Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6](N)=[CH:5][CH:4]=1.[OH:14]S(O)(=O)=O.N([O-])=O.[Na+]>O>[F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([OH:14])=[CH:5][CH:4]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
40.00 g of 4-pentafluorosulfanylaniline (Tetrahedron 56, (2000) 3399) were suspended in 500 ml of a 35% aqueous H2SO4 solution. At 0° C., a solution of 13.85 g of NaNO2 in 30 ml of water was then added dropwise within 10 minutes. The mixture was stirred at 0° C. for a further 35 minutes. A solution, cooled to 0° C., of 171.10 g of Cu(NO3)2 in 200 ml of water was then added to this suspension. Directly thereafter, 26.11 g of Cu2O were also added, and distinct gas evolution could be observed. The mixture was stirred at RT for a further 2 hours, then the mixture was extracted 3 times with 200 ml each time of CH2Cl2, the combined organic phases were dried over MgSO4 and the solvent was removed under reduced pressure. Chromatography on silica gel with DIP afforded 3.5 g of the phenol as a colorless oil.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[Cl:20][CH2:21][C:22](Cl)=[O:23]>ClCCl>[CH2:1]([N:8]([CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)[C:22](=[O:23])[CH2:21][Cl:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: c1ccc(CNCc2nccs2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CCl)N(Cc1ccccc1)Cc1nccs1
Reaction time: 1 h

Procedure:
A stirred solution of N-benzyl-N-2-thiazolylmethylamine (204 mg, 1.0 mmol) in 5 mL of dichloromethane was cooled to 0° C. The solution was treated with 5 mL of saturated, aqueous NaHCO3 followed by the addition of chloroacetyl chloride (0.088 mL, 1.1 mmol). The biphasic mixture was stirred vigorously for 1 hour and poured into a separatory funnel. The layers were separated and the aqueous layer extracted with an additional 5 mL portion of dichloromethane. The combined organic phases were dried (Na2SO4), filtered, and concentrated to provide the title compound which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[Cl:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C:35](Cl)=[O:36])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C:35]([N:24]([CH2:23][C:14]2[CH:15]=[C:16]([C:19]([F:21])([F:22])[F:20])[CH:17]=[CH:18][C:13]=2[C:7]2[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:27])=[O:2])[CH:6]=2)[CH2:25][CH3:26])=[O:36])=[CH:31][CH:30]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)COc1ccc(Cl)cc1

Procedure:
[2′-({[2-(4-Chloro-phenoxy)-acetyl]-ethyl-amino}-methyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]acetic acid (Compound 1-93) was prepared by following the procedures outlined in Example 1 and using (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 4-chlorophenoxyacetyl chloride.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[N:13][CH:14]=1.[H-].[Na+].O>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[N:13][CH:14]=1
Reactant: O=Cc1ccc(O)cn1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCOc1ccc(C=O)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methoxyethoxymethyl chloride (MEM) (19 g, 153 mmol) was added to a solution of 5-hydroxy-2-pyridinecarboxaldehyde (18.4 g, 149 mmol) in 300 ml DMF. NaH (6.3 g of 60% oil dispersion, 158 mmol) were added in portions while cooling the mixture to maintain 20°-30° C. The mixture was stirred an additional 1 hour at 25° C. 5 ml water were added, most of the solvent was evaporated, and water was added to the residue. The mixture was extracted with EtOAc. The extracts were dried over Na2SO4, filtered, and evaporated to a residue. The residue was chromatographed on silica gel eluting with EtOAc-hexanes (35:65) to obtain 5-[(2-methoxyethoxy)methoxy]-2-pyridinecarboxaldehyde: C10H13NO4 (211.22); 1H-NMR (CDCl3) δ10.01 (s,1), 8.52 (d,1), 7.93 (d,1), 7.49 (m,1), 5.39 (s,2), 3.80 (m,2), 3.53 (m,2), 3.32 (s,3).
Reaction SMILES: [N:1]#[C:2]Br.[CH2:4]([C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9])[CH3:5]>C(OCC)C>[CH2:4]([C:6]1[CH:7]=[C:8]([NH:9][C:2]#[N:1])[CH:10]=[CH:11][CH:12]=1)[CH3:5]
Reactant: N#CBr
Reactant: CCc1cccc(N)c1
Solvent: CCOCC
Product: CCc1cccc(NC#N)c1
Temperature: 24 °C
Reaction time: 12 h
Yield: 74.2 %

Procedure:
A solution of cyanogen bromide (11.36 g, 107 mmol) in anhydrous diethylether (50 mL) was added slowly to a stirred solution of 3-ethylaniline (20.8 g, 171 mmol) in diethylether at 4° C. After the addition, the reaction mixture was stirred at 24° C. for 12 hours and it became a brown solution with a white precipitate. The precipitate was filtered off; the filtrate was washed with aqueous HCl (1N, 3×150 mL) and brine (60 mL). Then the etherate solution was dried over MgSO4, filtered, and concentrated to yield a thick liquid. The crude product was further purified by chromatography (SiO2, hexanes, hexanes/CH2Cl2, CH2Cl2) to afford 3-ethylphenylcyanamide (11.6 g, 76% in yield) as a liquid.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].Cl.[F:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([NH2:16])[C:12]=1[C:13]([OH:15])=[O:14]>O1CCCC1.Cl>[F:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[NH:16][C:1](=[O:2])[O:15][C:13](=[O:14])[C:12]=12
Reactant: Nc1cccc(F)c1C(=O)O
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2cccc(F)c2c(=O)o1

Procedure:
Phosgene is conducted at 35°-40° C. for 3 hours into a solution of 23 g (0.148 mol) of 6-fluoroanthranilic acid hydrochloride in a mixture of 300 ml of tetrahydrofuran and 150 ml of 4 N hydrochloric acid. After removal of the phosgene, the mixture is diluted with 500 ml of water and the precipitate is filtered off. There is obtained crude 6-fluoroisatoic acid anhydride of melting point 265°-267° C. (decomposition).
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:10][C:11]1[N:15]2[N:16]=[C:17](Cl)[CH:18]=[CH:19][C:14]2=[N:13][N:12]=1.O>O1CCCC1>[Cl:10][C:11]1[N:15]2[N:16]=[C:17]([O:9][CH:3]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)[CH:18]=[CH:19][C:14]2=[N:13][N:12]=1
Reactant: OC1CCCCC1
Reactant: Clc1ccc2nnc(Cl)n2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1nnc2ccc(OC3CCCCC3)nn12
Reaction time: 0.25 h
Yield: 27.5 %

Procedure:
106 mg of sodium hydride at 60% in oil are added to a solution of 530 mg of cyclohexanol in 5 cm3 of tetrahydrofuran at 0° C. under argon. After stirring for 15 min, 500 mg of 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine (commercial) are added. The brown suspension is stirred, allowing the temperature to return gradually to 20° C. for 24 h. The reaction medium is poured into water and the mixture is extracted with ethyl acetate. After concentration to dryness under vacuum, a brown powder is obtained, which is washed with ether. The filtrate is concentrated to dryness and the oily yellow residue is chromatographed on Biotage Quad 12/25 (KP-SIL, 60 Å; 32-63 μm), elution being carried out with a gradient of 100% dichloromethane to 95:5 dichloromethane/methanol. 184 mg of 3-chloro-6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazine are thus obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [O:1]([C:8]1[S:9][CH:10]=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1>CO.O>[O:1]([C:8]1[S:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1csc(Oc2ccccc2)n1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1csc(Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 2-phenoxythiazole-4-carboxylate (0.17 g, 0.68 mmol) and LiOH monohydrate (0.14 g, 3.40 mmol) in 2 mL of MeOH, 2 mL of H2O, and 2 mL of THF was stirred at RT overnight, the solvents were removed in vacuo and the residue was diluted with water. The aqueous mixture was acidified with 1N HCl (aq) to pH=1−2, then extracted with EtOAc, the combined organic portions were washed with brine, dried over MgSO4, filtered, removal of the solvents in vacuo yielded the title compound as a white solid. EI-MS =222.4 (M+H)+. Calc'd for C10H7NO3S: 221.01.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=1)[CH3:2].[Br:10]N1C(=O)CCC1=O>ClCCCl>[Br:10][CH:1]([C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc(Br)cn1
Solvent: ClCCCl
Product: CC(Br)c1ccc(Br)cn1
Yield: 80 %

Procedure:
A solution of 2-ethyl-5-bromopyridine (1.86 g, 10 mmol), N-bromosuccinimide (1.78 g, 10 mmol) in 1,2-dichloroethane (20 ml) was brought to reflux before the addition of azoisobutyronitrile (AIBN) (20 mg). The solution was then refluxed for a further two hours. The cooled suspension was filtered and evaporated in vacuo. Purification by column chromatography (silica gel, eluting with 1:1 dichloromethane/hexane) gave the desired product as a pale yellow oil (2.12 g, 80%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9](O)[CH2:8][CH:7]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH:21]([NH:24][CH:25]([CH3:27])[CH3:26])([CH3:23])[CH3:22].[H][H].[ClH:30]>C1(C)C=CC=CC=1.[OH-].[OH-].[Pd+2]>[ClH:30].[CH:21]([N:24]([CH:25]([CH3:27])[CH3:26])[CH2:9][CH2:8][CH:7]([C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][OH:1])[CH:13]=[CH:12][C:11]=1[OH:10])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:23])[CH3:22]
Reactant: CC(C)NC(C)C
Reactant: [H][H]
Reactant: OCCc1ccc2c(c1)C(c1ccccc1)CC(O)O2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)N(CCC(c1ccccc1)c1cc(CCO)ccc1O)C(C)C
Temperature: 25 °C
Yield: 61 %

Procedure:
A mixture of 6-(2-hydroxy-ethyl)-4-phenyl-chroman-2-ol (Example 7, 30 g, 111 mmol, 1 equiv), diisopropylamine (33.7 g, 333 mmol, 3 eq) and palladium hydroxide on carbon [50% wet catalyst (50% by weight is water), 6 g, 0.2 equiv] in toluene (120 mL) was hydrogenated at 621×103 Nm−2 (90 psi) hydrogen pressure at 110° C. The reaction mixture was cooled to room temperature and filtered through arbocel and evaporated under reduced pressure. The resulting oil was dissolved in acetonitrile (200 mL) and concentrated hydrochloric acid (11.6 mL, 1.05 equiv) was added. The mixture was distilled at ambient pressure, removing approximately 100 mL of acetonitrile, and the distilled solvent replaced with fresh acetonitrile. The mixture was allowed to cool and crystallise overnight. The product was filtered and washed with a small portion of acetonitrile and dried overnight in vacuo at 50° C. to give the title compounds as a white solid (26.7 g, 68.1 mmol, 61%).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][S:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([OH:28])=[O:27].C(N(CC)CC)C>O>[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25](=[CH:14][C:13]1[CH:16]=[CH:17][C:10]([S:9][CH3:8])=[CH:11][CH:12]=1)[C:26]([OH:28])=[O:27]
Reactant: Cc1ccccc1CC(=O)O
Reactant: CSc1ccc(C=O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CSc1ccc(C=C(C(=O)O)c2ccccc2C)cc1
Temperature: 100 °C

Procedure:
A mixture of acetic anhydride (160 mL), 4-(methylthio)benzaldehyde (25.32 g, 166 mmol), 2-methylphenylacetic acid (24.95 g, 166 mmol), and triethylamine (17.89 g, 176 mmol) was heated to reflux for 2.67 hours. The reaction was cooled to 100° C., and water (200 mL) was added through an addition funnel. A clear oil formed that solidified upon chilling with an ice bath. The solid was collected by filtration, and recrystallized from a mixture of ethyl acetate and isooctane to give the desired acid in two crops (18.6 g, 39%): mp 134°-137° C. 1H NMR (CDCl3) 300 MHz 9.80 (br s, 1H), 7.91 (s,1H), 7.28 (m, 3H), 7.12 (d,J=7.5 Hz, 1H), 7.00 (d, J=8.5 Hz, 2H), 6.93 (d, J=8.5 Hz, 2H), 2.42 (s, 3H), 2.16 (s, 3H). High resolution mass spectrum Calc'd. for C17H16O2S: 284.0871. Found: 284.0863.
Reaction SMILES: C1([N:6]([C@@H:10]([C:44]([CH3:47])([CH3:46])[CH3:45])[C:11]([N:13]2[C@H:17]([C:18](=[O:32])[NH:19][CH:20]([CH2:29][CH2:30][CH3:31])[C@H:21]([OH:28])[C:22]([NH:24][CH:25]3[CH2:27][CH2:26]3)=[O:23])[CH2:16][C@@:15]3([CH2:36][C:35](=[O:37])[N:34]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:33]3)[CH2:14]2)=[O:12])[C:7](=O)[O-:8])CCCC1.O[NH-].CC(OI1(OC(C)=O)(OC(C)=O)O[C:61](=O)[C:60]2[CH:59]=[CH:58][CH:57]=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].[OH2:79]>C(Cl)Cl>[CH:57]1([O:79][C:7](=[O:8])[NH:6][C@@H:10]([C:44]([CH3:47])([CH3:46])[CH3:45])[C:11]([N:13]2[C@H:17]([C:18](=[O:32])[NH:19][C@@H:20]([CH2:29][CH2:30][CH3:31])[C:21](=[O:28])[C:22]([NH:24][CH:25]3[CH2:27][CH2:26]3)=[O:23])[CH2:16][C@@:15]3([CH2:36][C:35](=[O:37])[N:34]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH2:33]3)[CH2:14]2)=[O:12])[CH2:58][CH2:59][CH2:60][CH2:61]1
Reactant: CCCC(NC(=O)[C@@H]1C[C@@]2(CC(=O)N(c3ccccc3)C2)CN1C(=O)[C@@H](N(C(=O)[O-])C1CCCC1)C(C)(C)C)[C@H](O)C(=O)NC1CC1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: O
Agent: O=S([O-])([O-])=S
Agent: [NH-]O
Agent: [Na+]
Solvent: ClCCl
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@]2(CC(=O)N(c3ccccc3)C2)CN1C(=O)[C@@H](NC(=O)OC1CCCC1)C(C)(C)C)C(=O)C(=O)NC1CC1

Procedure:
The hydroxy amide cyclopentyl-(S)-1-((3S,5R)-3-((S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)-8-oxo-7-phenyl-2,7-diazaspiro[4.4]nonan-2-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (J6a) (4.1 mg, 6.3 μmol) was dissolved in CH2Cl2 (1.0 ml) and treated with Dess-Martin periodinane (DMP, 8.0 mg, 18.9 μmol, 3 eq) for 3 hrs at room temp. The reaction was quenched with 1M sodium thiosulfate in water (32 μl, 5 eq). The reaction was loaded onto silica (eluted with ethyl acetate/hexane gradient) to give cyclopentyl-(S)-1-((3S,5R)-3-((S)-1-(cyclopropylamino)-1,2-dioxohexan-3-ylcarbamoyl)-8-oxo-7-phenyl-2,7-diazaspiro[4.4]nonan-2-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (compound no. 1) (3.1 mg, 4.8 μmol) as a white solid. NMR (CDCl3) δ5195m, 46H), 1.96 (m, 1H), 2.25 (m, 1H), 2.61 (m, 2H), 2.80 (s, 2H), 3.60 (dd, 2H), 4.00 (d, 1H), 4.22 (m, 2H), 4.70 (m, 1H), 4.90 (m, 1H), 5.20 (d, 1H), 5.35 (m, 1H), 6.90 (s, 1H), 7.19 (m, 1H), 7.38 (m, 2H), 7.65 (d, 1H). LCMS for C35H49N5O7 651.36 [M], found ES+ 652.5 [M+H]+ and ES− 650.6 [M−H]−, at 3.2 minutes retention time, using 10-90% acetonitrile/water (with 0.1% formic acid buffer) gradient over 5 minutes. The minor diastereomer cyclopentyl (S)-1-((3S,5S)-3-((S)-1-(cyclopropylamino)-1,2-dioxohexan-3-ylcarbamoyl)-8-oxo-7-phenyl-2,7-diazaspiro[4.4]nonan-2-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (compound no. 4) (1.4 mg, 2 pimp was obtained in similar fashion. 1H NMR (CDCl3) δ0.52 (m, 2H), 71m, 14H), 1.0-2.0 (m, 22H), 2.10 (m, 1H), 2.45-2.75 (m, 4H), 3.64 (t, 2H), 3.90 (d, 2H), 4.15 (d, 1H), 4.60 (m, 1H), 5.00 (m, 1H), 5.13 (d, 1H), 5.25 (m, 1H), 6.80 (m, 1H), 7.10 (m, 2H), 7.30 (m, 4H), 7.50 (m, 2H), 7.90 (m, 1H); LCMS for C35H49N5O7 651.36 [M], found ES+652.5 [M+H]+ and ES− 650.6 [M−H]−, at 3.2 minutes retention time, using 10-90% acetonitrile/water (with 0.1% formic acid buffer) gradient over 5 minutes.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([C:14]([OH:16])=[O:15])[C:7]([C:11](O)=[O:12])=[CH:8][CH:9]=2)[C:4]([CH3:17])=[N:3]1.C(OC(=O)C)(=O)C>>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]3[C:14](=[O:16])[O:15][C:11](=[O:12])[C:7]3=[CH:8][CH:9]=2)[C:4]([CH3:17])=[N:3]1
Reactant: Cc1nn(C)c2ccc(C(=O)O)c(C(=O)O)c12
Solvent: CC(=O)OC(C)=O
Product: Cc1nn(C)c2ccc3c(c12)C(=O)OC3=O
Temperature: 5 °C

Procedure:
A mixture of 1,3-dimethyl-1H-indazole-4,5-dicarboxylic acid (6.30 g, 26.9 mmol) and acetic anhydride is stirred at reflux temperature for 3 hours, cooled to 5° C. and filtered The filter cake is air-dried to give the title product as chartreuse needles (4.80 g, 82.5%), mp 214°-215.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([Br:12])([F:11])[F:10])[CH:5]=[C:4]([O:18][CH:19]([F:21])[F:20])[C:3]=1[NH:22][C:23]([C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N+:31]([O-])=[CH:30][CH:29]=[CH:28]2)=[O:24].[N:36]12CCCN=C1CCCC[CH2:37]2.O.C(OCC)(=O)C>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([Br:12])([F:11])[F:10])[CH:5]=[C:4]([O:18][CH:19]([F:21])[F:20])[C:3]=1[NH:22][C:23]([C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30]([C:37]#[N:36])[CH:29]=[CH:28]2)=[O:24]
Reactant: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)Br)cc1OC(F)F)c1ccc2c(ccc[n+]2[O-])c1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc2cc(C(=O)Nc3c(Br)cc(C(F)(C(F)(F)F)C(F)(F)Br)cc3OC(F)F)ccc2n1
Temperature: 60 °C
Reaction time: 5 h
Yield: 36.1 %

Procedure:
N-[2-Bromo-4-(1-bromo-1,1,2,3,3,3-hexafluoropropan-2-yl)-6-(difluoromethoxy)phenyl]-quinoline-6-carboxamide-1-oxide (0.41 g) was dissolved in tetrahydrofuran (50 ml), added with trimethylsilylnitrile (0.23 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.39 g), and stirred at 60° C. for 5 hours. Water was added to the reaction solution and extraction was carried out twice using ethyl acetate. The organic phases were combined and washed with water, and dried over anhydrous magnesium sulfate. The drying agent (anhydrous magnesium sulfate) was removed by filtration and the solvent was distilled off under the reduced pressure. The resulting residues were purified by column chromatography to obtain N-[2-bromo-4-(1-bromo-1,1,2,3,3,3-hexafluoropropan-2-yl)-6-(difluoromethoxy)phenyl]-2-cyanoquinoline-6-carboxamide (0.15 g, 36%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O>C(Cl)Cl.FC(F)(F)C(OC(=O)C(F)(F)F)=O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][CH2:11][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:10][C:6]=3[C:7](=[O:9])[C:14]=2[CH:15]=1
Reactant: O=C(O)c1cc(Br)ccc1COc1ccc(Br)cc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1c2cc(Br)ccc2COc2ccc(Br)cc21
Temperature: 0 °C
Yield: 47 %

Procedure:
A solution of 5-bromo-2-(4-bromophenoxymethyl)benzoic acid (100 g, 0.26 mole), and trifluoroacetic anhydride (160 mL) in one liter of methylene chloride containing 20 drops of boron trifluoride-ether complex was refluxed for three hours. The mixture was poured into ice water and then extracted with diethyl ether. Concentration of ether solution under reduced pressure and chromatography of the residue on a silica gel column (Waters Associates, Prep 500) with hexane/ethyl acetate (9:1) gave the ketone (45 g) mp 193°-194° C. pmr (DMSO-d6) δ: 8.12 (d, J=2.7 Hz, 1H, H10), 7.27-7.91 (m, 4H, aromatic H), 7.10 (d, J=8.8 Hz, 1H, H4), 5.32 (s, 2H, ArCH2O).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.Cl[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.CN(C)C(=O)C>[Cl:29][C:28]1[C:23]([N:16]2[CH2:17][CH2:18][C:19]3[C:10]([NH:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:20])[F:21])=[CH:8][CH:7]=4)=[N:11][CH:12]=[CH:13][C:14]=3[CH2:15]2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: Clc1cccnc1Cl
Reactant: FC(F)(F)c1ccc(Nc2nccc3c2CCNC3)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1ccc(Nc2nccc3c2CCN(c2ncccc2Cl)C3)cc1
Temperature: 150 °C
Yield: 27.6 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine (200 mg, 0.68 mmol) was dissolved in a mixture of dioxane/N,N-dimethylacetamide (4:1) (3 mL). To the mixture was added 2,3-dichloropyridine (200 mg, 1.36 mmol) and N,N-diisopropylethylamine (0.24 mL, 1.36 mmol). The mixture was heated at 150° C. in a Personal Chemistry microwave for 16 h. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give a brown residue. The residue was purified by flash chromatography over silica gel using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as an off-white powder (76 mg).
Reaction SMILES: CN1C(S[C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)/[C:10](=[N:19]/[S:20]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)(=[O:22])=[O:21])/[CH:9]=2)=NN=N1.[NH2:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([OH:34])=[O:33].N1C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[O:18]=[C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[N:19][S:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)(=[O:22])=[O:21])[CH:9]=[C:8]1[NH:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([OH:34])=[O:33]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: Cn1nnnc1SC1=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc2C1=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(NC2=CC(=NS(=O)(=O)c3cccs3)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
33.8 mg (E)-N-(3-(1-methyl-1H-tetrazol-5-ylthio)-4-oxonaphthalen-1(4H)-ylidene)thiophene-2-sulfonamide (12a) was dissolved in 3 ml THF, to which was added 13.7 mg 3-aminobenzoic acid. The resulting orange solution was stirred at r.t. for 30 min and 0.2 ml THF solution containing 1 eq. pyridine was added. The reaction was continued for 30 min. The mixture was diluted to 50 ml with ethyl acetate and washed with 0.5 N NaHSO4 solution, water and brine. Dried over Na2SO4, the organic phase was filtered and the filtrate was concentrated. The residue was washed with dichloromethylene/hexane (1:1) affording the title compound 32.5 mg (74.2%) as a red solid, m.p.: 230° C. (dec.).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH2:28][C:29]#[C:30][CH3:31])[C@H:3]([O:21]C1CCCCO1)/[CH:4]=[CH:5]/[C@@H:6]1[C@@H:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:9](=[O:20])[CH2:8][CH2:7]1>C(O)(=O)C.O.C1COCC1>[CH3:1][C:2]([CH3:32])([CH2:28][C:29]#[C:30][CH3:31])[C@H:3]([OH:21])/[CH:4]=[CH:5]/[C@@H:6]1[C@@H:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:9](=[O:20])[CH2:8][CH2:7]1
Reactant: CC#CCC(C)(C)[C@@H](/C=C/[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)O)OC1CCCCO1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC#CCC(C)(C)[C@H](O)/C=C/[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)O

Procedure:
280 mg. of (13E)-(15R)-16,16-dimethyl-9-oxo-15-(tetrahydropyran-2-yloxy)-13-prosten-18-ynoic acid is agitated for 17 hours at 23° with 8 ml. of a mixture of glacial acetic acid/water/THF (65/35/10), evaporated under vacuum, and the residue purified by column chromatography on silica gel. With methylene chloride/5% methanol, 185 mg. of the title compound is obtained as a colorless oil.