Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9][CH2:10]Cl)=[C:4](Cl)[N:3]=1.[OH-:13].[Na+].O>C(O)(C)(C)C>[Cl:8][C:6]1[C:5]2[CH2:9][CH2:10][O:13][C:4]=2[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Nc1nc(Cl)c(CCCl)c(Cl)n1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: Nc1nc(Cl)c2c(n1)OCC2

Procedure:
A suspension of 6.0 g of 2-amino-5-(2-chloroethyl)-4,6-dichloropyrimidine, 29 ml of 2 N aqueous sodium hydroxide solution, 35 ml water and 75 ml of t-butanol was heated to reflux (60°) for 24 hours then cooled. The solid was collected by filtration, rinsed with water and dried to yield 2.4 g of 4-chloro-5,6-dihydrofuro[2,3-d]pyrimidin-2-amine, m.p. 258°-263°. The product showed characteristic triplet absorption bands at 3.40 and 5.10 ppm in the nuclear magnetic resonance spectrum (60 MHz), indicating the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[S:8][C:4]=2[CH:3]=1.Br[CH2:13][CH2:14][F:15].C([O-])([O-])=O.[Cs+].[Cs+].O>CN1C(=O)CCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([S:9][CH2:13][CH2:14][F:15])[S:8][C:4]=2[CH:3]=1
Reactant: FCCBr
Reactant: Sc1nc2ccc(Br)cc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: FCCSc1nc2ccc(Br)cc2s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46.3 %

Procedure:
To 6-bromobenzo[d]thiazole-2-thiol (160 mg, 0.65 mmol) and 1-bromo-2-fluoroethane (165 mg, 1.3 mmol) in 5 mL of NMP was added Cs2CO3 (635 mg, 1.95 mmol). The mixture was stirred at rt for 5 hours. It was added water (20 mL) and precipitate was collected through filtration and washed with water (10 mL) and dried under high vacuum. The crude product was purified with silica chromatography (5% to 30% EtOAc in hexane) to afford 6-Bromo-2-(2-fluoroethylthio)benzo[d]thiazole as a yellow solid (88 mg, 46%). MS (ESI) m/z 291.9, 293.9 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:35][O:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[N:41][CH:42]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:39]5[CH:40]=[N:41][CH:42]=[C:37]([O:36][CH3:35])[CH:38]=5)[CH:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)c4)cc3)cc2)CC1
Reactant: COc1cncc(B(O)O)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cncc(OC)c5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(3-bromo-phenylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 5-methoxypyridine-3-boronic acid.
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][C:8]1[N:16]2[C:11]([CH:12]=[CH:13][C:14]([CH2:17][N:18]([CH3:20])[CH3:19])=[CH:15]2)=[CH:10][C:9]=1[CH3:21])(C)(C)C.FC(F)(F)C(O)=O.C(C1NC=CN=1)(C1[NH:33]C=CN=1)=O>C(Cl)Cl>[CH3:19][N:18]([CH2:17][C:14]1[CH:13]=[CH:12][C:11]2[N:16]([C:8]([CH2:7][C:6]([NH2:33])=[O:5])=[C:9]([CH3:21])[CH:10]=2)[CH:15]=1)[CH3:20]
Reactant: Cc1cc2ccc(CN(C)C)cn2c1CC(=O)OC(C)(C)C
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2ccc(CN(C)C)cn2c1CC(N)=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 91.7 %

Procedure:
(6-Dimethylaminomethyl-2-methyl-indolizin-3-yl)-acetic acid tert-butyl ester (122 mg, 0.40 mmol) is dissolved in CH2Cl2 (10 ml) containing 5% of trifluoroacetic acid. The mixture is stirred for 14 hours at room temperature and then concentrated in vacuo. The residue is azeotroped twice with toluene, dissolved in N,N-dimethylformamide (2.0 ml) and treated with carbonyl diimidazole (76 mg, 0.44 mmol, 1.1 equiv). After 1 hour at room temperature, the volatiles are removed in vacuo, and the activated acid is taken up in concentrated aqueous ammonia (10 ml). The mixture is stirred for 30 minutes at room temperature and then concentrated in vacuo. The residue is purified via flash chromatography (CH2Cl2/MeOH 7:1) to afford the title compound (90 mg, 91%). 1H NMR (400 MHz, d6-DMSO): δ=7.31 (s, 1H), 7.27 (s, 1H), 6.75 (s, 1H), 6.61 (dd, J=9.3/1.5 Hz, 1H), 4.06 (s, 2H), 3.38 (s, 2H), 2.66 (s, 6H), 2.13 (s, 3H). MS (ES+): 246 (M+H)+.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:44]=[CH:43][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[C:27]([NH:29][C:30]([N:32]3[CH2:37][CH2:36][C:35]([OH:42])([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:34][CH2:33]3)=[O:31])[CH:28]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:25])([CH3:24])[C:20]([O:22]C)=[O:21])=[CH:15][CH:14]=2)=[CH:6][CH:5]=1>CO.C1COCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[C:27]([NH:29][C:30]([N:32]3[CH2:33][CH2:34][C:35]([OH:42])([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:36][CH2:37]3)=[O:31])[CH:28]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:24])([CH3:25])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2)=[CH:43][CH:44]=1
Reactant: COC(=O)C(C)(C)c1ccc(Oc2cc(NC(=O)N3CCC(O)(CC(C)C)CC3)cc(Oc3ccc(F)cc3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CC1(O)CCN(C(=O)Nc2cc(Oc3ccc(F)cc3)cc(Oc3ccc(C(C)(C)C(=O)O)cc3)c2)CC1
Temperature: 45 °C
Yield: 82.6 %

Procedure:
At room temperature, in a 1 L pear-shaped evaporating flask, the compound prepared in Example 8 (24.8 g) was dissolved in a mixed solution of methanol (150 mL) and THF (150 mL) and the solution was stirred. The solution was then heated to 45° C., gradually added with a 1 N sodium hydroxide aqueous solution (107 mL) and stirred overnight at 45° C. The solution was added with a 2 N sodium hydroxide aqueous solution (20 mL). After stirring for 1 hour, the solvent was distilled off under reduced pressure and the solution was further stirred for 1.5 hours at 45° C. A 2 N sodium hydroxide aqueous solution (12 mL) was further added and the solution was stirred for 45 minutes at 55° C. The solution was cooled to 0° C. and added with ice and a 5 N hydrochloric acid aqueous solution until the reaction system was acidic (pH=2). The reaction system was diluted with ethyl acetate and extracted. An organic layer was further washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulphate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=65:35→44:56→30:70) to give the titled compound (20 g) having the following physical properties.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][OH:20])([CH:8]([CH3:10])[CH3:9])[O:5][C:4](=[O:21])[CH:3]=1.[C:22]([C:26]1[C:27]2[CH:45]=[CH:44][CH:43]=[CH:42][C:28]=2[S:29][C:30]=1[S:31]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:22]([C:26]1[C:27]2[CH:45]=[CH:44][CH:43]=[CH:42][C:28]=2[S:29][C:30]=1[S:31][C:3]1[C:4](=[O:21])[O:5][C:6]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][OH:20])([CH:8]([CH3:9])[CH3:10])[CH2:7][C:2]=1[OH:1])([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1ccc(S(=O)(=O)Sc2sc3ccccc3c2C(C)(C)C)cc1
Reactant: CC(C)C1(CCc2ccccc2CO)CC(O)=CC(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C1(CCc2ccccc2CO)CC(O)=C(Sc2sc3ccccc3c2C(C)(C)C)C(=O)O1

Procedure:
The title compound was prepared according to General Method 16a using 4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one (Example E-34; 0.20 g, 0.73 mmol), toluene-4-thiosulfonic acid S-(3-tert-butyl-benzo[b]thiophen-2-yl)ester (Example BB-8; 0.302 g, 0.803 mmol), potassium carbonate (0.11 g, 0.80 mmol), and DMF (2.0 mL). The product was purified via column chromatography (eluting with EtOAc) to the title compound, mp 92-94° C.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH3:15][N+:16]([O-:18])=[O:17].C1CCN2C(=NCCC2)CC1>>[N+:16]([CH2:15][CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:2](=[O:1])[CH2:7]1)([O-:18])=[O:17]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC=CC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(C[N+](=O)[O-])CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.1 %

Procedure:
A solution of tert-butyl 2-oxo-5,6-dihydropyridine-1(2H)-carboxylate (2.1 g, 11 mmol) in CH3NO2 (22.7 g, 372 mmol) under N2 was added DBU (2.52 g, 16.5 mmol). The mixture was stirred at room temperature overnight and then condensed and purified by flash chromatography to give compound tert-butyl 4-(nitromethyl)-2-oxopiperidine-1-carboxylate (0.6 g, 22%) as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:13][S:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)(=[O:11])=[O:12])=[O:23])=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1cc2ccccc2o1
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1cc2ccccc2o1
Yield: 48.7 %

Procedure:
To a solution of benzofuran (4.55 g, 38.5 mmol) in 100 mL of anhydrous tetrahydrofuran under a nitrogen atmosphere at -78° C. was added a 1.3 M hexanes solution of n-butyllithium (29.6 mL, 38.5 mmol). The reaction was warmed to 0° C. and stirred for 30 minutes. Sulfur dioxide gas was bubbled through this mixture for 20 minutes at 0° C. and the reaction was concentrated under vacuum. The residue was dissolved in 100 mL of water, to which were added 304 millimoles of sodium acetate and 100 millimoles of hydroxylamine-0-sulphonic acid. This reaction was stirred at room temperature for 1.5 hours. The mixture was diluted with 200 mL of water, and the aqueous layer was separated and poured into 600 mL of diethyl ether. The ether layer was extracted with 1 N sodium hydroxide (3×100 mL). The combined aqueous extract was acidified with about 300 mL of 1 N hydrochloric acid, and then extracted with methylene chloride. The combined methylene chloride extract was dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide 2.3 g of 2benzofuransulfonamide. The sulfonamide (11.7 mmol) was reacted with 4-chlorophenylisocyanate (11.7 mmol) as described in Method A above to obtain 2 grams of the title product as a solid. 1H NMR (CD3SOCD3); δ9.23 (s, 1 H), 7.87 (d, J=9 Hz, 1 H), 7.82 (s, 1 H), 7.78 (d, J=9 Hz, 1 H), 7.58 (dd, J=9, 9 Hz, 1 H), 7.46 (m, 1 H), 7.44 (d, J=9 Hz, 2 H), 7.32 (d, J=9 Hz, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[F:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: Fc1ccccc1CBr
Reactant: N#Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: N#Cc1cc(Br)ccc1OCc1ccccc1F
Yield: 92 %

Procedure:
A solution of 5-bromo-2-hydroxybenzonitrile (3.31 g, 16.71 mmol), synthesized as described in J. Org. Chem. 1997, 13, 4504-4506, 2-fluorobenzylbromide (commercially available, 2.02 ml, 3.16 g, 16.71 mmol) and potassium carbonate (3.46 g, 25.06 mmol) was stirred overnight at room temperature. Then diethylether was added and the solution was washed with water, 1M NaOH and brine. The organic layer was dried (Na2SO4), filtered and evaporated to afford the title compound (4.74 g, 92%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.0 (M, 1H), 7.9 (m, 1H), 7.6 (m, 1H), 7.5-7.3 (m, 2H), 7.2 (m, 2H), 5.3 (s, 2H).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH:10]([NH:17][C:18]1[C:27]2[C:22](=[C:23]([C:30](=[O:32])[NH2:31])[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C)(C)(C)C.C1COCC1.Cl>O1CCOCC1>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[C:23]([C:30]([NH2:31])=[O:32])[CH:24]=1)[N:21]=[CH:20][N:19]=[C:18]2[NH:17][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][NH:7][CH3:6]
Reactant: COc1cc(C(N)=O)c2ncnc(NC(CN(C)C(=O)OC(C)(C)C)c3ccccc3)c2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CNCC(Nc1ncnc2c(C(N)=O)cc(OC)cc12)c1ccccc1
Reaction time: 8 h
Yield: 100 %

Procedure:
A scintillation vial equipped with a stir bar was charged with [2-(8-carbamoyl-6-methoxy-quinazolin-4-ylamino)-2-phenyl-ethyl]-methyl-carbamic acid tert-butyl ester (150 mg, 0.33 mmol) and THF, (5 mL). Then, 4 M HCl in dioxane, (5 mL) was added at RT and the mixture was stirred overnight. After 18 h, a white precipitate had formed and LCMS indicated consumption of SM. The mixture was diluted with Et2O (30 mL) and the precipitate was filtered through a filter paper and washed with Et2O, (30 mL). The solid was dried under vacuum. Amount obtained: 114 mg, 0.32 mmol, 100% yield. LCMS (ESI) 352 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[O:30](S(C(F)(F)F)(=O)=O)[S:31]([C:34]([F:37])([F:36])[F:35])(=O)=[O:32]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[S:31]([O:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[O:14])=[CH:4][CH:3]=1)(=[O:32])=[O:30]
Reactant: Cc1cccc2c(O)ccc(C(=O)N3CCOCC3)c12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2c(OS(=O)(=O)C(F)(F)F)ccc(C(=O)N3CCOCC3)c12
Reaction time: 0.17 h

Procedure:
To a solution of (4-hydroxy-8-methylnaphthalen-1-yl)(morpholino)methanone (above Step-7 intermediate) (1 equiv) in dry CH2Cl2 (4 mL) under nitrogen was added DIPEA (3 equiv) at 0° C. and the mixture was stirred for 10 min. To this, Tf2O (1.5 equiv) was added drop wise and the reaction mixture was stirred for another 1.5 h at 0° C. Then it was slowly quenched with water (10 mL) and the aqueous layer was extracted with CH2Cl2 (4×10 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried (Na2SO4) and filtered. The solvent was removed under reduced pressure and the residue was purified by column to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O[CH2:14][S:15]([CH2:18][CH2:19][Cl:20])(=[O:17])=[O:16].S(=O)(=O)(O)O>C(Cl)CCl>[Cl:1][C:2]1[C:10]([NH:11][CH2:14][S:15]([CH2:18][CH2:19][Cl:20])(=[O:17])=[O:16])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1cc(Cl)cc(C(=O)O)c1Cl
Reactant: O=S(=O)(CO)CCCl
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: O=C(O)c1cc(Cl)cc(NCS(=O)(=O)CCCl)c1Cl
Temperature: 40 °C
Reaction time: 3 h

Procedure:
20.6 g (0.1 mole) of 2,5-dichloro-3-aminobenzoic acid and 18.7 g (0.12 mole) of hydroxymethyl-(β-chloroethyl)-sulfone were suspended in 100 ml of ethylene chloride, 1 ml of concentrated sulfuric acid was added thereto and the mixture was stirred for 3 hours at 40° C. The mixture was then cooled and the product which had crystallized out was filtered off and recrystallized from acetonitrile. This gave 30.8 g (89% of theory) of 2,5-dichloro-3-[(β-chloroethyl)-sulfonylmethylamino]-benzoic acid in the form of colorless crystals of melting point 156° C (with decomposition).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:12](=[O:13])[CH2:11][C@H:10]1O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:12](=[O:13])[CH:11]=[CH:10]1
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCCC[C@H](O)/C=C/[C@H]1C=CC(=O)[C@@H]1CCCCCCC(=O)O

Procedure:
Alternately, the PGE1 -type compound is transformed to a bis-trifluoroacetate, for example by reaction with trifluoroacetic anhydride in the presence of pyridine in a solvent at 0° to 5° C., and thereafter contacted with a low-boiling alcohol (preferably b.p. below 110° C.) with a tertiary amine to form a PGA1 -type compound.
Reaction SMILES: [F:1][CH:2]([F:16])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]#[N:13])[C:8]([C:14]#[N:15])=[CH:7][CH:6]=2.Cl[CH2:18][C:19]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[O:21][N:20]=1>>[F:16][CH:2]([F:1])[C:3]1[N:4]([CH2:18][C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)[O:21][N:20]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]#[N:13])[C:8]([C:14]#[N:15])=[CH:7][CH:6]=2
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1C#N
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1C#N

Procedure:
Synthesized as described in Example 23 from 2-(difluoromethyl)-1H-indole-4,5-dicarbonitrile and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole: MS (ES) m/z 444 (M+1).
Reaction SMILES: [CH:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[C:9]([Cl:18])[C:10]([Cl:17])=[C:11]([OH:16])[CH:12]=3)[C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:21][C:22]([O:24]CC)=[O:23].[OH-].[K+]>C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>[O:19]=[C:7]1[C:8]2[C:13](=[CH:12][C:11]([O:16][CH2:21][C:22]([OH:24])=[O:23])=[C:10]([Cl:17])[C:9]=2[Cl:18])[CH2:14][CH2:15][CH:6]1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)CBr
Reactant: O=C1c2c(cc(O)c(Cl)c2Cl)CCC1C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)CC2
Reaction time: 3 h

Procedure:
2-Cyclopentyl-6-hydroxy-7,8-dichloro-1-tetralone (9.45 g., 0.03 mole) is heated in a mixture of potassium carbonate (5.52 g.) and ethyl bromoacetate (6.68 g., 0.04 mole) in DMF 70 ml.) at 55°-60° C. for three hours. Potassium hydroxide (2.24 g., 0.04 mole) is added. This solution is added to the reaction mixture and the whole is refluxed for 1 hour. Most of the methanol is evaporated and the residue is added to water (ca. 200 ml.). The solid that separates upon acidification is collected, washed with water and crystallized from ethanol to obtain (1-oxo-2-cyclopentyl-7,8-dichloro-1,2,3,4-tetrahydro-6-naphthyloxy)acetic acid.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([C:26](=O)[C:27]([F:30])([F:29])[F:28])[CH:22]=[C:23]([Cl:25])[CH:24]=1.[OH-].[Ca+2].[OH-].CN(C)C=O>COC(C)(C)C>[Cl:18][C:19]1[CH:20]=[C:21]([C:26]([C:27]([F:30])([F:28])[F:29])=[CH:2][C:1]([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:5]=2)=[O:3])[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: COC(=O)c1ccc(C(C)=O)c2ccccc12
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: [Ca+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: COC(=O)c1ccc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)c2ccccc12
Reaction time: 15 h

Procedure:
A mixture of methyl 4-acetyl-1-naphthalenecarboxylate (5.36 g, 23.4 mmol), 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (5.68 g, 23.4 mmol), calcium hydroxide (0.172 g, 2.3 mmol), N,N-dimethylformamide (16 mL), and tert-butyl methyl ether (32 mL) was placed in a thermometer-equipped reaction vessel. The reaction vessel was connected to a ten-plate Oldershaw column, the output of which was condensed and fed into a decanter initially filled with tert-butyl methyl ether. A nitrogen atmosphere was maintained in the apparatus. The upper part of the decanter was connected to return condensate to the fifth plate of the Oldershaw column. This arrangement ensured that wet (containing dissolved water) tert-butyl methyl ether from the decanter was not returned to the reaction vessel. A drain valve at the bottom of the decanter allowed removing tert-butyl methyl ether in addition to water from the decanter. The reaction mixture was heated to distill the tert-butyl methyl ether/water azeotrope. As the decanter trap contained an amount of tert-butyl methyl ether sufficient to dissolve all of the water formed by the reaction, the condensate in the trap did not separate into layers containing predominately water and predominately tert-butyl methyl ether. Because the reaction mixture initially contained mostly tert-butyl methyl ether, the mixture boiled at a temperature not much exceeding the normal boiling point of tert-butyl methyl ether (e.g., about 65-70° C.). The reaction appeared to proceed relatively slowly at this temperature, so condensate was gradually drained from the decanter trap to remove tert-butyl methyl ether. As the concentration of tert-butyl methyl decreased in the reaction mixture, the temperature of the boiling mixture increased. Tert-butyl methyl ether was removed by draining the decanter until the temperature of the boiling reaction mixture reached about 75 to 80° C. To maintain this temperature range, tert-butyl methyl ether was added as needed to compensate for loss of solvent from the apparatus. The total time from beginning heating the reaction mixture to stopping distillation, not including a shutdown period overnight, was about 15 h. During this time period a further portion of calcium hydroxide (1.34 g, 18.1 mmol) was added to increase the reaction rate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[CH3:27][CH:28]([CH2:31][CH3:32])[CH2:29][SH:30].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:27][CH:28]([CH2:31][CH3:32])[CH2:29][S:30][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1ncc(Br)cc12
Reactant: CCC(C)CS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCC(C)CSc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Temperature: 25 °C

Procedure:
A mixture of (S)-3-bromo-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (53 mg, 0.130 mmol), 2-methylbutane-1-thiol (14.21 mg, 0.130 mmol), tris(dibenzylideneacetone)dipalladium (5.93 mg, 6.48 μmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (3.75 mg, 6.48 μmol), N,N-diethyl-N-isopropylpropan-2-amine (45.1 μL, 0.259 mmol), and dry 1,4-dioxane (0.5 mL) was irradiated in microwave glass vessel at 160° C. for 35 minutes. The whole was cooled to rt and the resulting solid was filtered off and washed with MeOH (3 mL). The filtrates were combined, concentrated, and purified with reverse phase HPLC. Fractions containing the product were combined, and concentrated. TFA was removed using catch and release with strong cation exchange with 2 g SCX columns. First, the material was loaded in the column with MeOH. The column washed with MeOH to remove the TFA, then with 2M NH3 in MeOH to collect the product. The basic wash was collected and dried to afford (4′S)-3-(2-methylbutylthio)-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a white solid.