][CH2:23][CH2:24][C:7]=12)(=O)C.O.C(N(CC)CC)C>CO>[OH:4][CH2:5][C:6]1[CH:19]=[C:18]2[C:9]([C:10](=[O:21])[C:11]3[C:16]([C:17]2=[O:20])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:8]2[CH2:22][CH2:23][CH2:24][C:7]=12
Reactant: CC(=O)OCc1cc2c(c3c1CCC3)C(=O)c1ccccc1C2=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C1c2ccccc2C(=O)c2c1cc(CO)c1c2CCC1
Temperature: 55 °C

Procedure:
A mixture of 2,3-dihydro-4-acetoxymethyl-1H-cyclopent[a]anthracene-6,11-dione (74 mg, 0.23 mmol) in MeOH (12 mL) containing H2O (3mL) and triethylamine (2mL) is heated at 55° C. for 3 hours. The mixture is evaporated in vacuo, and the residue is coevaporated twice with EtOH (10 mL) to dryness. The residue is recrystallized from CHCl3 to give2,3-dihydro-4-hydroxymethyl-1H-cyclopent[a]anthracene-6,11-dione, 48 mg (75%), mp 191°-192° C. 1H NMR (DMSO-d6): δ2.14 (2H, q, J=7.6 Hz, CH2 -2), 2.88 (2H, t, J=7.6 Hz, CH2 -3), 3.40 (2H, t, J=7.6 Hz, CH2 -1), 4.61 (2H, d, J=5.5 Hz, CH2 --OH), 5.53 (1 H, t, J=5.5 Hz, OH), 7.90-8.18 (5H, m, Ar--H). Anal. Calc'd for C18H14O3 : C, 77.68; H, 5.07. Found: C, 77.70; H, 5.06.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[C:7]1([CH:14]=[CH:13][C:11]([OH:12])=[CH:10][CH:9]=1)O.I[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21]>CN(C=O)C>[CH2:16]([O:12][C:11]1[CH:13]=[CH:14][C:7]([O:4][CH2:1][CH2:13][CH2:14][CH2:7][CH:9]=[CH2:10])=[CH:9][CH:10]=1)[CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21]
Reactant: C=CCCCCI
Reactant: Oc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCCCCOc1ccc(OCCCCC=C)cc1
Temperature: 100 °C
Reaction time: 10 h
Yield: 142.1 %

Procedure:
To a 60 mL DMF suspension of potassium carbonate (3.98 g, 28.8 mmol) were added hydroquinone (1.05 g, 9.54 mmol) and 6-iodo-1-hexene (6.01 g, 28.6 mmol) at room temperature. The reaction mixture was warmed to 100° C. and stirred for 10 h. After cooling to room temperature, the mixture was quenched with 10% aqueous sodium hydroxide (60 mL). The mixture was extracted with diethyl ether (3×50 mL). The combined organic solutions were washed with aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by MPLC (80:1, hexane:ethyl acetate) to give the olefin 10 (1.86 g, 71%) as a white solid (mp=29.0°-30.0° C.); Anal. Calcd for C18H26O2 : C, 78.79%; H, 9.55%. Found: C, 78.69%; H, 9.37%; cap gc: tR =10.49 min; column: 25 m×0.25 mm, OV-101; temp prog: 50° C. /4 min/20° C. min-1 / 250° C./ 0 min; tlc: Rf =0.48 in 9:1 hexane:ethyl acetate.
Reaction SMILES: [CH3:1][C:2]([S:6]([CH3:9])(=[O:8])=[O:7])([CH3:5])[C:3]#[N:4].C([Li])CCC.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:32])=[C:20](/[C:22](=[N:25]/[S@@:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])/[CH2:23][F:24])[CH:21]=1.B(F)(F)F.CCOCC>C1COCC1>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:32])=[C:20]([C:22]([NH:25][S@@:26]([C:28]([CH3:30])([CH3:29])[CH3:31])=[O:27])([CH2:23][F:24])[CH2:9][S:6]([C:2]([C:3]#[N:4])([CH3:5])[CH3:1])(=[O:8])=[O:7])[CH:21]=1
Reactant: CC(C)(C#N)S(C)(=O)=O
Reactant: CC(C)(C)[S@@](=O)/N=C(\CF)c1cc(Br)ccc1F
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[S@@](=O)NC(CF)(CS(=O)(=O)C(C)(C)C#N)c1cc(Br)ccc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methyl-2-(methylsulfonyl)propanenitrile (1.654 g, 11.24 mmol) in THF (14 mL) at −78° C. was added a 2.5 M solution of n-butyllithium in hexanes (4.49 mL, 11.24 mmol) dropwise via syringe. After 30 minutes at −78° C., a 0° C. solution of (R,Z)—N-(1-(5-bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (1.9 g, 5.62 mmol) in THF (14.00 mL), which had been pretreated with boron trifluoride diethyl etherate (0.693 mL, 5.62 mmol) at 0° C. for 15 minutes, was added dropwise via cannula. The reaction was stirred for 2 hours at −78° C., and then quenched with saturated aqueous ammonium chloride at −78° C. and diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered, concentrated, and purified by silica-gel chromatography, eluting with 25% ethyl acetate in hexanes followed by 40% ethyl acetate hexane to provide the title compound. The product was isolated as a 2:1 mixture of diastereomers. LC/MS (ESI+) m/z=485, 487 (M+H; 2 bromine isotopes).
Reaction SMILES: [CH3:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH2:10][CH:11]([C:14]#[N:15])[C:12]#[N:13])[CH:6]=1)([OH:4])[CH3:3].I[CH2:17][CH2:18][CH:19]=[CH2:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:20]([C:11]([CH2:10][C:7]1[CH:6]=[C:5]([C:2]([CH3:1])([OH:4])[CH3:3])[O:9][N:8]=1)([C:12]#[N:13])[C:14]#[N:15])[CH2:19][CH:18]=[CH2:17]
Reactant: CC(C)(O)c1cc(CC(C#N)C#N)no1
Reactant: C=CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCC(C#N)(C#N)Cc1cc(C(C)(C)O)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
0.41 g of {[5-(1-methyl-1-hydroxyethyl)isoxazol-3-yl]methyl}malononitrile and 0.63 g of 4-iodo-1-butene were dissolved in 6 ml of N,N-dimethylformamide, and 0.55 g of potassium carbonate was then added under ice-cooling. The mixture was stirred at room temperature overnight. After water was added, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.43 g of (3-butenyl){[5-(1-methyl-1-hydroxyethyl)isoxazol-3-yl]methyl}malononitrile represented by the following formula:
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:57][N:56]4[CH2:58][CH2:59][CH2:60][C@@H:55]4[CH2:54]3)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].CO>O1CCCC1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:57][N:56]4[CH2:58][CH2:59][CH2:60][C@@H:55]4[CH2:54]3)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc([C@@H]3C[C@H]4CCCN4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1nc2ccc([C@@H]3C[C@H]4CCCN4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 86.9 %

Procedure:
To a solution of 0.886 g of CIS-(+/-)-2-Butyl-6-(hexahydropyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone dissolved in 2.0 ml of tetrahydrofuran is added 10.0 ml of methanol. The reaction mixture is heated at reflux for 18 hours, cooled and concentrated in vacuo to a residue which is purified by chromatography on silica gel using 9:1 chloroform-methanol to give 0.534 g of the desired product as a white foam. FAB mass spec 548 (M+H).
Reaction SMILES: [I:1]Cl.[C:3]1([S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Ca+2]>CO>[I:1][C:14]1[CH:13]=[C:12]([S:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)(=[O:10])=[O:11])[CH:17]=[CH:16][C:15]=1[NH2:18]
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Reactant: ClI
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: Nc1ccc(S(=O)(=O)c2ccccc2)cc1I
Temperature: 25 °C
Reaction time: 72 h
Yield: 64 %

Procedure:
Iodine chloride (1.94 g, 12 mmol) in methanol (30 mL) was added to a mixture of [4-(phenylsulfonyl)phenyl]amine (Step 1, 2.33 g, 10 mmol) and calcium carbonate (2.0 g, 20 mmol) in methanol (20 mL). The reaction was stirred at room temperature for 72 hours. The reaction mixture was filtered and the filtrate evaporated. The residue was taken up in ethyl acetate and washed with sodium sulfite solution and brine, then evaporated. The residue was triturated with diethyl ether to give [2-iodo-4-(phenylsulfonyl)phenyl]amine (2.3 g). 1H NMR (400 MHz, d6-DMSO) δ 7.99 (1H, d, J=2.1 Hz), 7.87-7.85 (2H, m), 7.64-7.54 (4H, m), 6.77 (1H, d, J=8.6 Hz), 6.24 (2H, s).
Reaction SMILES: [CH3:1][CH:2]([C:10]#[N:11])[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:18]=[O:19].[OH-].C([N+](CC)(CC)CC)C1C=CC=CC=1>O>[C:10]([C:2]([C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[CH:7][CH:8]=1)([CH3:1])[CH2:18][OH:19])#[N:11]
Reactant: CC(C#N)c1ccc(Cl)cc1
Reactant: C=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CC(C#N)(CO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To an ice cold stirred solution of α-methyl-4-chlorobenzyl cyanide* (50 g., 0.3 mole) in 500 ml. of pyridine containing a suspension of paraformaldehyde (36 g., 1.2 mole) is added 1 ml. of benzyl triethylammonium hydroxide. The mixture is stirred under nitrogen at room temperature for 72 hours. The reaction mixture is poured into water and extracted with ether. The combined ether extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give a thick oil, 58.4 g, which is identified by nmr.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].Cl.[C:17](Cl)(=[NH:19])[NH2:18].CS(C)(=O)=O>O>[NH2:18][C:17]1[NH:19][C:4](=[O:5])[C:3]2[C:2](=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=2)[N:1]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Reactant: N=C(N)Cl
Agent: CS(C)(=O)=O
Agent: Cl
Solvent: O
Product: COC(=O)c1ccc2c(=O)[nH]c(N)nc2c1
Temperature: 150 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Into a round bottom flask was added dimethyl 2-aminoterephthalate (1.0 g, 4.8 mmol) mixed with carbamimidic chloride-HCl (1.10 g, 9.6 mmol) and dimethyl sulfone (4.5 g, 47.8 mmol). The reaction mixture was heated to 150° C. and stirred overnight. The mixture was cooled to rt, water added and the solid was filtered. The solid was then washed with acetic acid to afford methyl 2-amino-4-oxo-3,4-dihydroquinazoline-7-carboxylate (1.0 g, 95%). LC-MS: (FA) ES+ 220.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)CCC.C1(C)C=CC=CC=1>C(OCC)(=O)C.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>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:2]1[N:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc2ncc(I)n2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2ncc(-c3ccccn3)n2c1
Yield: 75.4 %

Procedure:
A mixture of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate (1.00 g, 3.30 mmol), 2-(tri-n-butylstannyl)pyridine (2.44 mg, 6.62 mmol), tetrakis(triphenylphosphine)palladium(0) (381 mg, 0.33 mmol) and toluene (50 mL) was heated under reflux overnight. After cooling, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=4/1-1/1) to give the title compound (630 mg, yield 75%) as colorless crystals.
Reaction SMILES: [Na].[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][OH:6].Cl[C:9]1[C:18]2[C:19](=[O:29])[C:20]3[C:25]([C:17]=2[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[CH:24][C:23]1[O:26][CH2:27][O:28][C:22]=1[CH:21]=3>>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][O:6][C:9]1[C:18]2[C:19](=[O:29])[C:20]3[C:25]([C:17]=2[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[CH:24][C:23]1[O:26][CH2:27][O:28][C:22]=1[CH:21]=3
Reactant: CN(C)CCO
Reactant: O=C1c2cc3c(cc2-c2c1c(Cl)nc1ccccc21)OCO3
Agent: [Na]
Product: CN(C)CCOc1nc2ccccc2c2c1C(=O)c1cc3c(cc1-2)OCO3
Temperature: 60 °C
Yield: 68.1 %

Procedure:
To a solution prepared with sodium (1.78 g, 77.4 mmol) and 2-dimethylaminoethanol (80 ml, 796 mmol) was added 6-chloro-9,10-methylenedioxy-7H-indeno[2,1-c]quinoline-7-on (8 g, 25.8 mmol) obtained in reference example 2, and the mixture was stirred with heat at 60° C. for 24 hours. The reaction mixture was poured into ice water and extracted with chloroform. The chloroform layer was dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol=10:1(v/v)) and crystallized from ethyl acetate to give 6.37 g (yield: 68.1%) of title compound. The physicochemical properties thereof are shown in table 2.
Reaction SMILES: [OH-:1].[K+].[NH2:3][C:4]1[N:9]=[C:8]([NH:10][C@@H:11]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][CH2:13][OH:14])[C:7]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]#N)=[CH:22][C:21]=2[F:29])=[C:6]([CH3:30])[N:5]=1.C[OH:32]>>[NH2:3][C:4]1[N:9]=[C:8]([NH:10][C@@H:11]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][CH2:13][OH:14])[C:7]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:32])=[O:1])=[CH:22][C:21]=2[F:29])=[C:6]([CH3:30])[N:5]=1
Reactant: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1F
Reactant: CO
Reactant: [OH-]
Agent: [K+]
Product: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1F
Temperature: 70 °C

Procedure:
A 5M aqueous solution of potassium hydroxide (0.58 mL) was added to a stirred solution of the product from step (iv) (0.11 g) in MeOH (1.5 mL). The mixture was heated at 70° C. for 15 h. The solvent was evaporated under reduced pressure and the aqueous residue was adjusted to pH ˜7 with concentrated HCl. The aqueous was extracted with EtOAc and the combined organic phase was dried, filtered and evaporated to the subtitle compound, 0.102 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][NH:31][CH2:30]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][N:31]([C:16]1[C:17]([F:19])=[C:18]3[C:13]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][C:15]=1[F:21])[CH2:30]2
Reactant: Clc1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(N3Cc4ccc(Cl)cc4C3)c(F)cc2c1=O
Yield: 10.2 %

Procedure:
178 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 89 mg of 5-chloroisoindoline, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 25 mg of the target compound.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[N:7]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:8]([CH3:27])=[CH:9][C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19].ClCCl.C([O-])(O)=O.[Na+]>C(#N)C>[C:1]([C:9]1[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])=[C:6]([CH3:5])[N:7]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:8]=1[CH3:27])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)Cn1c(C)cc(Cc2ccccc2S(=O)(=O)c2ccccc2)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)c2ccccc2)c(C(C)=O)c1C
Reaction time: 0.08 h
Yield: 73.5 %

Procedure:
In a round-bottomed flask equipped with a magnetic stir bar, acetyl chloride (1.7 μL, 0.024 mmol) was added to a solution of ethyl 2-(2,5-dimethyl-3-(2-(phenylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (10 mg, 0.024 mmol) in acetonitrile (0.5 mL) at room temperature. The reaction was stirred for 5 minutes, then dichloromethane (10 mL) and NaHCO3 (sat. aq. 10 mL) were added. The dichloromethane layer was separated and dried over Na2SO4, filtered and concentrated to yield ethyl 2-(3-acetyl-2,5-dimethyl-4-(2-(phenylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (8 mgs, 72%).
Reaction SMILES: Cl.[F:2][C:3]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>ClCCl>[C:27]([N:9]1[CH2:10][CH2:11][CH:6]([O:5][C:4]2[C:12]([F:19])=[C:13]([F:18])[C:14]([F:17])=[C:15]([F:16])[C:3]=2[F:2])[CH2:7][CH2:8]1)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirring solution of 4.76 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine hydrochloride in 100 ml of dichloromethane was treated with 4.46 ml of triethyl amine followed by a solution of 1.413 g of acetyl chloride in 60 ml of dichloromethane (dropwise). After stirring at ambient temperature for 18 hours, the reaction mixture was washed with water followed by a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. Filtration, followed by evaporation of the solvents afforded an oil which was purified by means of high pressure liquid chromatography (silica gel; elution with 10% ethyl acetate/dichloromethane). The resultant oil solidified upon standing and this material was sublimed to 3.2 g (64.7%) of 1-acetyl-4-(2,3,4,5,6-pentafluorophenoxy)piperidine, m.p. 60°-65° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:8](=O)(=[O:11])([OH:10])[OH:9]>>[CH:6]1[C:1]([OH:7])=[CH:2][CH:3]=[C:4]([S:8]([OH:11])(=[O:10])=[O:9])[CH:5]=1
Reactant: Oc1ccccc1
Reactant: O=S(=O)(O)O
Product: O=S(=O)(O)c1ccc(O)cc1

Procedure:
A treatment for canker sores was formulated. A solution of phenolsulfonic acid was prepared as described in Example 1, except that the weight of available stock liquefied phenol USP was calculated and prepared for 2.4 moles of phenol. The amount of available stock sulfuric acid NF that contained 5.26 moles was calculated. The weight of sulfuric acid NF was 515.90 grams. The 5.26 moles of sulfuric acid NF was treated as described in Example 1. A quantity of 400 mL of Liquified Phenol USP was added to a 600 mL beaker. A quantity of 2.4 moles of phenol as Liquefied Phenol USP was added to a 1 L Corning Pyrex No. 1395 bottle using the Mettler PS-5002-S balance.