Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:11]([N+:20]([O-:22])=[O:21])=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:19])=[CH:13]2.IC.[C:31](=O)([O-])[O-].[Cs+].[Cs+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:31][N:15]1[C:16]2[C:12](=[C:11]([N+:20]([O-:22])=[O:21])[C:10]([O:9][C:8]3[CH:7]=[CH:6][C:5]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][C:3]=3[O:2][CH3:1])=[CH:18][CH:17]=2)[CH:13]=[C:14]1[CH3:19]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Cc1ccc(Oc2ccc3[nH]c(C)cc3c2[N+](=O)[O-])c(OC)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(Oc2ccc3c(cc(C)n3C)c2[N+](=O)[O-])c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a room temperature solution of 3.1 (38 mg, 0.099 mmol) and iodomethane (6.8 μL, 0.11 mmol) dissolved in N,N-dimethylformamide (1 mL) was added cesium carbonate (35 mg, 0.11 mmol). The resulting intense red solution was stirred at room temperature overnight. After 19 h, the color had dissipated to a faint pink and HPLC indicated no 3.1 remained. Several drops of aqueous 20% citric acid solution were added and the mixture partitioned between ethyl acetate and water. The separated aqueous layer was extracted again with ethyl acetate. The combined organic extracts were washed with water twice then brine. The organic separation was stirred over magnesium sulfate, filtered and the filtrate concentrated in vacuo on a rotary evaporator to afford a yellow solid. The product was used without further purification. 1H NMR (400 MHz) (CDCl3) δ 7.35 (d, J=8.8 Hz, 1H); 6.95 (s, 1H); 6.83-6.76 (m, 3H); 6.71 (s, 1H); 4.16 (q, J=9.6 Hz, 2H); 3.88 (s, 3H); 3.70 (s, 3H); 2.48 (s, 3H); 1.27 (t, J=9.6 Hz, 3H) ppm.
Reaction SMILES: C[O:2][CH2:3][C@H:4]([CH3:36])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][CH2:30][C@@H:31]([C@@H:33]([OH:35])[CH3:34])[N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:35][C@H:33]([C@@H:31]1[CH2:30][O:29][C:28]([C:26]2[NH:27][C:23]([C:8]3[CH:7]=[C:6]([CH:11]=[C:10]([O:12][C:13]4[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=4)[CH:9]=3)[O:5][C@@H:4]([CH3:36])[CH2:3][OH:2])=[CH:24][CH:25]=2)=[N:32]1)[CH3:34]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H]([C@H](C)O)CO3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](O)[C@@H]1COC(c2ccc(-c3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(O[C@@H](C)CO)c3)[nH]2)=N1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
(1S)-1-{(4S)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol (187 mg, 0.36 mmol) synthesized in Example (93b) was dissolved in methylene chloride (5 mL) and subsequently cooled to −78° C., and boron tribromide (1.0 mol/L methylene chloride solution, 0.73 mL, 0.73 mmol) was added under nitrogen atmosphere. The temperature was raised naturally, followed by stirring at room temperature for 30 minutes, and subsequently a saturated aqueous sodium hydrogencarbonate solution was added to neutralize the reaction solution, followed by extraction with methylene chloride (70 mL). The organic layer was washed with a 1N aqueous sodium hydroxide solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-4%) to afford the desired compound (134 mg, 74%) as a white solid.
Reaction SMILES: [OH:1][CH:2]([CH2:15][OH:16])[CH2:3][NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:7][CH:6]=1.Cl[C:18]1[CH:23]=[CH:22][C:21]([S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:31]([O-:33])=[O:32].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)(Cl)Cl.C(O)(C)C>[OH:1][CH:2]([CH2:15][O:16][C:18]1[CH:23]=[CH:22][C:21]([S:24]([C:27]([F:29])([F:30])[F:28])(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:31]([O-:33])=[O:32])[CH2:3][NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9]([NH2:12])(=[O:10])=[O:11])=[CH:7][CH:6]=1
Reactant: NS(=O)(=O)c1ccc(NCC(O)CO)cc1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: NS(=O)(=O)c1ccc(NCC(O)COc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])cc1

Procedure:
A mixture of N4-(2,3-dihydroxypropyl)sulfanilamide (82 mg, 0.33 mmol), 1-chloro-2-nitro-4-trifluoromethanesulfonyl-benzene (135 mg, 0.47 mmol) and potasium carbonate (190 mg, 1.33 mmol) in acetonitrile (2 mL) was heated to reflux for 2 days. The reaction was diluted with chloroform/isopropanol mixture, washed with brine, dried, concentrated and column chromatographed to give the title compound (mono-arylated) and 4-[2,3-bis-(2-nitro-4-trifluoromethanesulfonyl-phenoxy)-propylamino]-benzenesulfonamide (di-arylated) example 62. 1H NMR (300 MHz, DMSO-d6) δ 8.63 (d, 1H), 8.35 (dd, 1H), 7.75 (d, 1H), 7.63 (d, 2H), 6.68 (d, 2H), 4.35 (d, 2H), 3.98 (t, 1H), 3.2 (m, 2H). MS −ve APCI 498 [M−1].
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+].Cl>O1CCCC1>[F:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1cc([N+](=O)[O-])c(F)cc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(CO)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.2 %

Procedure:
To a solution of 2,4-difluorobenzaldehyde (2.27 g) in methylene chloride (6 mL) was added concentrated sulfuric acid (6 mL) under ice-cooling, and the mixture was stirred for 15 minutes. To the mixture was added fuming nitric acid (1 mL) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Then the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate. To the mixture was added water, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution twice, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=7/3) to give 2,4-difluoro-5-nitrobenzaldehyde (2.63 g). The obtained 2,4-difluoro-5-nitrobenzaldehyde (1 g) was dissolved in tetrahydrofuran (15 mL). To the solution was added sodium borohydride (0.3 g), and the mixture was stirred at room temperature for 5 minutes. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane −n-hexane/ethyl acetate=1/1) to give the title compound (0.76 g)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[C:12]1[NH2:18].Cl.[CH3:20][C:21](=O)[CH2:22][C:23](=O)[CH3:24]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:12]2[C:13](=[C:21]([CH3:20])[CH:22]=[C:23]([CH3:24])[N:18]=2)[C:14]([C:16]#[N:17])=[CH:15]1
Reactant: CC(=O)CC(C)=O
Reactant: CC(C)c1ccc(-n2cc(C#N)cc2N)c(Br)c1
Agent: Cl
Solvent: CCO
Product: Cc1cc(C)c2c(C#N)cn(-c3ccc(C(C)C)cc3Br)c2n1
Reaction time: 4 h

Procedure:
Part C: A mixture of 18.51 g (0.0609 mole) of 1-(2-bromo-4-isopropylphenyl)-2-amino-4-cyano-pyrrole, 300 mL of ethanol, 0.6 mL of conc. hydrochloric acid, and 10 mL (9.75 g, 0.0974 mole) of 2,4-pentanedione was refluxed with stirring under a nitrogen atmosphere for 4 hrs. The mixture was allowed to cool and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate. The solution was washed with 10% sodium bicarbonate solution, then with brine. The solution was dried with anhydrous sodium sulfate and evaporated to give 21.76 g of dark, tarry residue. The residue was chromatographed on silica gel by eluting in step gradients of 0, 10, 15, 20, 25, and 30% ethyl acetate in hexane. The initial fraction is 17.6 g (78%) 1-(2-bromo-4-isopropylphenyl)-3-cyano-4,6-dimethyl-7-azaindole; m.p. 105.8°. Mass spec: (m+H° =368.0749; calculated, 368.0762 (79Br). Rf =0.45 on silica gel thin layer chromatography with 70:30 hexane-ethyl acetate.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[N:3]=1.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[OH:19].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1nc(Cl)ccc1C#N
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(Oc2ccc(F)cc2F)ccc1C#N
Temperature: 80 °C

Procedure:
A mixture of 6-chloro-2-methylnicotinonitrile (Example 1, step 1; 500 mg, 3.27 mmol), 2,4-difluorophenol (0.47 mL, 4.91 mmol) and cesium carbonate (1.60 g, 4.91 mmol) in DMF (5 mL) was heated in an oil bath at 80° C. for 5 h. The reaction mixture was treated with water and extracted with EtOAc (2×20 mL). The combined organic layers were washed with 1 N NaOH (15 mL) followed by brine, dried over MgSO4 and concentrated. Purification on an ISCO (40 g column, 5-50% EtOAc in hexanes) provided 6-(2,4-difluorophenoxy)-2-methylnicotinonitrile as a white crystalline solid. MS (ESI, pos.ion) m/z: M+1=247.0
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:17])([CH3:16])[CH2:8][CH2:7]1>C(O)(=O)C.C(OC(=O)C)(=O)C>[N+:1]([C:13]1[CH:12]=[CH:11][C:10]2[C:9]([CH3:17])([CH3:16])[CH2:8][CH2:7][C:6]([CH3:18])([CH3:5])[C:15]=2[CH:14]=1)([O-:4])=[O:2]
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC1(C)CCC(C)(C)c2cc([N+](=O)[O-])ccc21
Reaction time: 8 h

Procedure:
77.2 ml of glacial acetic acid and 20.8 ml of nitric acid (98% strength) were mixed while cooling and then added dropwise within 2 hours to a solution of 65.8 g (0.35 mol) of 1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene in 154 ml of glacial acetic acid and 257 ml of acetic anhydride in a salt/ice bath. After the addition was complete, the reaction mixture was washed to room temperature and stirred overnight. The solution was then poured into water, and the precipitate was filtered off with suction, washed with water and dried. 79.7 g of crude 2-nitro-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene of melting point 46°-50° C. were obtained.
Reaction SMILES: O1CCOCC1.[F:7][C:8]1[C:16]([F:17])=[C:15]([F:18])[C:14]([F:19])=[CH:13][C:9]=1[C:10](Cl)=[O:11].[CH3:20][N:21]([CH3:28])[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[O:25]>C(N(CC)CC)C>[CH3:20][N:21]([CH3:28])[CH:22]=[C:23]([C:10](=[O:11])[C:9]1[CH:13]=[C:14]([F:19])[C:15]([F:18])=[C:16]([F:17])[C:8]=1[F:7])[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)C=CN(C)C
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)C(=CN(C)C)C(=O)c1cc(F)c(F)c(F)c1F
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
To dioxane (80 ml) solution of 2,3,4,5-tetrafluorobenzoyl chloride (21.25 g) was added dioxane (25 ml) solution of methyl 3-dimethylaminoacrylate (12.92 g) with ice-cooling, and triethylamine (14.46 ml) was added thereto with ice-cooling. The mixture was stirred for 30 minutes at the same temperature, then for 3 hours at room temperature, and then for one hour at 50° to 60° C. The mixture was concentrated under reduced pressure, then dissolved in methylene chloride (200 ml), washed with water (200 ml) and brine (100 ml) in order, then dried with sodium sulfate and concentrated under reduced pressure to obtain a syrup product. The syrup product was subjected to column chromatography with silica gel and eluted with a mixed liquid of methanol/methylene chloride (3/97, V/V) to obtain methyl 3-dimethylamino-2-(2,3,4,5-tetrafluorobenzoyl)acrylate (15.47 g) as a syrup product.
Reaction SMILES: [Br-].OCCC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[N:41]([S:45]([C:48]1[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=1[O:56][C:57]([F:60])([F:59])[F:58])(=[O:47])=[O:46])[C:40](=[O:61])[C:39]2([N:73]1[CH2:82][C@H:81]([OH:83])[CH2:80][C@H:74]1[C:75]([N:77]([CH3:79])[CH3:78])=[O:76])[C:62]1[CH:67]=[C:66]([CH2:68]C=O)[CH:65]=[CH:64][C:63]=1[O:71][CH3:72].[NH4+].[Cl-].[CH2:86]1[CH2:90][O:89][CH2:88][CH2:87]1>>[Cl:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[N:41]([S:45]([C:48]1[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=1[O:56][C:57]([F:60])([F:58])[F:59])(=[O:47])=[O:46])[C:40](=[O:61])[C:39]2([N:73]1[CH2:82][C@H:81]([OH:83])[CH2:80][C@H:74]1[C:75]([N:77]([CH3:79])[CH3:78])=[O:76])[C:62]1[CH:67]=[C:66]([CH2:68][CH:90]=[CH:86][CH2:87][CH2:88][OH:89])[CH:65]=[CH:64][C:63]=1[O:71][CH3:72]
Reactant: C1CCOC1
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CC=O)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CC=CCCO)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere, to a suspension of 497 mg of (3-hydroxy propyl)(triphenyl) phosphonium bromide in THF (5 ml) was added dropwise a solution of 1 mol/L lithium bis-(trimethylsilyl) amide in THF (1.43 ml) under ice cooling. After stirring at room temperature for one hour, the solution was cooled by ice, 300 mg of compound obtained in Example 219 in THF (5 ml) was added to a solution and the reaction mixture was stirred at room temperature for one hour. A saturated aqueous solution of NH4Cl was added to the solution and the resulting mixture was extracted with EtOAc; the organic layer was washed with saturated brine and dried over Na2SO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60N; mobile phase: CHCl3/MeOH=20/1 to 10/1; v/v) to obtain 206 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:24])[CH:3]=1.[C:25]([N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])(=[O:27])[CH3:26]>>[C:25]([N:28]1[CH2:32][CH2:31][N:30]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[C:4]([CH3:24])[CH:3]=2)[C:29]1=[O:33])(=[O:27])[CH3:26]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)c(C)c2)C1=O
Yield: 62.4 %

Procedure:
Using (4-bromo-2-methylphenyl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (233 mg) described in Preparation Example 118 and 1-acetylimidazolidin-2-one (115 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (163 mg) was obtained.
Reaction SMILES: CC(C)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:11](Br)[CH:12]=[C:13]([CH3:15])[CH3:14].[OH:17][C:18]1[CH:28]=[CH:27][C:21]2[N:22]=[C:23]([C:25]#[N:26])[S:24][C:20]=2[CH:19]=1>CCCCCCC.C(OCC)(=O)C>[CH2:11]([O:17][C:18]1[CH:28]=[CH:27][C:21]2[N:22]=[C:23]([C:25]#[N:26])[S:24][C:20]=2[CH:19]=1)[CH:12]=[C:13]([CH3:15])[CH3:14]
Reactant: CC(C)=CCBr
Reactant: N#Cc1nc2ccc(O)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)=CCOc1ccc2nc(C#N)sc2c1
Reaction time: 28 h
Yield: 124.3 %

Procedure:
To a dry 25-ml round-bottomed flask containing acetone (5 mL), anhydrous potassium carbonate (1.2 g, 8.4 mmol), and prenyl bromide (839 microliters, 7.3 mmole) was added 6-hydroxy-2-cyanobenzothiazole (1.0 g, 5.6 mmol). The mixture was refluxed under argon with stirring. Reaction progress was monitored by TLC analysis, developing with 2:1 heptane-ethyl acetate. After 28 h, the potassium carbonate was filtered from the cooled reaction mixture. The solution was concentrated in vacuo to yield 1.7 g of solid. The solid was further purified by flash chromatography using 9:1 heptane-ethyl acetate and gradually stepping to 4:1 heptane-ethyl acetate. Appropriate fractions were pooled and evaporated to yield 0.8 g of solid. The structure was confirmed by 1H NMR analysis in DMSO-d6.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@@H:14]([C:22]([OH:24])=O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O:32]1[CH2:37][CH2:36][CH:35]([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([CH2:45][NH2:46])[CH2:41][CH2:40]2)[CH2:34][CH2:33]1.[OH-].[Na+]>O1CCCC1>[C:28]([O:27][C:25](=[O:26])[NH:13][C@@H:14]([C:22](=[O:24])[NH:46][CH2:45][CH:42]1[CH2:41][CH2:40][N:39]([CH2:38][CH:35]2[CH2:34][CH2:33][O:32][CH2:37][CH2:36]2)[CH2:44][CH2:43]1)[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: NCC1CCN(CC2CCOCC2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)NCC1CCN(CC2CCOCC2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
6.7 g of carbonyldiimidazole is added to a solution of 10 g of Boc-D-Phe-OH in 80 ml of tetrahydrofuran, cooled to 0° C. The resulting solution is maintained under stirring at 0° C. for 1 hour. A solution consisting of 8.0 g of (11) in 20 ml of tetrahydrofuran is dripped into the reaction mixture at a rate such that the temperature does not exceed 5° C. The solution is maintained under stirring at 0° C. for 1 hour, and at ambient temperature for 1 hour. 100 ml of 1M NaOH is added to the mixture, and the tetrahydrofuran is evaporated at low pressure. Dichloromethane and water are added to the residue; the two phases are separated, the organic phase is washed with water (2×), and after a low-pressure solvent change with ethyl acetate, compound (12) is crystallised from ethyl acetate to obtain 14.73 g of white solid. Yield 85%.
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]3)=[O:17])[CH:13]=[CH:14][C:3]1=2.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CCN=C=NCCCN(C)C.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[O:1]=[S:2]1(=[O:27])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH:15][C:16]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:26])[CH2:22][CH2:23]3)=[O:17])[CH:13]=[CH:14][C:3]1=2
Reactant: O=C(O)C1CCN(C(=O)Nc2ccc3c(c2)-c2ccccc2S3(=O)=O)CC1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2c(c1)-c1ccccc1S2(=O)=O)N1CCC(C(=O)N2CCOCC2)CC1

Procedure:
5,5-Dioxo-2-(4-carboxypiperidinocarbonylamino)dibenzothiophene (Example 84; 75 mg, 0.19 mmol), DMF (2.5 ml), morpholine (16.5 mg, 0.19 mmol), EDAC (44 mg, 0.23 mmol), 1-hydroxybenzotriazole hydrate (25.65 mg, 0.19 mmol) were stirred together for 18 hours. The solvent was removed under vacuum and the residue partitioned between H2O/EtOAc. The organic layers were washed with water, saturated aqueous NaHCO3 then brine, and then dried, filtered and evaporated to an amorphous solid. NMR: 9.08 (s, 1H)) 8.21 (d, 1H), 7.93 (m, 2H), 7.79 (m, 2H), 7.65 (m, 2H), 4.14 (m, 2H), 3.52 (m, 6H), 3.45 (m, 2H), 2.92 (m, 3H), 1.68 (m, 2H), 1.53 (m, 2H); m/z 456.73.
Reaction SMILES: C(OC)(=O)CCCCC(OC)=O.[CH2:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O=O.[CH2:23]([CH:31]([CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[C:32]([O:34][CH3:35])=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C([O-])(=O)C.[Mn+2].C([O-])(=O)C.C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(O)(=O)C>[CH2:23]([CH:31]([CH2:36][CH2:37][CH:38]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:39]([O:41][CH3:42])=[O:40])[C:32]([O:34][CH3:35])=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCC(CCCC(=O)OC)C(=O)OC
Reactant: C=CCCCCCC
Agent: [Co+2]
Agent: [Mn+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: COC(=O)CCCCC(=O)OC
Product: CCCCCCCCC(CCC(CCCCCCCC)C(=O)OC)C(=O)OC

Procedure:
A mixture of 20 mmol of dimethyl adipate, 2 mmol of 1-octene, 0.04 mmol of manganese(II) acetate, 0.002 mmol of cobalt (II) acetate and 2 ml of acetic acid was stirred at 90° C. in an atmosphere of a gaseous mixture of nitrogen and oxygen (9:1) (1 atm=0.101 MPa) for 3 hours. The resulting reaction mixture was analyzed to find that dimethyl 2-octyladipate and dimethyl 2,5-dioctyladipate were produced in yields of 36% and 2%, respectively, with a conversion from 1-octene of 60%.
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[C:10]([O:13][CH2:14]Br)(=[O:12])[CH3:11].[Br-].C(OC[Zn+])(=O)C.Cl[C:24]1[N:29]=[C:28]([O:30][C:31]2[C:32]([F:41])=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35]([CH3:40])=[CH:34]3)[CH:27]=[CH:26][N:25]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[NH4+].[Cl-]>CN(C=O)C.[Zn].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:10]([O:13][CH2:14][C:24]1[N:29]=[C:28]([O:30][C:31]2[C:32]([F:41])=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35]([CH3:40])=[CH:34]3)[CH:27]=[CH:26][N:25]=1)(=[O:12])[CH3:11]
Reactant: Cc1cc2c(F)c(Oc3ccnc(Cl)n3)ccc2[nH]1
Reactant: CC(=O)OCBr
Agent: [Pd+2]
Agent: CC(=O)OC[Zn+]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: BrCCBr
Product: CC(=O)OCc1nccc(Oc2ccc3[nH]c(C)cc3c2F)n1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
1,2-Dibromoethane (425 μL, 5.0 mmol) is added to a suspension of zinc powder (2.83 g, 43.2 mmol) in dry DMF (8 mL). The reaction mixture is heated at 60° C. for 10 min, then cooled to room temperature. TMSCl (500 μL, 4.0 mmol) is added (caution: exothermic!) and the resulting mixture is sonicated for 30 min. Zinc powder is allowed to settle and the supernatant is removed by syringe. DMF (8 mL) is added, followed by bromomethyl acetate (2.12 mL, 21.61 mmol). The mixture is stirred at 23° C. for 2.5 h. Zinc is allowed to settle and the solution of acetoxymethylzinc bromide is then transferred to a solution of 5-(2-chloropyrimidin-4-yloxy)-4-fluoro-2-methyl-1H-indole (2.00 g, 7.20 mmol), palladium acetate (0.081 g, 0.360 mmol), and S-phos (0.355 g, 0.864 mmol) in DMF (10 mL) at 23° C. The resulting mixture is stirred at 23° C. for 15 h. Saturated aqueous NH4Cl (100 mL) is added and the mixture is then partitioned between EtOAc (150 mL) and water (150 mL). The aqueous layer is extracted with EtOAc (2×100 mL). The combined organic layers are washed with brine (60 mL), dried (Na2SO4), and concentrated. The residue is purified by silica gel chromatography (0-100% EtOAc/heptane) to give (4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-yl)methyl acetate.