Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C(=O)([O-])O.[Na+].ON1C(=O)CCC1=O.[C:23]([O:27][C:28]([NH:30][CH2:31][C:32]([OH:34])=O)=[O:29])([CH3:26])(C)C.[C:35](O)(=O)[CH2:36][C:37]([CH2:42][C:43](O)=O)(C(O)=O)O>O.O1CCOCC1>[CH2:23]([O:27][C:28]([NH:30][CH2:31][C:32]([N:5]1[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]1[C:7]([OH:9])=[O:8])=[O:34])=[O:29])[C:26]1[CH:43]=[CH:42][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NCC(=O)N1C[C@H](O)C[C@H]1C(=O)O)OCc1ccccc1
Reaction time: 8 h
Yield: 100 %

Procedure:
3,4-Dehydroproline 1 (0.011 g, 0.097 mmol) and sodium hydrogen carbonate (0.0082 g, 0.097 mmol) were dissolved in water (1 cm3). A solution of N-tert-butyloxycarbonylglycine N-hydroxysuccinimide 2 (0.024 g, 0.088 mmol) in dioxane (1 cm3) was added dropwise and stirred overnight. The reaction mixture was diluted with water, acidified with solid citric acid and extracted with dichloromethane (3×). The combined organic layers were dried (MgSO4), filtered and the solvent removed to afford crude acid 3 (0.0242 g, ca. 100%) that was used without further purification. Acid 3 was shown to be a 75:25 trans:cis mixture of conformers by 1H NMR analysis (the ratio was estimated from the integration of the Proα protons at δ 5.21 and 5.13 of the major and minor conformers respectively): δH (300 MHz; CDCl3; Me4Si) 1.411 [2.25H, s, C(CH3)3], 1.42 [6.75H, s, C(CH3)3], 3.83-4.08 (2H, m, Glyα-H2), 4.25-4.45 (2H, m, Proδ-H2), 5.13* (0.25H, br d, J 2.8, Pros-H), 5.21 (0.75H, br d, J 3.1, Proα-H), 5.55-5.80 (2H, br m, O—H and N—H) and 5.86-6.02 (2H, m, Proβ-H and Proγ-H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[CH:17]=[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19]1=[O:27]>>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][CH:17]=[C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][C:19]3=[O:27])=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: O=C1Nc2ccccc2C1=CO
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCN2CCCC2)cc1
Yield: 63.5 %

Procedure:
In a manner similar to that described in Example 231, 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (767 mg, 1.2 equiv.) and 3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 3.11 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (690 mg, 64%).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)[NH2:3].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[ClH:10].[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:3][CH:2]([CH3:1])[C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: CC(N)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CC(Nc1ccc(Cl)cc1[N+](=O)[O-])c1cccnc1
Product: Cl
Yield: 34 %

Procedure:
A mixture of 52.5 parts of α-methyl-3-pyridinemethanamine, 84.5 parts of 1,4-dichloro-2-nitrobenzene, 53 parts of sodium carbonate and 320 parts of 1-butanol is stirred and refluxed for 72 hours. The reaction mixture is evaporated and water is added to the residue. The oily product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is converted into the hydrochloride salt in 2,2'-oxybispropane, 4-methyl-2-pentanone and 2-propanol. The oily salt is separated and crystallized from 2-propanol, yielding 46 parts (34%) of N-(4-chloro-2-nitrophenyl)-α-methyl-3-pyridinemethanamine monohydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31].Cl>ClCCl>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][N:9]2[C:29]([O:30][CH3:31])=[O:32])=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCNC(CCc2ccc(F)cc2)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(CCc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
Methyl 2-(4-fluorophenethyl)piperidine-4-carboxylate (3.89 g, 14.65 mmol) was dissolved in dichloromethane (150 mL). DIPEA (3.06 mL, 17.58 mmol) was added, followed by methyl carbonochloridate (1.615 mL, 20.51 mmol). The mixture was stirred at room temperature for 2 h. 0.1 HCl and DCM were added. The phases were separated and the aqueous phase was extracted with DCM. The combined organic layers were washed with satd NaHCO3, filtered through a phase separator and evaporated. Dimethyl 2-(4-fluorophenethyl)piperidine-1,4-dicarboxylate (3.19 g, 67%) was isolated. MS m/z 324 (M+H)+
Reaction SMILES: C([O:3][C:4](=[O:14])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])C.O.[OH-].[Li+]>C1COCC1.O>[CH3:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:13])[C:6]=1[CH2:5][C:4]([OH:14])=[O:3]
Reactant: CCOC(=O)Cc1c(C)cccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(C)c1CC(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.3 %

Procedure:
To a mixture of (2,6-dimethyl-phenyl)-acetic acid ethyl ester (13.3 g, 69.2 mmol) in THF (550 mL) and water (224 mL) was added lithium hydroxide monohydrate (23.2 g, 553 mmol). The resulting mixture was stirred vigorously at rt. After 72 h, the mixture was heated to 50° C. for an additional 24 h. The mixture was cooled to rt and concentrated. To the resulting residue was added aqueous 2 N HCl (300 mL) to afford a colorless precipitate. The precipitate was collected by vacuum filtration and further purified by FCC to provide a colorless solid (8.9 g, 78%). MS (ESI): mass calcd. for C10H12O2, 164.1; m/z found, 163.1 [M−H]+. 1H NMR (CDCl3): 7.17-6.90 (m, 3H), 3.72 (s, 2H), 2.33 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.C([Li])CCC.[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.C([O:27]CC)C>CCCCCC>[OH:27][C:16]1([CH:19]=[CH:20][CH:21]=[CH:22][CH:15]1[C:14]([F:24])([F:23])[F:13])[CH2:17][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: Brc1cncnc1
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: CCCCCC
Product: OC1(Cc2cncnc2)C=CC=CC1C(F)(F)F
Temperature: -75 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 7.0 g of 5-bromopyrimidine in 150 ml of diethyl ether at -75° C., 20 ml of 2.5M butyl lithium in hexane were added while keeping the temperature below -50° C. The reaction mixture was then stirred at -75° C. for 1.5 hours. 7.66 g of 2-trifluoromethylbenzaldehyde were added while keeping the temperature below -50° C. and the reaction mixture was then stirred at -75° C. for one hour. The reaction mixture was then quenched with water. The resulting layers were separated. The aqueous layer was extracted again with diethyl ether. The combined organic layers were dried (MgSO4), filtered and concentrated to a yellow oil which turned orange upon standing overnight. Purification by column chromatography (silica gel), eluted first with a 1:1 mixture of hexane and diethyl ether, and then with diethyl ether, to yield 0.13 g of 5-(1-hydroxy-2,-trifluoromethylbenzyl)pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH:32]2[CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(#N)C.C(OCC)(=O)C>[CH:32]1([S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH:17]([O:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:24][CH:25]=2)(=[O:31])=[O:30])[CH2:33][CH2:34]1
Reactant: CCOC(=O)C(Br)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CC2)cc1
Reaction time: 12 h

Procedure:
To a solution of 2,4-difluorophenol in acetonitrile, was added potassium carbonate followed by bromo-(4-cyclopropanesulfonyl-phenyl)-acetic acid ethyl ester (obtained in step I) and stirred for 10-14 hours. After completion, the reaction mixture was filtered; the filtrate was concentrated to obtain a residue which was dissolved in ethyl acetate; this solution was washed with water followed by brine solution, dried over anhydrous sodium sulfate, solvent was removed under reduced pressure to provide a crude product which was purified by column chromatography to provide the compound A1-II.
Reaction SMILES: [CH:1]([N:3]=[C:4]=[O:5])=[CH2:2].[CH:6]1([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>C(OCC)(=O)C>[CH:1]([NH:3][C:4](=[O:5])[O:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[CH2:2]
Reactant: OC1CCCCC1
Reactant: C=CN=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCOC(C)=O
Product: C=CNC(=O)OC1CCCCC1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
69 parts of vinyl isocyanate and 89.5 parts of ethyl acetate are initially taken in a reaction vessel and are heated at 40° C. A mixture of 110 parts of cyclohexanol, 89.5 parts of ethyl acetate and 0.02% of dibutyltin dilaurate as the catalyst is added in the course of one hour, after which the mixture is allowed to continue reacting for a further 2 hours at 40° C. A pale yellow solution is obtained, from which, on cooling, the reaction product separates out in the form of crystals. Content of blocked isocyanate groups: 11.7%.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[C:11]([O:14][CH2:15][CH3:16])(=[O:13])[CH3:12].[C:17]1([C:23]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH3:33][O:32][C:28]1[CH:27]=[C:26]([CH2:25][C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([OH:24])[CH2:12][C:11]([O:14][CH2:15][CH3:16])=[O:13])[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(C)=O
Reactant: COc1cccc(CC(=O)c2ccccc2)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)(Cc1cccc(OC)c1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
Lithium hexamethyldisilazane (88.5 mL, 88.5 mmol) was added to THF (150 mL) at −78° C. After 15 min, ethyl acetate (7.79 g, 88.5 mmol) was added over 10 min and stirred at −78° C. for 30 min. The m-methoxybenzyl phenyl ketone in (10.0 g, 44.25 mmol) THF (100 mL) was added over 15 min and kept at that temperature for 3 h. The reaction mixture was quenched at that temperature with saturated ammonium chloride (15 mL). The reaction mixture was diluted with ether (200 mL) and the organic layer was washed with brine, (100 mL), dried and was concentrated to afford 12 g (86%) of the desired product. 1H NMR (CDCl3) δ 7.10-7.37 (m, 6H), 6.71-6.74 (m, 1H), 6.60-6.62 (m, 1H), 6.48 (s, 1H), 3.95-4.00 (m, 2H), 3.67 (s, 3H), 2.72-3.07 (m, 4H), 1.06 (m, 3H).
Reaction SMILES: [C:1]([C@@H:4]1[CH2:7][C@H:6]([N:8]=[N+:9]=[N-:10])[CH2:5]1)(O)=[O:2].C(Cl)(=O)C([Cl:14])=O>ClCCl.CN(C)C=O>[N:8]([C@@H:6]1[CH2:7][C@H:4]([C:1]([Cl:14])=[O:2])[CH2:5]1)=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=N[C@H]1C[C@@H](C(=O)O)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1C[C@@H](C(=O)Cl)C1
Temperature: 23 °C

Procedure:
A solution of cis-3-carboxycyclobutyl azide (1.86 g, 13.2 mmol) in dichloromethane (30 ml) was treated with oxalyl chloride (1.5 ml, 17.2 mmol) followed by one drop of N,N-dimethylformamide. The reaction mixture was stirred at 23° C. until the evolution of gas ceased (0.5-1 h) and the solvent was evaporated in vacuo leaving a yellow oil; 2.0 g, 95% ir (neat) νmax : 2100 (N3) and 1785 cm-1 (C=O of acylchloride).
Reaction SMILES: C(C1C=CC=CC=1O)#N.[C:10]([C:12]1[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=1[O:14][CH2:15][C@@H:16]1[CH2:20][O:19][C:18](C)([CH3:21])[O:17]1)#[N:11].CCO.[BrH:30]>C(O)(=O)C>[C:10]([C:12]1[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=1[O:14][CH2:15][C@@H:16]([O:17][C:18](=[O:19])[CH3:21])[CH2:20][Br:30])#[N:11]
Reactant: Br
Reactant: CC1(C)OC[C@@H](COc2ccccc2C#N)O1
Agent: N#Cc1ccccc1O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)O[C@@H](CBr)COc1ccccc1C#N

Procedure:
In the same way as in [H] but reacting 2-cyanophenol (7.1 g, 59.7 mmoles) with (S)-(+)-2,2-dimethyl-4-toxyloxymethyl-1,3-dioxolane (J. Org. Chem. 42, 1006 (1977)) (17.1 g, 59.7 mmoles) the (R)-(-)-4-(2-cyanophenoxymethyl)-2,2-dimethyl-1,3-dioxolane with [α]D (C=1, EtOH)=-30.18°, was obtained. The reaction of this compound (13.9 g, 59.6 mmoles) with 40% hydrobromic acid in acetic acid yields (R)-(-)-3-(2-cyanophenoxy)-2-acetoxy-1-bromopropane with [α]D (C=1, EtOH)=-15.9°.
Reaction SMILES: Br[C:2]1[C:3]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[NH2:21][C:22]1[CH:34]=[CH:33][C:25]([CH:26]=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CCOC(C)=O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:3]2[C:2]([NH:21][C:22]3[CH:23]=[CH:24][C:25](/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=3)=[C:6]([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=3)[S:5][C:4]=2[CH:15]=1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Br)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1ccc(Nc2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Yield: 15 %

Procedure:
To a large microwave vial (10-20 mL) was added 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (350 mg, 1.00 mmol), ethyl 4-aminocinnamate (383 mg, 2.00 mmol) and K3PO4 (425 mg, 2.00 mmol). 1,4-dioxane (6.0 mL) was then added followed by chloro-(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-t-butyl ether adduct (RuPhos palladacycle, 73.0 mg, 0.10 mmol) and the reaction was subjected to microwave irradiation at 120° C. for 3 h. Upon completion the reaction mixture was transferred to round bottom flask with EtOAc and concentrated in vacuo. The resulting material was partitioned between water and EtOAc and separated, the aqueous layer was then further extracted with EtOAc (3×) and the combined organic layers were passed through a phase separator to remove water and concentrated in vacuo. The crude material was purified by column chromatography (SiO2, 0-30% EtOAc/heptane) to afford (E)-ethyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)amino)phenyl)acrylate (69.0 mg, 0.15 mmol, 15% yield) as a white solid. LC/MS (m/z, MH+): 460.3.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[S:11][C:10]([N:12]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[C:13]2=[O:28])=[N:9][C:8]=1[CH3:29])=O.O.[NH2:32]N>C(O)C>[CH3:29][C:8]1[N:9]=[C:10]([N:12]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=3)[C:13]2=[O:28])[S:11][C:7]=1[C:5]1[CH:4]=[CH:3][NH:2][N:32]=1
Reactant: NN
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)/C=C/N(C)C
Solvent: O
Solvent: CCO
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1-c1cc[nH]n1
Yield: 72 %

Procedure:
To a solution of (E)-1-(5-(3-(dimethylamino)acryloyl)-4-methylthiazol-2-yl)-3-(4-(trifluoromethyl)benzyl)imidazolidin-2-one (0.44 g, 1.00 mmol) in ethanol (10 mL) was added hydrazine monohydrate (0.12 mL, 1.58 mmol). The reaction mixture was heated to reflux for 3 hours. The solvent was removed in vacuo, and the residue was purified by column chromatography to afford the title compound as a colorless solid in 72% yield (0.30 g): mp 212-213° C. (ethyl acetate): 1H NMR (300 MHz, CDCl3& CD3OD) δ 7.54-7.20 (m, 5H), 6.24 (s, 1H), 4.39 (s, 2H), 3.98-3.89 (m, 2H), 3.35-3.30 (m, 2H), 2.27 (s, 3H): 13C NMR (75 MHz, CDCl3 & CD3OD) δ 156.9, 155.8, 139.8, 130.2, 129.8, 129.3, 128.2, 125.6, 125.5, 122.0, 103.8, 47.2, 41.9, 41.8, 15.7: MS (ES+) m/z 408.1 (M+1).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[NH:32]1[CH2:41][CH2:40][CH:35]([C:36]([O:38][CH3:39])=[O:37])[CH2:34][CH2:33]1>C(Cl)Cl>[CH3:39][O:38][C:36]([CH:35]1[CH2:40][CH2:41][N:32]([CH:18]=[C:17]2[C:16]3[C:15]([CH3:30])([C:14]4[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]5([CH3:31])[CH:8]([C:13]=4[C:21](=[O:22])[C:20]=3[OH:19])[CH2:9][CH2:10][CH:11]5[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]2=[O:24])[CH2:33][CH2:34]1)=[O:37]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: COC(=O)C1CCNCC1
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN2CCC(C(=O)OC)CC2)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added methyl isonipecotate (63 μL, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 575 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12](=NO)[CH:11]=[CH:10][C:9]2=[O:16])([O-:3])=[O:2].[N+](C1C=CC=C2C=1C(=O)C=CC2=NO)([O-])=[O:18].[N+](C1C=CC=C2C=1C(N)=CC=C2O)([O-])=O>[Fe+2]>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:18])[CH:11]=[CH:10][C:9]2=[O:16])([O-:3])=[O:2]
Reactant: O=C1C=CC(=NO)c2c1cccc2[N+](=O)[O-]
Reactant: O=C1C=CC(=NO)c2cccc([N+](=O)[O-])c21
Agent: [Fe+2]
Agent: Nc1ccc(O)c2cccc([N+](=O)[O-])c12
Product: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]

Procedure:
5-Nitro-1,4-naphthoquinone is prepared by reducing 8-nitro-1,4-naphthoquinone-1-oxime and/or 5-nitro-1,4-naphthoquinone-1-oxime in an aqueous and/or organic reaction medium in the presence of iron (II) ions and a hydrogen halide at a temperature in the range of from -20° to 100°C, and thereafter oxidizing the 8- and and/or 5-nitro-4-amino-1-naphthol formed, or the corresponding salt, optionally without intermediate isolation, at a temperature in the range of from -10° to 100°C to form the desired 5-nitro-1,4-naphthoquinone.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Sn](C)(C)C)[N:5]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[C:3]=1[Cl:17].Br[C:19]1[C:27]([F:28])=[CH:26][C:22]2=[N:23][O:24][N:25]=[C:21]2[CH:20]=1.C(OCC)(=O)C.[Na+].[Cl-]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:19]2[C:27]([F:28])=[CH:26][C:22]3=[N:23][O:24][N:25]=[C:21]3[CH:20]=2)[N:5]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[C:3]=1[Cl:17]
Reactant: Fc1cc2nonc2cc1Br
Reactant: COC(=O)c1nc([Sn](C)(C)C)c(F)c(N)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(-c2cc3nonc3cc2F)c(F)c(N)c1Cl
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 18.8 %

Procedure:
Methyl 4-amino-3-chloro-5-fluoro-6-(trimethylstannyl)picolinate (320 mg, 0.86 mmol) and 5-bromo-6-fluorobenzo[c][1,2,5]oxadiazole (170 mg, 0.78 mmol) were combined in 5 mL dry N,N-dimethylformamide, deaerated with a stream of nitrogen for 15 min. Bis(triphenylphosphine)palladium(II) chloride (55 mg, 0.078 mmol) and cuprous iodide (15 mg, 0.078 mmol) were added and the mixture was heated to 70° C. for 4 h. The mixture was shaken with 20 mL ethyl acetate, 10 mL saturated NaCl, dried (Na2SO4) and the residue was chromatographed on silica with a 5-30% ethyl acetate-hexane gradient to give 50 mg of the title compound as a white solid (50 mg, 19%): mp 180-182° C.; 1H NMR (400 MHz, CDCl3) δ 8.16 (dd, J=6.2, 0.5 Hz, 1H), 7.54 (dd, J=8.7, 0.5 Hz, 1H), 5.07 (s, 2H), 4.00 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −105.64, −105.72, −137.68, −137.76; ESIMS m/z 341 ([M+H]+), 339 ([M−H]−).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:18]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:18])=[O:7])=[CH:4][CH:3]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)c1ccc(O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(O)cc1
Reaction time: 2 h

Procedure:
A solution of freshly prepared 4-hydroxybenzoic acid (635 mg; 4.6 mmol) and BOP (1.7 g; 5.06 mmol) in DMF (20 mL) was added dropwise and at room temperature to a solution of PEI (1 g, 23.2 mmol) in DMF (50 mL). After 2 hours under stirring, the DMF was removed by evaporation under reduced pressure. The crude product was taken in water, dissolved by addition of aqueous sodium hydroxide solution 1M (pH 11) and subjected to dialysis using a SpectraPor 12-14 kDa membrane against water (1 L, 2 changes over 24 h). Lyophilization provided 4-hydroxybenzamide-PEI (0.7 g) at a modification degree of 28%. 1H NMR (D2O) δppm: 2.6 (bm, 2.9H, —NHCH2CH2NH—), 3.22 (m, 0.55H, Phe-CONHCH2CH2NH—), 3.35 (m, 0.55H, Phe-CONHCH2CH2NH) 6.57 (d, J=7.3 Hz, 0.55 H, CHaro), 6.97 (m, 0.55H, CHaro).
Reaction SMILES: C(N1[C:12]2[C:7](=[CH:8]C=CC=2)[C:6](=O)[C:5]1=O)CC.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26].BrCCC(C)C>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:5][CH2:6][CH:7]([CH3:12])[CH3:8])[C:20](=[O:25])[C:19]2=[O:26]
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Solvent: CC(C)CCBr
Product: CC(C)CCN1C(=O)C(=O)c2cc(Cl)ccc21

Procedure:
This compound was prepared in a similar method as 1-propylindoline-2,3-dione by reacting commercially available 5-chloro isatin (purchase from Fisher Scientific) with commercially available 1-bromo-3-methylbutane (purchase from Fisher Scientific). 1H NMR δ 7.57 (m, 2H), 6.85 (d, 1H), 3.73 (t, 2H), 1.57 (m, 3H), 1.00 (d, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[C:16]([OH:20])(=O)[CH:17]=O.[C:21]1([CH3:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]2[O:15][C:16](=[O:20])[CH:17]([C:24]3[CH:25]=[CH:26][C:21]([CH3:27])=[CH:22][CH:23]=3)[C:7]=2[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1ccccc1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: O=CC(=O)O
Solvent: O
Product: Cc1ccc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1
Yield: 42 %

Procedure:
A mixture of 21.2 g (0.10 mol) of 2,4-di-tert-butylphenol (97%), 16.3 g (0.11 mol) of 50% aqueous glyoxylic acid, 2.0 g of Fulcat 22B and 50 ml of toluene is refluxed for 8 hours under nitrogen on a water separator. The Fulcat 22B catalyst is then removed by filtration and excess toluene is distilled off on a vacuum rotary evaporator. Crystallisation of the residue from 40 ml of ethanol yields 14.2 g (42%) of 5,7-di-tert-butyl-3-(4-methylphenyl)-3H-benzofuran-2-one, m.p. 130°-133° C. (compound (104), Table 1).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[F:7][C:8]([F:29])([F:28])[C:9]1[CH:27]=[CH:26][C:12]([O:13][C:14]2[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20](O)=[O:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1>CN(C)C=O.CCOCC>[F:7][C:8]([F:29])([F:28])[C:9]1[CH:27]=[CH:26][C:12]([O:13][C:14]2[CH:25]=[CH:24][C:17]([O:18][CH:19]([CH3:23])[C:20]([Cl:4])=[O:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Oxalyl chloride (1.56 g, 1.1 ml, 12.32 mmol) is added to a stirring solution of 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid (2.00 g, 6.16 mmol), dimethylformamide (DMF; 4 drops) and ether (50 ml). The mixture is stirred at RT for 3 hours. Insoluble material is filtered off and solvent is removed in vacuo to give 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid chloride.