Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(/[C:7](/[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:8](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)\[CH2:9][CH2:10]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:46]>C(#N)C>[Br:46][CH2:10][CH2:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1
Reactant: COc1ccc(/C(=C(/CCO)c2ccccc2)c2ccccc2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COc1ccc(C(=C(CCBr)c2ccccc2)c2ccccc2)cc1
Reaction time: 1 h

Procedure:
33.0 g of (Z)-1,2-diphenyl-1-(4-methoxyphenyl)-1-buten-4-ol are dissolved in 500 ml of dry acetonitrile. Then 39.3 g of triphenylphosphine and 49.8 g of carbon tetrabromide are added while stirring. The stirring is continued for 1 h at room temperature. The solvent is evaporated and the evaporation residue is dissolved in hot petrol ether. The insoluble material is removed by filtration. The mother liquor is evaporated, and the evaporation residue is recrystallized from methanol. The yield of the product is 26.7 g (68%) having m.p. 116°-8° C.
Reaction SMILES: C(SC1N=CNN=1)C.C(Cl)(Cl)=O.[C:13](N1C=NC(SCC)=N1)([N:15]1[CH:19]=[N:18][C:17]([S:20][CH2:21][CH3:22])=[N:16]1)=[O:14].[CH2:31]([NH:34][CH2:35][CH2:36][CH3:37])[CH2:32][CH3:33]>O1CCCC1.N1C=CC=CC=1>[CH2:31]([N:34]([CH2:35][CH2:36][CH3:37])[C:13]([N:15]1[CH:19]=[N:18][C:17]([S:20][CH2:21][CH3:22])=[N:16]1)=[O:14])[CH2:32][CH3:33]
Reactant: CCCNCCC
Reactant: CCSc1ncn(C(=O)n2cnc(SCC)n2)n1
Agent: CCSc1nc[nH]n1
Agent: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCN(CCC)C(=O)n1cnc(SCC)n1
Reaction time: 0.5 h

Procedure:
A solution of 51.6 g. 3-ethylthio-1,2,4-triazole and 31.6 g. dry pyridine in 100 ml. dry tetrahydrofuran was added dropwise to 200 ml. of a 10% w/v solution of phosgene in dry tetrahydrofuran (20 g. phosgene, 0.5 molecular proportion) with stirring and cooling to maintain the reaction temperature at 25° - 30°C. The mixture was stirred at 25° - 30°C. for a further period of 0.5 hour, and was then filtered to remove pyridine hydrochloride formed in the reaction. To the resulting solution of 1,1'-carbonylbis(3-ethylthio-1,2,4-triazole) was added dropwise with stirring a solution of 20.2 g. dipropylamine in 50 ml. dry tetrahydrofuran. The mixture was stirred for a further period of 0.5 hour, and was then evaporated under reduced pressure to remove solvent. The residual oil was dissolved in methylene dichloride and the resulting solution was washed successively with 0.5N sodium hydroxide solution, water, and finally 0.5N hydrochloric acid. The washed solution was distilled under reduced pressure to give 1-dipropylcarbamoyl-3-ethylthio-1,2,4-triazole, b.p. 130° - 132°C./0.5 mm. Elemental analysis satisfactory.
Reaction SMILES: Cl.[CH2:2]([C@@:5]1([OH:29])[C@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:8]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:7][C@@H:6]1[O:27][CH3:28])[CH:3]=[CH2:4]>>[C:11]([O:29][C@:5]1([CH2:2][CH:3]=[CH2:4])[C@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:8]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:7][C@@H:6]1[O:27][CH3:28])(=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=CC[C@]1(O)[C@@H](OC)O[C@H](COCc2ccccc2)[C@H]1OCc1ccccc1
Agent: Cl
Product: C=CC[C@]1(OC(=O)c2ccccc2)[C@@H](OC)O[C@H](COCc2ccccc2)[C@H]1OCc1ccccc1

Procedure:
The reaction mixture was then stirred with 1 N HCl and extracted with dichloro-methane. The organic layers were combined and washed with saturated aqueous NaHCO3 followed by brine. After drying with MgSO4, filtration and evaporation of the volatiles, the residue was purified by column chromatography (400 g silica) eluting with heptane to 15% ethyl acetate in heptane to give reaction product as an oil (as a mixture with compound 5). The mixture was purified again with CH2Cl2 as eluent (400 g silica). The pure fractions were collected and intermediate 6 was obtained as a colorless oil (13.05 g, 39%). HPLC Condition A, Rt: 3.41 min, m/z=457 (M-OMe)+. 1H NMR (400 MHz, CDCl3) δ ppm 8.1 (d, 2H, J=7.9 Hz), 7.68-7.28 (m, 13H), 5.84-5.77 (m, 1H), 5.12 (d, 1H, J=16 Hz), 4.95 (d, 1H, J=16 Hz), 4.92 (d, 1H, J=12.3 Hz), 4.56 (d, 1H, J=12.3 Hz), 4.48 (d, 1H, J=11.6 Hz), 4.40 (d, 1H, J=11.6 Hz), 4.2 (m, 1H), 3.85 (d, 1H, J=6.2 Hz), 3.53 (d, 1H, J=10.8 Hz), 3.7 (s, 3H), 3.45 (dd, 1H, J=10.8, 6.2 Hz), 3.25 (dd, 1H, J=15.5, 7.3 Hz), 2.45 (dd, 1H, J=15.5, 7.3 Hz).
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClC(C1C=CC=CC=1)C1C=CC=CC=1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:2]([N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: c1ccc2c(c1)CCN2
Agent: ClC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc(C(c2ccccc2)N2CCc3ccccc32)cc1

Procedure:
A mixture of 49.4 g (0.2 mole) of bromodiphenylmethane (an equimolar quantity of chlorodiphenylmethane may be used instead), 23.8 g (0.2 mole) of indoline, 55.2 g (0.4 mole) of anhydrous potassium carbonate, and 200 ml of toluene is refluxed for 16 hrs under nitrogen with good stirring. The salts are removed by filtration, and the solvent is evaporated. The residue is chromatographed on silica gel with 30:70 toluene-hexane as the eluent. The product is a viscous oil, which can be crystallized from ethanol to give 1-benzhydryl-indoline, m.p. 62°-63.5°. The structure is confirmed by nmr spectroscopy and elemental analysis:
Reaction SMILES: [C:1]([C@H:4]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[O:9][CH2:8][CH2:7][N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5]1)(=O)[NH2:2].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[C:1]([C@H:4]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[O:9][CH2:8][CH2:7][N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](C(N)=O)C1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](C#N)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-carbamoyl-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (437 mg) and triethylamine (0.344 ml) in THF (5.6 mL) was added trifluoroacetic anhydride (0.171 mL), and the mixture was stirred at 0° C. for 2 hr. Then, the mixture was stirred at room temperature for 1 hr, distilled water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (205 mg).
Reaction SMILES: [H-].[Na+].CO[C:5](=[O:8])[O:6][CH3:7].[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[CH2:15][CH2:14][CH2:13]2.Cl>O1CCCC1.CCOCC.CCCCCC>[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[CH:15]([C:5]([O:6][CH3:7])=[O:8])[CH2:14][CH2:13]2
Reactant: O=C1CCCc2cc(F)ccc21
Reactant: COC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C1CCc2cc(F)ccc2C1=O
Yield: 98.2 %

Procedure:
Hexane washed sodium hydride (3.5 g of 60%, 88 mmole) was covered with 75 ml of tetrahydrofuran and 5.4 ml (64 mmole) of dimethylcarbonate was added in one portion. The solution was heated to reflux and 6-fluoro-3,4-dihydro-1(2H)-naphthlenone (7.2 g, 44 mmole) in 25 ml of tetrahydrofuran was added dropwise while maintaining reflux. After the addition was complete, the reaction was refluxed for 1.5 hours. The reaction was then cooled in an ice bath and 10% aqueous HCl solution was carefully added. The solution was diluted with ether and the aqueous Phase was separated and extracted twice with ether. The combined organic phases were dried (MgSO4) and concentrated. The crude product was a pale yellow solid (9.6 g, 98% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:12]=NN(C)[CH:15]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:17][C:18]1C=C(B2OC(C)(C)C(C)(C)O2)C=[CH:20][N:19]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:15]=[CH:20][N:19]=[C:18]([CH3:17])[CH:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Product: Cc1ccc(-c2ccnc(C)c2)c(C(=O)O)c1

Procedure:
The title compound was synthesized following the same general protocol as described for 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid in Example A1, using 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. ESI-MS (m/z): 228 [M+1]+.
Reaction SMILES: Cl[C:2]([Cl:12])(OC(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][C:14]1[C:22]2[C:17](=[N:18]C=[CH:20][CH:21]=2)[S:16][N+:15]=1[O-].C(NC(C)C)(C)C>ClCCl>[Cl:12][C:2]1[N:18]=[C:17]2[S:16][N:15]=[C:14]([CH3:13])[C:22]2=[CH:21][CH:20]=1
Reactant: Cc1c2cccnc2s[n+]1[O-]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: Cc1nsc2nc(Cl)ccc12
Temperature: 25 °C
Yield: 46 %

Procedure:
A solution of triphosgene (190 mmol) in dichloromethane (200 mL) was added dropwise over 20 min to a solution of 3-methylisothiazolo[5,4-b]pyridine-N-oxide (47.4 mmol) in dichloromethane (150 mL) at −20° C. A solution of diisopropylamine (190 mmol) in dichloromethane (200 mL) was added dropwise over 1 h. The reaction mixture was allowed to warm to rt and was maintained for 16 h. The reaction mixture was quenched with water (40 mL) of water and the pH was adjusted to 7 by the addition of 10% sodium hydroxide. The organic layer was washed with water (100 mL). The combined aqueous layers were extracted with dichloromethane (10×100 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (1/80 ethyl acetate/petroleum ether) to provide 6-chloro-3-methylisothiazolo[5,4-b]pyridine in 46% yield as a colorless solid.
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:34][C:35]([CH3:40])([CH3:39])[C:36](O)=[O:37].[NH2:41][C@H:42]1[C:50]2[C:45](=[CH:46][CH:47]=[C:48]([C:51]([O:53][CH3:54])=[O:52])[CH:49]=2)[CH2:44][CH2:43]1>C1COCC1>[F:34][C:35]([CH3:40])([CH3:39])[C:36]([NH:41][C@H:42]1[C:50]2[C:45](=[CH:46][CH:47]=[C:48]([C:51]([O:53][CH3:54])=[O:52])[CH:49]=2)[CH2:44][CH2:43]1)=[O:37]
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Reactant: CC(C)(F)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)C(C)(C)F)CC2
Reaction time: 0.25 h
Yield: 52 %

Procedure:
DIPEA (1.68 ml, 10.2 mmol, 3 eq) and HATU (1.29 g, 3.4 mmol, 1 eq) were added to a solution, cooled to 0° C., of 2-fluoro-2-methylpropanoic acid (360 mg, 3.4 mmol, 1 eq) in THF (15 ml). The reaction mixture was stirred for 15 min, then a solution of (R)-methyl 3-amino-2,3-dihydro-1H-indene-5-carboxylate (A-07) (650 mg, 3.4 mmol, 1 eq) in THF (5 ml) was added and stirring was carried out for 16 h at room temperature. The reaction mixture was concentrated under reduced pressure, taken up in dichloromethane (50 ml) and washed with saturated sodium hydrogen carbonate solution (20 ml), saturated ammonium chloride solution (20 ml), water (20 ml) and saturated sodium chloride solution (20 ml). It was then dried over sodium sulfate and concentrated under reduced pressure, and the crude product was purified by column chromatography (silica gel, 2% methanol/dichloromethane). Yield: 52% (500 mg, 1.79 mmol)
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[N:22]=[CH:21][C:20]([C:23](=O)/[CH:24]=[CH:25]/[N:26](C)C)=[CH:19][CH:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.O.[NH2:31]N>CO>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:18]=[CH:19][C:20]([C:23]5[NH:31][N:26]=[CH:25][CH:24]=5)=[CH:21][N:22]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CN(C)/C=C/C(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Reactant: NN
Solvent: O
Solvent: CO
Product: c1cc(-c2ccc(Oc3ccc4c(c3)CCN(C3CCC3)CC4)nc2)[nH]n1

Procedure:
A mixture of (2E)-1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-3-(dimethylamino)-2-propen-1-one (D53) (195 mg, 0.5 mmol) and hydrazine hydrate (0.4 ml) in methanol (3 ml) was heated at reflux for 24 hours. The reaction mixture was cooled and applied to a SCX ion exchange cartridge (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia/methanol (1:9). The combined basic fractions were concentrated in vacuo and the resulting residue purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (1:9:90) to afford the title compound (E215). MS (ES+) m/e 361 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=O.C([O-])([O-])=O.[K+].[K+].[F:19][C:20]([F:29])([F:28])/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:4]2[C:3]=1[O:12][CH:21]([C:20]([F:19])([F:29])[F:28])[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5]2
Reactant: COc1cc(Cl)c(O)c(C=O)c1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(OC)cc(Cl)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A mixture of 3-chloro-2-hydroxy-5-methoxybenzaldehyde prepared as in Step 1 (9.00 g, 48.2 mmole), K2CO3 (6.67 g, 48.2 mmole) and ethyl 4,4,4-trifluorocrotonate (8.65 mL, 57.9 mmole) in anhydrous DMF (20 mL) under a dry N2 atmosphere was stirred at room temperature for 30 minutes and was then heated to 85° C. for 3 h. Additional ethyl 444-trifluorocrotonate (3.00 mL, 20.1 mmole) was then added and the mixture was stirred at 85° C. overnight. The mixture was then cooled and poured into 1 N HCl (200 mL). Following extraction with EtOAc (3×200 mL), the combined extracts were washed with 0.25 N NaOH until the washes were basic, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by crystallization from ethanol to give 11.0 g (68% yield) of the product as a yellow crystalline solid: 'H NMR (dmso-d6/300 MHz) 7.92 (s, 1H), 7.18 (d, 1H, J=2.8 Hz), 7.13 (d, 1H, J=2.8 Hz), 6.05 (q, 1H, J=7.3 Hz), 4.21-4.29 (m, 2H), 3.73 (s, 3H), 1.26 (t, 3H, J=7.1 Hz).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.OCCC[C:16]1[C:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=C[C:19]2[CH2:20][CH2:21]O[C:18]=2[CH:17]=1.[O-]C1C=CC=CC=1.[Na+].O>CN(C)C=O>[CH2:26]([O:25][CH2:24][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: OCCCc1cc2c(cc1OCc1ccccc1)CCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 80 °C
Yield: 104.9 %

Procedure:
A solution of 8a (0.440 g, 1.01 mmol) in dry dimethylformamide (1 mL) was added to a solution of sodium phenoxide (0.140 g, 1.20 mmol) and the mixture heated to 80° C. for three hours. The reaction mixture was cooled, poured into water, and extracted with ether. The ether extracts were washed sequentially with water and 20% NaCl, dried (Na2SO4), and concentrated. Flash chromatography gave a purified benzyl ether (0.210 g, mp 81°-82° C.) which was directly deprotected as described above for 10 to give 11a. 2,3-Dihydro-4-(3-phenoxypropyl)-5-benzofuranol (11b) can be produced from 8b in similar fashion. 11a: mp 114-115° C.; 11b: mp 107°-108° C.
Reaction SMILES: [O:1]=[O+][O-].[CH:4]([CH:9]1[O:14][C:13]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[O:12][CH:11]([CH2:20][C:21]([OH:23])=[O:22])[CH2:10]1)=CC=CC>C(Cl)Cl>[CH:4]([CH:9]1[O:14][C:13]2([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[O:12][CH:11]([CH2:20][C:21]([OH:23])=[O:22])[CH2:10]1)=[O:1]
Reactant: O=[O+][O-]
Reactant: CC=CC=CC1CC(CC(=O)O)OC2(CCCCC2)O1
Solvent: ClCCl
Product: O=CC1CC(CC(=O)O)OC2(CCCCC2)O1

Procedure:
Ozone was passed through a solution of 4-(1,3-pentadienyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid (570 mg, 2.0 mmol) in methylene chloride (25 mL) at -78° C. After the solution had attained a blue color, nitrogen was passed through the solution to remove the excess ozone. Dimethyl sulfide (0.5 mL) was added and the solution was concentrated under reduced pressure to afford the title compound as a viscous oil which was used without further purification in the subsequent step.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.FC(F)(F)S(O[C:49]1[N:54]=[C:53]2[C:55]3[N:62]([CH3:63])[N:61]=[C:60]([C:64](=[O:69])[N:65]([O:67][CH3:68])[CH3:66])[C:56]=3[CH2:57][CH2:58][CH2:59][C:52]2=[CH:51][N:50]=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[N:78]1([C:84]2[CH:89]=[CH:88][C:87]([NH2:90])=[CH:86][CH:85]=2)[CH2:83][CH2:82][O:81][CH2:80][CH2:79]1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:68][O:67][N:65]([CH3:66])[C:64]([C:60]1[C:56]2[CH2:57][CH2:58][CH2:59][C:52]3[C:53](=[N:54][C:49]([NH:90][C:87]4[CH:86]=[CH:85][C:84]([N:78]5[CH2:83][CH2:82][O:81][CH2:80][CH2:79]5)=[CH:89][CH:88]=4)=[N:50][CH:51]=3)[C:55]=2[N:62]([CH3:63])[N:61]=1)=[O:69]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CON(C)C(=O)c1nn(C)c2c1CCCc1cnc(OS(=O)(=O)C(F)(F)F)nc1-2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CON(C)C(=O)c1nn(C)c2c1CCCc1cnc(Nc3ccc(N4CCOCC4)cc3)nc1-2
Temperature: 80 °C
Yield: 31.2 %

Procedure:
A mixture of Pd(OAc)2 (2 mg, 0.009 mmol), Xantphos (11 mg, 0.019 mmol), 3-[methoxy(methyl)carbamoyl]-1-methyl-1,4,5,6-tetrahydropyrazolo[4′,3′:6,7]cyclohepta[1,2-d]pyrimidin-9-yl trifluoromethanesulfonate (40 mg, 0.09 mmol), K2CO3 (248 mg, 1.8 mmol), 4-Morpholin-4-yl-phenylamine (21 mg, 0.12 mmol) in dioxane (3 mL) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon and the reaction mixture was heated at 80° C. for 48 h. The reaction mixture was then allowed to cool to room temperature and concentrated. The crude solid was purified by RP flash chromatography to afford 13 mg (30% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6])[CH3:2].[F:18][C:19]([F:30])([F:29])[O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>>[F:18][C:19]([F:29])([F:30])[O:20][C:21]1[CH:22]=[CH:23][C:24]([CH:25]2[C:9]3[NH:10][C:11]4[C:16]([C:8]=3[CH2:7][CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:17])[NH:6]2)=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:27][CH:28]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Product: CCOC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccc(OC(F)(F)F)cc2)N1

Procedure:
The same method but starting from racemic tryptophan ethyl ester and 4-trifluoromethoxybenzaldehyde gave cis and trans isomers of the title compound.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7]([O:9]C(C)(C)C)=[O:8])=[CH:5][N:6]=1.[CH3:14][O-:15].[Na+].[OH-].[Na+]>CC#N.CO>[CH3:14][O:15][C:2]1[S:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=1
Reactant: CC(C)(C)OC(=O)c1cnc(Cl)s1
Reactant: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: COc1ncc(C(=O)O)s1
Temperature: 80 °C

Procedure:
To a solution of tert-butyl 2-chlorothiazole-5-carboxylate (100 mg, 0.455 mmol) in MeCN (880 μl) and MeOH (880 ul) was added 5.4M NaOMe in MeOH (337 μl, 1.821 mmol) followed by 2M NaOH (881 μl, 1.762 mmol). The reaction mixture was heated to 80° C. overnight and, after cooling to RT, the mixture was evaporated under reduced pressure. The residue was acidified with a minimal volume of 6M aqueous hydrochloric acid. The resulting precipitate was filtered, washed with water and dried in a high vacuum oven overnight to afford the title compound;
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]#[N:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[C:8]([S:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:42]=[N+:43]=[N-:44])(C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]3[NH:44][N:43]=[N:42][N:26]=3)=[CH:15][CH:16]=2)[C:8]([S:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(SCc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(OC(C#N)c2ccccc2)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCc1nnc(SCc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(OC(c2ccccc2)c2nnn[nH]2)cc1

Procedure:
A mixture of 3-butyl-4-[[4-[1-cyano-1-phenyl-methoxy]phenyl]methyl]-5-(4-nitrobenzylthio)-4H-1,2,4-triazole (from Example 3, Step B), trimethyltin azide (3.5 equivalents), and toluene is stirred at reflux for about 2 days. The mixture is then cooled and concentrated in vacuo. The residue is partitioned between 0.5N HCl and ethyl acetate. The ethyl acetate phase is dried (MgSO4), filtered, and concentrated. The residue is taken up in methanol and stirred with silica gel (4-5 g per mmol of cyano starting material) for about 1 hour. The mixture is then evaporated in vacuo to give a dry powder, which is layered on top of a column of silica gel packed in CH2Cl2. Elution of the column with a gradient of methanol in CH2Cl2 affords the title compound.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15]([OH:17])=O)[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[F:18][C:19]([F:25])([F:24])[CH2:20][CH2:21][CH2:22][NH2:23].C1(N=C=NC2CCCCC2)CCCCC1>CS(C)=O>[CH3:2][N:1]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15]([NH:23][CH2:22][CH2:21][CH2:20][C:19]([F:25])([F:24])[F:18])=[O:17])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: Cn1c(=O)c2c(ncn2CC(=O)O)n(C)c1=O
Reactant: NCCCC(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Product: Cn1c(=O)c2c(ncn2CC(=O)NCCCC(F)(F)F)n(C)c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1 mmol from theophylline-7-acetic acid (238 mg) and 4,4,4-trifluorobutan-1-amine (127 mg) was dissolved in 3 ml of DMSO. An equimolar amount of N,N′-dicyclohexylcarbodiimide (206 mg) was added and the solution was stirred for 48 h at ambient temperature. The solvent was filtered and concentrated under high vacuum. The oily residue, dissolved in minimal amount of ethyl acetate was subjected to flash chromatography. The following eluents were used: ethyl acetate:petroleum ether (2:1), ethyl acetate and ethyl acetate:methanol (9:1). The fractions containing the new spot (Rf=0.07, TLC, ethyl acetate) were collected and evaporated. The white powder was recrystallized from ethyl acetate/petroleum ether.