Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[C:21](OCC)(=[O:23])[CH3:22].O>O1CCCC1>[O:23]=[C:21]([CH3:22])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: CCOC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C(C)=O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
A stirred solution of 10 grams (0.061 mole) of ethyl phenylacetate in 125 mL of tetrahydrofuran is cooled to -78° C., and 33.5 mL (0.067 mole) of lithium diisopropylamide (2M solution in heptane-tetrahydrofuranethylbenzene) is slowly added dropwise at a rate to maintain the reaction mixture temperature below -60° C. Upon completion of addition, the reaction mixture is stirred at -78° C. for about one hour. After this time, 6.5 mL (0.067 mole) of ethyl acetate is added dropwise. Upon completion of addition, the reaction mixture is stirred for about one hour at -78° C. The reaction mixture is then allowed to warm to ambient temperature. After this time the reaction mixture is poured into 200 mL of water, and the mixture is extracted with one 100 mL portion of diethyl ether. The aqueous layer is made acidic with aqueous 10% hydrochloric acid, and then it is extracted with three 150 mL portions of diethyl ether. The combined extracts are dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 6.6 grams of ethyl 3-oxo-2-phenylbutanoate. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[N:7]=[C:8]([C:14]4O[CH:16]=[N:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.Cl.[CH:22]([NH2:25])([CH3:24])[CH3:23]>N1C=CC=CC=1>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:25]([CH:22]([CH3:24])[CH3:23])[CH:16]=[N:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)OCCc1sc(-c3nnco3)nc1-2
Reactant: CC(C)N
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)n1cnnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 160 °C
Yield: 40.2 %

Procedure:
To a solution of 8-bromo-2-[1,3,4]oxadiazol-2-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (4.38 g, 12.51 mmol) in pyridine (12 mL) was added isopropylamine hydrochloride (1.38 g, 12.51 mmol). The reaction mixture was heated at 160° C. for 30 minutes using microwave irradiation before being concentrated in vacuo. The residue was taken up into DCM then washed with 1M HCl then brine before being dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, gradient 0-3% methanol in DCM then further purified, gradient 0-4% MeOH in EtOAc) to yield the title compound as an orange solid (1.97 g, 40%). LCMS: RT=4.67 min, M+H+=391/393.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:8]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[C:14]([OH:16])=[O:15].[CH3:17][O:18][CH:19]([O:22][CH3:23])[CH2:20]Br.C(OCC)(=O)C>O1CCOCC1.CN(C)C=O>[CH3:3][C:4]1[C:8]2[CH:9]=[C:10]([O:13][CH2:20][CH:19]([O:22][CH3:23])[O:18][CH3:17])[CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[C:14]([OH:16])=[O:15]
Reactant: Cc1c(C(=O)O)oc2ccc(O)cc12
Reactant: COC(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(COc1ccc2oc(C(=O)O)c(C)c2c1)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred slurry of sodium hydride (0.11 g of 60% in oil, 2.7 mmol) in p-dioxane (10 mL) was added methyl 5-hydroxybenzofuran-2-carboxylic acid (0.5 g, 2.6 mmol) and the resulting green slurry was stirred at room temperature for 15 min. To this slurry was added a solution of bromoacetaldehyde dimethyl acetal (0.5 g, 3.0 mmol) in dimethylformamide (DMF) (10 mL) and the resulting solution was heated at reflux for 15 hours. The reaction mixture was poured into ethyl acetate, washed with water, brine, the organic phased dried (Na2SO4) and concentrated in vacuo. The resulting oil was flash chromatographed on silica gel (25% ethyl acetate:hexanes) to afford the title compound as a colorless solid, (0.16 g; m.p. 74-74° C.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=3)=[O:10])=[CH:4][CH:3]=1.Br[CH2:30][C:31](=O)[C:32]([CH3:35])([CH3:34])[CH3:33]>C(#N)C>[C:32]([C:31]1[N:1]=[C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]3[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=4)=[O:10])=[CH:6][N:7]2[CH:30]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: Nc1ccc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)cn1
Reactant: CC(C)(C)C(=O)CBr
Solvent: CC#N
Product: CC(C)(C)c1cn2cc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)ccc2n1
Yield: 99.8 %

Procedure:
Compound 7 was prepared according to a process similar to that described in step 4.3, by reacting 0.1 g (0.26 mmol) of N-[6-aminopyrid-3-yl]-5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 4.2, with 0.096 g (0.53 mmol) of 1-bromo-3,3-dimethylbutan-2-one in 4 mL of acetonitrile. 0.119 g of the expected product is thus obtained in the form of a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.CO>[C:1]([O:5][C:6]([C@@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(O[C@H]2CC[C@@H](C(=O)OC(C)(C)C)CC2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)O)cn2)CC1

Procedure:
1.33 g of ethyl cis-6-(4-tert-butoxycarbonylcyclohexyloxy)nicotinate (3.97 mmol, 1 eq.) are dissolved in 60 mL of a 1/1 mixture of THF/methanol. At 0° C., 0.333 g of lithium hydroxide monohydrate (7.93 mmol; 2 eq.) is added with stirring. After stirring for 16 hours at room temperature, the reaction medium is evaporated and aqueous 6% sulfur dioxide solution is added. The precipitate formed is filtered off and washed with water to give 1.25 g of cis-6-(4-tert-butoxycarbonylcyclohexyloxy)nicotinic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:26])[CH:24]=[O:25].[Li+].[BH4-]>CO.C1COCC1>[OH:25][CH2:24][C:23]([CH3:26])=[CH:22][CH2:21][C:4]1[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:20])[CH3:19])=[C:6]2[C:10]([CH2:9][O:8][C:7]2=[O:13])=[C:11]([CH3:12])[C:3]=1[O:2][CH3:1]
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)C=O)C(=O)OC2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CO)C(=O)OC2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 97.8 %

Procedure:
A solution of 4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal (103 mg, 0.27 mmol) in methanol (5 mL) was cooled to 0° C. A solution of CeCl3 (0.68 mL, MeOH: H2O, 9:1) was added, followed by LiBH4 (0.14 mL, 0.28 mmol of a 2M solution in THF). The ice bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred for an additional 40 minutes whereupon TLC indicated complete consumption of starting aldehyde. The reaction was worked up by addition of aqueous 1N HCl (0.5 mL) and the product was extracted with CH2Cl2. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography to provide 100 mg (97%) of the product as a clear liquid. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 1.20 (dd, 2H, J=7, 8 Hz), 1.81 (s, 3H), 2.13 (s, 3H), 3.38-3.50 (m, 2H), 3.74 (s, 3H), 3.95 (s, 2H), 4.27 (dd, 2H, J=7, 8 Hz), 5.08 (s, 2H), 5.17-5.44 (m, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1(Cl)[CH2:4][CH:3]1[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C>>[Cl:1][C@@H:2]1[CH2:4][C@H:3]1[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)C1CC1(Cl)Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H]1Cl
Temperature: 90 °C
Yield: 26.5 %

Procedure:
A mixture of tert-butyl 2,2-dichlorocyclopropanecarboxylate (1.0 g, 4.7 mmol), tributyltin hydride (1.68 g, 5.7 mmol) and AIBN (50 mg) were heated to 90° C. for 1 h. The mixture was cooled to room temperature and distillation afforded a mixture of cis and trans t-butyl 2-chloro-1-cyclopropane carboxylate (220 mg, yield: 26%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](Cl)=[O:13])=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[NH2:15][CH:16]1[C:23](=[O:24])[N:22]2[CH:17]1[S:18][CH2:19][C:20]([CH3:28])=[C:21]2[C:25]([OH:27])=[O:26]>C(OCC)(=O)C>[N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:15][CH:16]2[C:23](=[O:24])[N:22]3[CH:17]2[S:18][CH2:19][C:20]([CH3:28])=[C:21]3[C:25]([OH:27])=[O:26])=[O:13])=[CH:7][CH:6]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCc1ccc(CC(=O)Cl)cc1
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccc(CN=[N+]=[N-])cc3)C2SC1

Procedure:
A mixture of p-azidomethylphenylacetyl chloride (0.6 g) and 7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (0.6 g) in 250 ml of ethyl acetate was refluxed for 50 minutes after which the solvent was removed under vacuum yielding an oily residue which was purified by chromatography using 60 g of silica gel and benzene-acetone as the eluant to give 7-[[2-[4-(azidomethyl)-phenyl]acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid. M.P. 154°-155° C.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:5].[CH:14](=O)[CH:15]([CH3:17])[CH3:16].C(O)(=O)C>O.CO>[CH3:14][CH:15]([CH:17]=[CH:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[CH3:16]
Reactant: CC(C)C=O
Reactant: COc1ccc(C(C)=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)C=CC(C)C)cc1
Reaction time: 3.5 h

Procedure:
17 g of potassium hydroxide were dissolved in 125 ml of water and 125 ml of methanol, and 150 g of 4-methoxyacetophenone were added. 80 g of isobutyraldehyde were added dropwise (in the course of 1.5 hours) at 50° C. After 3.5 hours, the mixture was cooled to room temperature and neutralized with acetic acid (about 20 ml). The dimeric condensation product was filtered off, washed with methanol and dried in air. Yield: 175 g. The solid was mixed with 5 g of sodium acetate and the mixture was distilled under a waterpump vacuum. 165 g of a yellow oil which solidified at room temperature and was a mixture of 2-methyl-5-oxo-5-(4'-methoxyphenyl)-2-pentene and 2-methyl-5-oxo-5-(4'-methoxyphenyl)-3-pentene were obtained. Boiling point of the isomer mixture=158°-165° C./17 mbars.
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[NH:15][C:14]2=[O:24])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[C:25](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[F:1][C:2]1[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[N:15]([CH3:25])[C:14]2=[O:24])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc2N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc3c(cc2F)OCC(=O)N3)c1=O
Reaction time: 4 h
Yield: 119.9 %

Procedure:
0.85 g of 3-(7-fluoro-3-oxo-2H-1,4-benzoxazin-6-yl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione was dissolved in 8.5 ml of N,N-dimethylformamide. Then 0.17 g of anhydrous potassium carbonate and 0.15 ml of methyl iodide were added and the mixed solution was stirred for 4 hours. After the reaction was completed, N,N-dimethylformamide was distilled off and the residue was extracted with ethyl acetate by adding water. The extract was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then ethyl acetate was distilled off to obtain a crude product. This product was purified by column chromatography using chloroform as developing solvent to yield 0.53 g of the objective compound as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][C:13]([Cl:17])=[N:14][CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[C:25](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][C:13]([Cl:17])=[N:14][CH:15]=3)[N:10]([C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Clc1ncc2c(-c3cccc(Br)c3)n[nH]c2n1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Clc1ncc2c(-c3cccc(Br)c3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-(3-bromo-phenyl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidine (from Example 38 supra) (4.0 g, 12.9 mmol) and Et3N (2.6 g, 25.8 mmol) in DMF (40 mL) was added the solution of trityl chloride (4.3 g, 15.5 mmol) in DMF (40 mL) at room temperature. This mixture was stirred at room temperature for 2 hours. The reaction solution was then poured into water (400 mL), and the yellow precipitate was collected by filtration. This crude product was purified by chromatography (silica gel, dichloromethane:petroleum ether, 1:1) to give 3-(3-bromo-phenyl)-6-chloro-1-trityl-1H-pyrazolo[3,4-d]pyrimidine as a light yellow solid. (Yield 3.5 g, 30%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.[H-].[Na+].[CH3:15][Si:16]([CH2:19][CH2:20][O:21][CH2:22]Cl)([CH3:18])[CH3:17]>CN(C=O)C.[Cl-].[NH4+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:22][O:21][CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=c1ccc2cc(Br)cnc2[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(=O)ccc2cc(Br)cnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
To a solution of 6-bromo-1,8-naphthyridin-2(1H)-one (0.1 g, 0.444 mmol) in DMF (2 mL) was added sodium hydride (0.021 g, 0.889 mmol) at 0° C. The reaction was stirred at 0° C. for 30 min, then SEM-Cl (0.118 mL, 0.667 mmol) was added. The reaction was stirred at room temperature overnight, then diluted with ammonium chloride solution, extracted with ethyl acetate, dried over Na2SO4, and concentrated. The crude product was purified by flash chromatography on silica gel using 20% ethyl acetate in petroleum ether to give 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,8-naphthyridin-2(1H)-one (0.12 g, 76%). 1HNMR 400 MHz (CDCl3): 0.034 (s, 9H), 0.95-0.99 (m, 2H), 3.73-3.77 (m, 2H), 5.92 (s, 2H), 6.75-6.77 (m, 1H), 7.56-7.58 (m, 1H), 7.96-7.98 (m, 1H), 8.63-8.64 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([B:21]3OC(C)(C)C(C)(C)[O:22]3)=[C:17]([CH:30]=[O:31])[CH:16]=2)[N:7]=1)=[O:5])[CH3:2].[BH4-].[Na+].Cl>CO>[CH2:1]([O:3][C:4]([C:6]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]3[B:21]([OH:22])[O:31][CH2:30][C:17]=3[CH:16]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(C=O)c2)ccc1C#N
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1nc(Oc2ccc3c(c2)COB3O)ccc1C#N
Reaction time: 1 h
Yield: 107.3 %

Procedure:
To a solution of 3-cyano-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-pyridine-2-carboxylic acid ethyl ester (25, 0.11 g, 0.23 mmol) in methanol (5 mL) was added sodium borohydride (0.01 g, 0.27 mmol) at 0° C. After 1 h at 0° C., 2 M HCl was added until pH is 2˜3. The solvent was removed under reduced pressure to give crude product, which was purified by reverse phase prep HPLC using CH3CN/H2O (0.1% AcOH) as the eluent to yield the title compound (D45) (0.08 g, 20%) as a white solid after lyophilization. Mp 204-206° C. 1H NMR 400 MHz (DMSO-d6) δ: 9.26 (s, 1H), 8.47 (d, J=9.0 Hz, 1H), 7.80 (d, J=9.4 Hz, 1H), 7.39 (d, J=8.6 Hz, 1H), 7.32 (s, 1H), 7.24-7.19 (m, 1H), 4.99 (s, 2H), 4.32-4.23 (m, 2H), 1.39-1.20 (m, 3H); MS (ES) m/z: 325 (M+1)+; HPLC purity: 96.01% (Maxplot), 98.13% (220 nm), 97.47% (254 nm).
Reaction SMILES: [O:1]=[C:2]([CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][NH:54][C:55](=[O:69])[CH2:56][CH2:57][CH2:58][CH2:59][CH:60]1[CH:67]2[CH:63]([NH:64][C:65](=[O:68])[NH:66]2)[CH2:62][S:61]1)[NH:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:39]=[CH:38][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1.O[N:71]1[C:75](=[O:76])[CH2:74][CH2:73][C:72]1=[O:77].C(Cl)CCl>C(Cl)Cl>[O:1]=[C:2]([CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][NH:54][C:55](=[O:69])[CH2:56][CH2:57][CH2:58][CH2:59][CH:60]1[CH:67]2[CH:63]([NH:64][C:65](=[O:68])[NH:66]2)[CH2:62][S:61]1)[NH:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:39]=[CH:38][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][C:35]([O:37][N:71]3[C:75](=[O:76])[CH2:74][CH2:73][C:72]3=[O:77])=[O:36])=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CCOCCOCCOCCOCCNc1ccc(C(=O)c2ccc(OCCCNC(=O)CCOCCOCCOCCOCCNC(=O)CCCCC3SCC4NC(=O)NC43)cc2)cc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(CCCCC1SCC2NC(=O)NC21)NCCOCCOCCOCCOCCC(=O)NCCCOc1ccc(C(=O)c2ccc(NCCOCCOCCOCCOCCC(=O)ON3C(=O)CCC3=O)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of crude 1-((4-(4-((5,21-dioxo-25-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-8,11,14,17-tetraoxa-4,20-diazapentacosyl)oxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oic acid (1.85 g, 1.89 mmol) in anhydrous DCM (43.0 ml) was added N-hydroxysuccinimide (239 mg, 2.08 mmol) followed by EDC (471 mg, 2.46 mmol). The reaction was stirred at r.t. for 4 hs. Upon completion, reaction was concentrated under reduced pressure and purified by silica gel chromatography (DCM to DCM:iPrOH, gradient) to provide 2,5-dioxopyrrolidin-1-yl 1-((4-(4-((5,21-dioxo-25-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-8,11,14,17-tetraoxa-4,20-diazapentacosyl)oxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oate as slightly yellow oil.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[O:9]=[C:10]1[CH:14]=[CH:13][C:12](=[O:15])[N:11]1[CH2:16][CH2:17][C:18](=[O:73])[NH:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][C:34](=[O:72])[NH:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:71]=[CH:70][C:43]([C:44]([C:46]2[CH:51]=[CH:50][C:49]([NH:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67](O)=[O:68])=[CH:48][CH:47]=2)=[O:45])=[CH:42][CH:41]=1.C(Cl)CCl>C(Cl)Cl>[O:9]=[C:10]1[CH:14]=[CH:13][C:12](=[O:15])[N:11]1[CH2:16][CH2:17][C:18](=[O:73])[NH:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][C:34](=[O:72])[NH:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:41]=[CH:42][C:43]([C:44]([C:46]2[CH:51]=[CH:50][C:49]([NH:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67]([O:1][N:2]3[C:6](=[O:7])[CH2:5][CH2:4][C:3]3=[O:8])=[O:68])=[CH:48][CH:47]=2)=[O:45])=[CH:70][CH:71]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CCOCCOCCOCCOCCNc1ccc(C(=O)c2ccc(OCCCNC(=O)CCOCCOCCOCCOCCNC(=O)CCN3C(=O)C=CC3=O)cc2)cc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(CCOCCOCCOCCOCCNC(=O)CCN1C(=O)C=CC1=O)NCCCOc1ccc(C(=O)c2ccc(NCCOCCOCCOCCOCCC(=O)ON3C(=O)CCC3=O)cc2)cc1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
N-hydroxysuccinimide (438 mg, 4.00 mmol) was added to a solution of crude 1-((4-(4-((1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,19-dioxo-7,10,13,16-tetraoxa-4,20-diazatricosan-23-yl)oxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oic acid (3.00 g) in anhydrous DCM (20 ml) was added followed by EDC (946 mg, 5.00 mmol). The reaction was stirred at r.t. for 2-3 hs. Upon completion, reaction was concentrated under reduced pressure and purified by silica gel chromatography (DCM to DCM:iPrOH gradient) to provide 2.15 g (2.12 mmol) of 2,5-dioxopyrrolidin-1-yl 1-((4-(4-((1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,19-dioxo-7,10,13,16-tetraoxa-4,20-diazatricosan-23-yl)oxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oate as slightly yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[O:6]/[C:5](=[C:7]2/[C:8](=[O:27])[NH:9][C:10]3[C:15]/2=[CH:14][CH:13]=[C:12]([S:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21]C)=[O:20])[CH:11]=3)/[CH:4]=[C:3]1[N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[OH-].[Na+].O>CO>[CH3:1][C:2]1([CH3:34])[O:6]/[C:5](=[C:7]2/[C:8](=[O:27])[NH:9][C:10]3[C:15]/2=[CH:14][CH:13]=[C:12]([S:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([OH:21])=[O:20])[CH:11]=3)/[CH:4]=[C:3]1[N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: COC(=O)c1ccccc1Sc1ccc2c(c1)NC(=O)/C2=C1\C=C(N2CCOCC2)C(C)(C)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(Sc4ccccc4C(=O)O)ccc32)C=C1N1CCOCC1
Temperature: 66 °C

Procedure:
A mixture of methyl 2-{[(3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-2-oxo-2,3-dihydro-1 H-indol-6-yl]thio}benzoate (50 mg) and 1 M NaOH (3 mL) in 20 mL of MeOH was heated in 66° C. bath for 2 hours. The mixture was cooled to room temp, poured into 100 mL of water, and acidified to about pH 3. The precipitates were filtered, washed with water and dried in vacuo to give 2-{[(3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]thio}benzoic acid as a brown solid. Yield: 50 mg, 97%.