Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][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](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1.C1COCC1.C(=O)([O-])[O-].[K+].[K+]>O>[Br:1][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:26]4[CH:27]=[N:22][CH:23]=[N:24][CH:25]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: OB(O)c1cncnc1
Reactant: NC1=N[C@@]2(CO1)c1cc(I)ccc1Oc1ncc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1ncc(Br)cc12
Temperature: 110 °C

Procedure:
A 10-20 mL microwave vial was charged with (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (503 mg, 1.098 mmol), pyrimidin-5-ylboronic acid (143 mg, 1.153 mmol), pd(ph3p)4 (127 mg, 0.110 mmol). The vial was flushed with Ar(g), then THF (5489 μL, 1.098 mmol) and potassium carbonate (1.5 M) (1464 μL, 2.195 mmol) (aq. solution) were added in sequence. The vial was sealed and heated at 110° C. for 2 hours. The mixture was diluted with water and extracted with 10% i-PrOH/EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 100-g SNAP column, eluting with 0-100% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM to provide (S)-3-bromo-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as an off-white solid. Step 2: A vial was charged with (S)-3-bromo-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (68.1 mg, 0.166 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (105 mg, 0.498 mmol), tetrakis(triphenylphosphine)palladium (19.18 mg, 0.017 mmol), THF (830 μL), and potassium carbonate (415 μL, 0.830 mmol) (as a 2.0 M aq. solution). The vial was sealed and placed in a 110° C. for 5 hours. The layers were separated, and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 25-g SNAP column, eluting with 0-60% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM to give (S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a white solid
Reaction SMILES: C[O-].[Na+].C(O[C:7](=[O:19])[CH:8]([O:16][CH2:17][CH3:18])[C:9](=O)[C:10]([O:12][CH2:13]C)=[O:11])C.Cl.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[NH:27])=[C:24]([F:31])[C:23]=1[O:32][CH3:33].Cl>CO>[CH3:13][O:12][C:10]([C:9]1[C:8]([O:16][CH2:17][CH3:18])=[C:7]([OH:19])[N:27]=[C:26]([C:25]2[CH:29]=[CH:30][C:22]([Cl:21])=[C:23]([O:32][CH3:33])[C:24]=2[F:31])[N:28]=1)=[O:11]
Reactant: CCOC(=O)C(=O)C(OCC)C(=O)OCC
Reactant: COc1c(Cl)ccc(C(=N)N)c1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCOc1c(O)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 0 %

Procedure:
Sodium methoxide (12 mL, 62.74 mmol) was added dropwise to a solution of 2-ethoxy-3-oxo-succinic acid diethyl ester (9.7 g of 75% purity, 31.37 mol), 4-chloro-2-fluoro-3-methoxybenzamidine hydrochloride (5 g, 20.91 mol) and MeOH (24 mL). The reaction was allowed to stir for 1 hour. The reaction was cooled to 0° C. and 1 N HCl was added to acidify the reaction. The reaction was extracted with ethyl acetate thrice. The organic extracts were combined, washed with brine, dried, filtered and concentrated. The product was purified by flash chromatography on silica gel (0-50% EtOAc/hexane) the recrystallized from dichloromethane/hexane to give a white solid (623 mg, 8% yield): mp 173-175° C.: 1H NMR (CDCl3) δ 11.28 (br s, 1H), 7.78 (dd, 1H), 7.31 (dd, 1H), 4.35 (q, 2H), 4.02 (s, 3H), 3.98 (s, 3H), 1.38 (t, 3H).
Reaction SMILES: [NH3:1].F[C:3]1[N:8]=[C:7]([F:9])[N:6]=[C:5]([O:10][C:11]([F:14])([F:13])[F:12])[N:4]=1>O1CCCC1>[NH2:1][C:3]1[N:8]=[C:7]([F:9])[N:6]=[C:5]([O:10][C:11]([F:14])([F:13])[F:12])[N:4]=1
Reactant: N
Reactant: Fc1nc(F)nc(OC(F)(F)F)n1
Solvent: C1CCOC1
Product: Nc1nc(F)nc(OC(F)(F)F)n1
Temperature: -70 °C
Reaction time: 8 h

Procedure:
4.4 g (0.259 mol) of gaseous ammonia were passed over the course of 45 minutes into a stirred mixture of 26.0 g (0.1293 mol) of 2,4-difluoro-6-trifluoromethoxy-1,3,5-triazine and 100 ml of tetrahydrofuran at -70° to -65° C. The mixture was then stirred for 2 hours at -70° C. and overnight while warming to 22° C. The residue from concentration under reduced pressure was stirred with water, filtered off with suction and washed. Drying yielded 22 g (85.9% of theory) of the title compound of melting point 138°-139° C.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]3[CH3:21])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:22]([C:25]1[S:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])[CH3:23]>>[CH3:21][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][N:15]1[CH2:14][CH2:13][CH2:12][NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:28]3[S:29][C:25]([C:22](=[O:24])[CH3:23])=[CH:26][CH:27]=3)=[CH:3][N:4]=2)[N:7]=1
Reactant: CC(=O)c1ccc(B(O)O)s1
Reactant: CC1CCCCN1CCCNc1ccc2ncc(Br)n2n1
Product: CC(=O)c1ccc(-c2cnc3ccc(NCCCN4CCCCC4C)nn23)s1
Yield: 71 %

Procedure:
The reaction of 3-bromo-N-(3-(2-methylpiperidin-1-yl)propyl)imidazo[1,2-b]pyridazin-6-amine with (5-acetylthiophen-2-yl)boronic acid, under the Suzuki coupling condition described in example 5.6.19, afforded the desired compound in 71% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34 (d, J=6.57 Hz, 3H) 1.45-1.59 (m, 1H) 1.67-1.96 (m, 5H) 2.13-2.31 (m, 2H) 2.60 (s, 3H) 2.74 (dd, J=10.86, 4.80 Hz, 1H) 2.83-2.95 (m, 1H) 3.11 (br. s., 1H) 3.17-3.31 (m, 1H) 3.34-3.46 (m, 1H) 3.53-3.72 (m, 2H) 6.72 (d, J=9.85 Hz, 1H) 7.56 (d, J=4.04 Hz, 1H) 7.64-7.73 (m, 2H) 7.94 (s, 1H); LRMS (ESI) m/e 398.0 [(M+H)+, calcd for C21H27N5OS 397.0].
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[C:11](=O)[N:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:13][C:9]=3[C:8]([CH2:21][CH3:22])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH:1]1([N:6]2[C:10]3[CH2:11][N:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:13][C:9]=3[C:8]([CH2:21][CH3:22])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1nn(C2CCCC2)c2c1CN(c1ccccc1)C2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCc1nn(C2CCCC2)c2c1CN(c1ccccc1)C2
Temperature: 0 °C
Yield: 61.3 %

Procedure:
To a stirred solution of 1-cyclopentyl-3-ethyl-6-oxo-5-phenyl-4,6-dihydro-1H-pyrazolo[3,4-c]pyrrole (0.17 g, 0.58 mmole) in anhydrous ether (15 ml) was added lithium aluminum hydride (0.17 g, 4.6 mmole). The majority of the ether (12-13 ml) was then removed by distillation, and the remaining mixture diluted with toluene (25 ml) and heated to reflux over 24 hours. The mixture was cooled to 0° C. and cautiously treated with ice. The resulting mixture was filtered through celite, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was chromatographed on a silica column using 1:9 ethyl acetate/hexane as eluent to give 100 mg of a colorless oil. 1H NMR (250 MHz, CDCl3) δ1.26 (t, J=7.6 Hz, 3H), 1.65-2.25 (m, 8H), 2.67 (q, J=7.6 Hz, 2H), 4.35 (s, 2H), 4.45 (s, 2H), 4.53 (pentet, J=7.5 Hz, 1H), 6.61 (d, J=8.1 Hz, 2H), 6.74 (t, J=7.4 Hz, 1H), 7.29 (dd, J=7.5 and 8.4 Hz 2H); MS m/z 282.
Reaction SMILES: [F:1][C:2]1[C:3](=O)[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:11].O1CCOCC1>N1C=CC=CC=1>[F:1][C:2]1[C:3](=[S:11])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=c1[nH]cc(F)c(=S)[nH]1
Yield: 80 %

Procedure:
Prepared from 5-fluorouracil by the method of Ueda and Fox (see above) using phosphorus pentasulphide in pyridine. We find that dioxan is a better solvent in this reaction in which case the yield was 80% of a more pure product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([F:22])[C:15]=2[F:23])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>ClCCl>[F:22][C:16]1[C:15]([F:23])=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:19]=[CH:18][C:17]=1[C:20]#[N:21].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)c(F)c2F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(N2CCNCC2)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-Cyano-2,3-difluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.72 g) in dichloromethane (5 mL) was added trifluoroacetic acid, and the reaction mixture was stirred at room temperature for 30 minutes. After such time the reaction mixture was concentrated in vacuo to yield the title compound (0.63 g). MS (m/e): 224.3 (M+H+, 100%).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:14]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19])([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][C:9](=[O:10])[C:8]1[CH:12]=[CH:13][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)([O-:16])=[O:15]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2[N+](=O)[O-])cc1
Yield: 20 %

Procedure:
Using the procedure described in Example 93, Part A, 4-tert-butylbenzoyl chloride (398 mmol) and 2-nitroaniline (362 mmol) yielded 21.6 g (100%) of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)(=[O:8])=[O:7].[CH3:17][O:18][C:19](=[O:32])[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH3:31]>>[CH3:17][O:18][C:19](=[O:32])[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=2)[C:23]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])=[C:22]1[CH3:31]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1ccccc1S(=O)(=O)c1cccs1
Product: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)c2cccs2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using 2-(thiophene-2-sulfonyl)benzaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.C(N)(N)=[O:18].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N+:7]([O-:18])[CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1
Reactant: O=c1c2cc(Br)ccc2oc2cccnc12
Reactant: NC(N)=O
Agent: OO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=c1c2cc(Br)ccc2oc2ccc[n+]([O-])c12
Reaction time: 2 h

Procedure:
To a solution of 8-bromo-10H-chromeno[3,2-b]pyridin-10-one (60 g, 217 mmol) and urea peroxide (42.9 g, 456 mmol) in 120 mL of DCM at 0° C. was added dropwise trifluoroacetic anhydride (63.9 mL, 456 mmol). The resulting reaction was stirred for 2 h. The reaction was quenched with 10% Na2S2O3, extracted with DCM, dried over Na2SO4 and evaporated to dryness to give crude 8-bromo-10-oxo-10H-chromeno[3,2-b]pyridine 1-oxide as a pale yellow solid.
Reaction SMILES: COC1C=CC(COC([N:11]2[CH2:15][C@@H:14]([S:16][C:17](=[O:19])[CH3:18])[CH2:13][C@H:12]2[C:20](=[O:29])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=O)=CC=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[CH2:22]([NH:21][C:20]([C@@H:12]1[CH2:13][C@H:14]([S:16][C:17](=[O:19])[CH3:18])[CH2:15][NH:11]1)=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(COC(=O)N2C[C@@H](SC(C)=O)C[C@H]2C(=O)NCc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)S[C@@H]1CN[C@H](C(=O)NCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
177 mg of (2S,4S)-1-p-methoxybenzyloxycarbonyl-2-benzylcarbamoyl-4-acetylthiopyrrolidine and 86 mg of anisole were dissolved in 0.5 ml of trifluoroacetic acid, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed successively with an aqueous solution of sodium bicarbonate and water and dried over sodium sulfate. The solvent was removed by distillation, and the residue was subjected to silica gel thin layer chromatography to obtain (2S,4S)-2-benzylcarbamoyl-4-acetylthiopyrrolidine.
Reaction SMILES: [CH3:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[K+].C>O>[CH3:1][C:2]1[C:8]([C:9]([F:10])([F:11])[F:12])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:14]1[C:15]([C:16]([OH:18])=[O:17])=[CH:19][CH:20]=[CH:21][N:22]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: Cc1c(N)cccc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1c(Nc2ncccc2C(=O)O)cccc1C(F)(F)F
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
) A mixture of 2-methyl-3-trifluoromethylaniline (368 g, 2.1 moles) and 2-chloronicotinic acid (158.0 g, 1.0 mole) in 400 ml of water is heated at 100° C. for 24 hours together with p-toluenesulfonic acid (15.0 g) monohydrate as the acid catalyst. Potassium hydroxide (ca. 145 g) in water (255 ml) is added and the pH is maintained above 11. After diluting the reaction mixture to 1.2 liters with water, the mixture is cooled to 50° C., adjusted to pH 11, treated with 7 g of a decolorizing charcoal and 15 g of a filter aid, and clarified by filtration. The flitrate is diluted with 750 ml of water and the pH is adjusted to 5.0 with concentrated sulfuric acid. Agitation of the suspension for 10 minutes and filtration gives crude, precipitated 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylic acid (flunixin) (83% yield). The compound can be further purified by crystallization in methanol and washing with water.
Reaction SMILES: Cl[C:2]1[C:7]([Br:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][NH:14][CH3:15]>>[Br:8][C:7]1[C:2]([N:14]([CH3:15])[CH3:13])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Br)c1
Reactant: CNC
Product: CN(C)c1ncc(C(F)(F)F)cc1Br
Yield: 82 %

Procedure:
2-Chloro-3-bromo-5-trifluoromethylpyridine (509 mg, 1.95 mmol) was treated with ethanolic dimethylamine solution (10 ml) and heated at reflux for 2 hrs before being concentrated. The residue was partitioned between water (10 ml) and ethyl acetate (10 ml), and the organic phase washed with brine (10 ml) and dried (Na2SO4). The solution was then concentrated to give the product as a yellow oil (430 mg, 82% yield).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[O:7]=[CH:8][C:9]([Cl:12])([Cl:11])[Cl:10].C(N(CC)CC)C>CCOCC>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:8]([OH:7])[C:9]([Cl:12])([Cl:11])[Cl:10]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: Cn1cccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cn1cccc1C(O)C(Cl)(Cl)Cl
Temperature: 25 °C
Yield: 102.4 %

Procedure:
To a solution of N-methylpyrrole (1.62 g, 20 mmol) in ether (10 ml) was added a solution of chloral (3.24 g, 22 mmol) in ether (10 ml). To this was added Amberlyst (160 mg) and the mixture was stirred under reflux for 18 hours. After cooling to room temperature and adding triethylamine (0.3 ml), the mixture was stirred for 5 minutes and filtered through a layer of Celite. The filtrate was concentrated under reduced pressure to afford the crude adduct 1-methyl-2-(2',2',2'-trichloro-1'-hydroxyethyl)pyrrole (4.68 g) as pale brown prisms.
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>O>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:9][CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a dimethylformamide (30 mL) solution of (4-bromophenyl)methanol (3.00 g), imidazole (2.18 g) and tert-butyldimethylsilyl chloride (2.89 g) were added in this order. The reaction solution was stirred at room temperature for one hour. To the reaction solution, water (10 mL) was added and the aqueous layer was extracted twice with ethyl acetate (50 mL). The combined organic layer was washed in turn with 1N hydrochloric acid (10 mL) and saturated sodium chloride solution (10 mL) and then dried over anhydrous magnesium sulfate. After removing the anhydrous magnesium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0→9:1) to obtain the title compound (3.77 g) having the following physical properties.
Reaction SMILES: [F:1][C:2]([F:27])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].Br([O-])(=O)=[O:29].[Na+].S(=O)(=O)(O)[O-].[Na+].O>C(#N)C>[F:27][C:2]([F:1])([O:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:29])=[O:24])=[CH:25][CH:26]=3)=[N:15]2)=[CH:12][CH:13]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Yield: 95.1 %

Procedure:
A solution of 4-[1-(4-pentafluoroethyloxy-phenyl)-1H-[1,2,4]triazol-3-yl]-benzaldehyde (1.7 g, 4.4 mmol), sodium bromate (2.1 g, 13.9 mmol) and sodium bisulfate (0.53 g, 4.5 mmol) in 50 mL of acetonitrile was heated to reflux for 5 h, during which time a voluminous precipitate formed. The solution was then cooled and poured into 100 mL of water, filtered, and dried to furnish 1.67 g of the acid as a white solid. 1H NMR (300 MHz, CDCl3) δ 10.1 (s, 1H), 8.65 (s, 1H), 8.40 (d, J=8.4 Hz, 2H), 8.0 (d, J=8.4 Hz, 2H), 7.85 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 2H); ESIMS 399.2 (M+H+); mp 225° C.
Reaction SMILES: C(Cl)(=O)C.[N:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(NC1C=C[C:45]([C:48](=[O:53])NCCC)=[CH:44]C=1)=O)C2>>[C:48]([N:8]1[CH2:9][CH2:10][N:5]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:6][CH2:7]1)(=[O:53])[CH2:45][CH3:44]
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)N1Cc2ccccc2C1
Solvent: CC(=O)Cl
Product: CCC(=O)N1CCN(c2ccc(NC(=O)N3Cc4ccccc4C3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 278, substituting propionyl chloride for acetyl chloride and N-(4-(piperazin-1-yl)phenyl)isoindoline-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.14 (s, 1H), 7.38-7.44 (m, 2H), 7.28-7.39 (m, 4H), 6.87-6.90 (m, 2H), 4.74 (s, 4H), 3.54-3.60 (m, 4H), 2.95-3.10 (m, 4H), 2.36 (q, J=7.4 Hz, 2H), 1.03 (s, 1H), 1.00 (d, J=7.4 Hz, 2H); MS (ESI(+)) m/e 379 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[C:24]1([CH:30]2[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O>[CH3:8][C:6]1[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=[C:2]([N:32]2[CH2:33][CH2:34][CH2:35][CH:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:31]2)[N:7]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: c1ccc(C2CCCNC2)cc1
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCC(c3ccccc3)C2)nc1-c1ccc(C)cc1
Temperature: 110 °C
Yield: 32.9 %

Procedure:
A mixture of methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.104 g; 0.312 mmol), 3-phenylpiperidine (0.151 g; 0.937 mmol) and triethylamine (0.220 mL; 1.56 mmol) in tetrahydrofuran (2 mL) was heated to 110° C. in a sealed tube for 5 h. The reaction mixture was diluted with a saturated solution of hydrogen carbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-15%) in heptane furnished 0.047 g (33%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:60])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+]=[N-])[CH:46]([O:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH2:45]2)[CH:7]([CH3:61])[CH2:6][CH2:5][C:4]1=[O:62])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:60])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH2:45]2)[CH:7]([CH3:61])[CH2:6][CH2:5][C:4]1=[O:62])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(Oc4ccccc4)C3)C(C)CCC1=O)C(C)CC2OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N)C(Oc4ccccc4)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.3 %

Procedure:
17-Ethyl-1-hydroxy-12-[2'-(4"-azido-3"-phenoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]-octacos-18-ene-2,3,10,16-tetraone (64 mg) in THF (1.5 mml) containing 1 drop of water was treated with triphenylphosphine (24 mg) and the mixture stirred at room temperature for 72 hours. The reaction mixture was purified directly by preparative thin layer chromatography eluting with 90% dichloromethane:10% methanol to give the title compound (43 mg, 68%) as a white solid. (1H NMR analysis was consistent with the desired structure).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[O:11]1[C:21]2[C:16](=[CH:17][C:18]([CH:22]=O)=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:12]1=[O:13]>>[O:13]=[C:12]1[CH:14]=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[C:18]([CH2:22][NH:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1]([OH:10])=[O:9])[CH:17]=2)[O:11]1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=Cc1ccc2oc(=O)ccc2c1
Product: O=C(O)c1ccccc1NCc1ccc2oc(=O)ccc2c1

Procedure:
Prepared by a similar procedure as described for preparation 1A, starting from anthranilic acid and coumarin-6-carboxaldehyde (Matrix). 13C-NMR (DMSO-d6) δ 169.9, 159.9, 152.5, 150.4, 144.1, 135.8, 134.3, 131.7, 130.7, 126.4, 118.6, 116.4, 116.3, 114.6, 111.6, 110.5, 45.0.