Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[I-].C(N(CC)CC)C.[F:26][C:27]([F:38])([F:37])[C:28]([NH:30][CH2:31][CH2:32][O:33][CH2:34][C:35]#[CH:36])=[O:29]>[Cu].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C(O)(=O)C>[F:26][C:27]([F:37])([F:38])[C:28]([NH:30][CH2:31][CH2:32][O:33][CH2:34][C:35]#[C:36][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1)=[O:29]
Reactant: C#CCOCCNC(=O)C(F)(F)F
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Agent: [Cu]
Agent: [Pd]
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: O=C(NCCOCC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of 5-iodo-2'-deoxyuridine (3.54 g, 10 mmol), copper(l) iodide (0.19 g, 1 mmol) and tetrakis(triphenylphosphine)palladium(O) (0.58 g, 0.5 mmol) is dried in vacuo at 60° for 3 hours and placed under argon. A suspension of the mixture in dry DMF (20 ml) is stirred under argon and treated with dry triethylamine (1.7 ml, 12 mmol) followed by 3-(2-Trifluoroacetamidoethoxy)propyne (3.17 g, 16 mmol). The mixture is cooled at room temperature in a water bath and stirred for 17 hours. The mixture is treated with 2% acetic acid (100 ml), the catalyst is removed by filtration and washed with 50% methanol. The filtrates are combined and passed onto a LiChroprep RP-18 column (5×25 cm), the column is washed, then eluted with 1% acetic acid in 50% (v/v) methanol. The fractions with the main product are combined, evaporated, and dried in vacuo. The resultant foam is stirred with 150 ml of ether to give crystalline product; yield 3.6 g (85%); m.p. 145-1520.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][OH:6].C[O:8][C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:17].[C:26]([OH:31])(=[O:30])[C:27]([OH:29])=[O:28]>CO>[C:26]([OH:31])(=[O:30])[C:27]([OH:29])=[O:28].[OH:6][NH:5][C:9](=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:17]
Reactant: COC(=O)CCCCCNS(=O)(=O)c1cccnc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CO
Product: O=C(CCCCCNS(=O)(=O)c1cccnc1)NO
Reaction time: 0.17 h
Yield: 43.7 %

Procedure:
A solution of sodium methylate (12 mmol) in methanol (10 ml) was added to a solution of hydroxylamine hydrochloride (0.56 g, 8 mmol) in methanol (16 ml). The mixture was stirred for 10 min, and NaCl was filtered off. 6-(Pyridine-3-sulfonylamino)hexanoic acid methyl ester (93c) (0.58 g, 2 mmol) was added to the filtrate and the mixture was left to stand overnight at ambient temperature. The precipitate was filtered off, dissolved in water (20 ml) and oxalic acid (0.36 g, 4 mmol) was added to the solution. Water was removed under reduced pressure and the product was crystallised from methanol. The title compound (0.33 g, 44%) was obtained as white solid. M.p. 132-134° C. 1H NMR δH (90 MHz, DMSO-d6) δ: 0.78-1.49 (6H, m, CH2); 1.83 (2H, t, J=6.5 Hz, CH2); 2.76 (2H, t, J=6.5 Hz, CH2N); 7.54 (1H, dd, J=5.0 Hz, J=8.2 Hz, C5HN); 8.12 (1H, dt, J=2.0 Hz, J=8.2 Hz, C5HN); 8.61 (1H, dd, J=2.0 Hz, J=5.0 Hz, C5HN); 8.81 (1H, d, J=2.0 Hz, C5HN). HPLC analysis on Symmetry C18 column: impurities <1% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 5:95; detector UV 254 nm; sample concentration 1.0 mg/ml). Anal. Calcd for C11H17N3O4S*(COOH)2: C, 41.38; H, 5.07; N, 11.13. Found: C, 41.53; H, 5.10; N, 19.83.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]2([C:19]#[N:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:6]=1)=[O:4].O>CO>[OH:4][CH2:3][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]2([C:19]#[N:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:6]=1
Reactant: N#CC1(n2cc(C=O)c3cccnc32)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#CC1(n2cc(CO)c3cccnc32)CCCC1
Reaction time: 2 h

Procedure:
0.45 g of sodium borohydride is added in small portions at between 20° and 25° C. to a solution of 4.6 g of compound of stage 1 above in 80 ml of methanol. The mixture is stirred for 2 hours, 2 ml of water are then added, the resulting mixture is evaporated, the residue is taken up with dichloromethane, the dichloromethane solution is washed with water, dried over Na2SO4, filtered and evaporated and the residue is chromatographed on silica gel(eluant: ethyl acetate/hexane, 8:2).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:15][CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.N([O-])=O.[Na+].[I-:33].[K+]>C(#N)C.O.C(OCC)(=O)C>[I:33][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: CCOC(=O)C(C)c1ccc(N)c(OC)c1
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=N[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(C)c1ccc(I)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
To a stirred solution of ethyl 2-(4-amino-3-methoxyphenyl)propanoate (447 mg, 2.002 mmol) in acetonitrile and water were added p-toluenesulfonic acid monohydrate (1.142 g, 6.006 mmol), sodium nitrite (276 mg, 4.004 mmol) and potassium iodide (831 mg, 5.005 mmol). The reaction mixture was stirred for 4 h at room temperature. The mixture dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. Ethyl 2-(4-iodo-3-methoxyphenyl)propanoate (468 mg) was obtained as 70% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](=O)[NH:19][CH2:20][C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)=O.[OH-].[NH4+:35]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH:17]([C:18]2[NH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:35]=2)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2CC1C(=O)NCC(=O)c1ccccc1
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1Cc2ccccc2CC1c1nc(-c2ccccc2)c[nH]1
Temperature: 25 °C

Procedure:
The product prepared in Step A above (3.55 g, 9 mmol), NH4OAc (ammonium acetate) (20.8 g, 270 mmol) and AcOH (acetic acid) (30 mL) were combined at room temperature and the reaction mixture was warmed on a steam bath for about 3 hours. The reaction mixture was then cooled to room temperature and poured into an ice slurry mix (400 g). To this mixture was added concentrated ammonium hydroxide (50 mL) and ethyl ether. The layers were separated, and the aqueous phase washed with a second portion of ethyl ether. The organic phases were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to yield a brown foam. This sample was purified by preparative HPLC to yield the purified title compound as a white powder. LC indicated the sample was 96% pure at 214 nm.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:6][C:5]([CH3:14])=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[O:26][CH3:27])[N:3]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[CH3:41][NH2:42].CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.CCCCCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:10]([CH:9]([O:8][C:7]1[C:2]([NH:42][CH3:41])=[N:3][C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[O:26][CH3:27])=[C:5]([CH3:14])[CH:6]=1)[CH2:12][CH3:13])[CH3:11]
Reactant: CN
Reactant: CCC(CC)Oc1cc(C)c(-c2ccc(OC(F)(F)F)cc2OC)nc1Cl
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCC(CC)Oc1cc(C)c(-c2ccc(OC(F)(F)F)cc2OC)nc1NC
Temperature: 55 °C

Procedure:
Pd2dba3 (4 mg) is added to a solution of compound 45 (70 mg, 0.173 mmol) in toluene (1 ml), followed by the addition of P(t-Bu)3 (1.4 mg), methylamine (2M in THF, 0.17 ml, 0.347 mmol) and t-BuOK (1M in THF, 0.26 ml, 0.26 mmol). The resulting mixture is sealed and heated to 55° C. overnight, then cooled to room temperature. The reaction mixture is diluted with 30% EtOAc in hexane, washed with water, brine, dried, filtered and evaporated. The crude product is purified by chromatograph (eluted with 6% EtOAc in hexane) to give the product 48 as a light yellow solid. 1H NMR (CDCl3) δ 0.97 (t, J=7.6 Hz, 6H), 1.71 (m, 4H), 1.98 (s, 3H), 2.99 (s, 3H), 3.79 (s, 3H), 4.13 (m, 1H), 4.77 (brs, 1H), 6.67 (s, 1H), 6.77 (s, 1H), 6.87 (dd, 1H), 7.32 (d, J=8.4 Hz, 1H). LCMS 399.4 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([CH2:10]O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.S(Cl)([Cl:14])=O>ClCCl>[Cl:14][CH2:10][C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[CH:2][S:1][C:5]=2[CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc2ncsc2c1
Solvent: ClCCl
Product: ClCc1ccc2ncsc2c1

Procedure:
To a dichloromethane solution (1.2 mL) of benzo[d]thiazol-6-yl-methanol (60 mg, 0.36 mmol), thionyl chloride (53 μL) was added at room temperature and the resultant solution was stirred for 1 day. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product of the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:11]=[CH:12][CH:13]=2)[N:5]=[CH:6][C:7]=1[C:8]([NH2:10])=[O:9].Cl.[F:15][C:16]1([C@H:19]([NH2:21])[CH3:20])[CH2:18][CH2:17]1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.CO>[F:15][C:16]1([C@H:19]([NH:21][C:2]2[C:3]3[N:4]([CH:11]=[CH:12][CH:13]=3)[N:5]=[CH:6][C:7]=2[C:8]([NH2:10])=[O:9])[CH3:20])[CH2:18][CH2:17]1
Reactant: NC(=O)c1cnn2cccc2c1Cl
Reactant: C[C@@H](N)C1(F)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN1CCCC1=O
Product: C[C@@H](Nc1c(C(N)=O)cnn2cccc12)C1(F)CC1
Temperature: 25 °C
Yield: 15 %

Procedure:
A solution of 4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 3, 20 mg, 0.102 mmol), (R)-1-(1-fluorocyclopropyl)ethanamine hydrochloride (22 mg, 0.153 mmol), and diisopropylethylamine (0.054 mL, 0.31 mmol) in NMP (0.5 mL) was heated to 120° C. for 10 min in the CEM microwave. The mixture was cooled to rt, diluted with MeOH and purified by reverse-phase Prep HPLC (condition A). The fraction containing the major product was concentrated on the rotovap to remove the MeOH and the aqueous slurry of the product was neutralized by addition of ˜1 mL of saturated aqueous sodium bicarbonate. Sonication of the slurry followed by vacuum filtration and air drying in the funnel afforded 4 mg (14%) of a pale yellow solid as the title compound. HPLC (condition B): retention time=3.26 min. LCMS (condition B): MH+ m/z 263.2. 1H NMR (500 MHz, MeOD) δ ppm 8.17 (1 H, s), 7.64 (1 H, dd, J=2.64, 1.53 Hz), 7.27 (1 H, dd, J=4.44, 1.39 Hz), 6.74 (1 H, dd, J=4.44, 2.77 Hz), 5.07 (1 H, br. s.), 1.37-1.56 (3 H, m), 1.01-1.37 (4 H, m).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:23]([OH:25])=[O:24])[CH:9]=[C:10]([S:19]([NH2:22])(=[O:21])=[O:20])[C:11]=1[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.S(Cl)(Cl)=O.[CH3:30]O>>[NH2:22][S:19]([C:10]1[CH:9]=[C:8]([CH:7]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][CH3:1])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:23]([O:25][CH3:30])=[O:24])(=[O:21])=[O:20]
Reactant: CO
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCCCNc1cc(C(=O)OC)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 0.08 h
Yield: 89 %

Procedure:
To a slurry of bumetanide (1.2 g, 3.29 mmol) in methanol (12 mL) under nitrogen, was added a mixture of thionyl chloride (70 uL) in methanol (6 mL) over 5 minutes. After stirring for 5 minutes the reaction mixture became soluble. The reaction was stirred for an additional 30 minutes, at which time the reaction was complete as determined by thin layer chromatography (TLC). The methanol was removed under reduced pressure and the residue was brought up in ethyl acetate and washed with saturated sodium bicarbonate, water and brine. The ethyl acetate was dried over anhydrous magnesium sulfate and concentrated to yield 1.1 g (89%) of methyl 3-aminosulfonyl-5-butylamino-4-phenoxybenzoate as a white solid.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:12]=[C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[N:24]=3)[N:10]=2)[CH:6]=[CH:5][CH:4]=1)#[N:2].C(Cl)Cl.CO.[NH4+].[OH-]>C(O)(=O)C>[NH2:30][CH2:29][C:25]1[N:24]=[C:23]([C:11]2[CH:12]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH:14]=[C:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([CH2:1][NH2:2])[N:8]=3)[N:10]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(-c2cc(-c3cccc(C#N)n3)nc(-c3cccc(C#N)n3)c2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2cc(-c3cccc(CN)n3)nc(-c3cccc(CN)n3)c2)cc1
Temperature: 50 °C
Reaction time: 19 h

Procedure:
6,6"-Dicyano-4'-(4-methoxyphenyl)-2,2':6',2"-terpyridine (1.556 g, 4.0 mmole) prepared in example 14 was dissolved in Ultrex acetic acid (130 mL, Baker) in a Parr hydrogenation bottle by warming to 50° C. for 25 minutes. The solution was sparged with argon for 5 minutes, 10% Pd/C (470 mg) was added under argon, and the reaction mixture was hydrogenated at 45 psi and 45° C. for 19 hours in a Parr hydrogenation apparatus. After venting excess hydrogen and replacing it with argon, the catalyst was removed by filtration using 5 mL of acetic acid as a wash. Most of the solvent was then evaporated under reduced pressure at 35° C. Residual acetic acid was removed by a series of consecutive additions and co-evaporations using 2×30 mL aliquots of toluene, then 2×30 mL aliquots of methylene chloride, and finally 2×30 mL aliquots of ethanol. The product was then dried under vacuum at 30° C. overnight to give 2.3 g (99.5 % recovery) of product as an off-white solid. Thin layer chromatography (silica gel; 85% methylene chloride, 5% methanol, 10% NH4OH, v/v/v) showed the desired product as a spot with an Rf of 0.3 (with some streaking) plus a trace amount of a small spot at the origin. Infrared and mass spectra were in good agreement for the desired product. 1H NMR (DMSO-D6) 3.85 (s, 3H, OCH3), 4.07 (s, 4H, CH2 --N), 7.16 (d, 2H), 7.55 (d, 2H), 7.99 (d, 2H), 8.03 (t, 2H), 8.52 (d, 2H) and 8.78 ppm (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.[O:7]=[C:8]([CH3:19])[CH2:9][CH2:10][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>O1CCCC1>[OH:7][C:8]([CH3:19])([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][N:5]=1)[CH2:9][CH2:10][P:11](=[O:18])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17]
Reactant: CCOP(=O)(CCC(C)=O)OCC
Reactant: Cn1cncn1
Solvent: C1CCOC1
Product: CCOP(=O)(CCC(C)(O)c1ncnn1C)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.4 %

Procedure:
To a solution of 1-methyl-1,2,4-triazole (3.0 g, 36.1 mmol) in tetrahydrofurane (60 ml) was added n-buthyllithium (43.3 mmol, 1.2 eq) at -78° C. under nitrogen. The mixture was stirred for 1 hour, then diethyl 3-oxo-butylphosphonate (8.3 g, 39.7 mmol, 1.1 eq) was added. The mixture was stirred for 2 hours and quenched with aq. NH4Cl (ca. 15 ml). The mixture was warmed to room temperature and extracted with CH2Cl2 (5×100 ml). The extract was dried over MgSO4, concentrated in vacuo, and purified by a silica gel column chromatography (200 g, AcOEt-EtOH) to give (2.99 g, 28% yield) of diethyl 3-hydroxy-3-methyl-3-(1-methyl-1,2,4-triazol-5-yl)propyl-phosphonate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24]CC4C=CC=CC=4)[CH:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cccc(OCc4ccccc4)c3)cc(C)c21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cccc(O)c3)cc(C)c21
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
A mixture of [6-(3-benzyloxy-phenoxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (1.22 g, 2.82 mmol) and 10% Pd/C (1.0 g) in EtOH (20 mL) was hydrogenated at 40 psi for 30 minutes. The mixture was filtered through a pad of celite and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (hexane:EtOAc 50:50) to give [1-hydroxy-6-(3-hydroxy-phenoxy)-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.65 g, 68%). 1H NMR (400 MHz, DMSO): δ 7.13 (t, J=8.4 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 6.95 (d, J=1.6 Hz, 1H), 6.50 (dd, J=1.6, 8.0 Hz, 1H), 6.38 (dd, J=1.6, 8.0 Hz, 1H), 6.32 (t, J=2.4 Hz, 1H), 5.48 (dd, J=2.4 Hz, 1H), 4.02 (q, J=7.2 Hz, 2H), 3.09 (dd, J=2.4 Hz, 1H), 2.29-2.23 (m, 1H), 2.26 (s, 3H), 1.12 (t, J=4.4 Hz, 3H). MS (ESI) m/z=341 [M−H]−.
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.FC(F)(F)COP([CH2:31][C:32]([O:34][CH3:35])=[O:33])(OCC(F)(F)F)=O.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH:48](=O)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>O1CCCC1.C1(C)C=CC=CC=1>[C:49]1(/[CH:48]=[CH:31]\[C:32]([O:34][CH3:35])=[O:33])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)/C=C\c1ccccc1
Temperature: -78 °C

Procedure:
9.4 g of 18-crown-6 and 1.7 ml of methyl [bis(2,2,2-trifluoroethoxy)-phosphoryl]acetate are dissolved under argon in 120 ml of dry tetrahydro-furan and cooled to −78° C. 14.3 ml of a 0.5 molar solution of potassium bis(trimethylsilyl)amide in toluene are added to this mixture, followed by 0.85 ml of benzaldehyde. After stirring at −78° C. for thirty minutes, the reaction mixture is quenched by adding saturated ammonium chloride solution and extracted with five portions each of 50 ml of ethyl acetate. The combined organic phases are dried over MgSO4 and then the solvent is removed in vacuo. The residue is purified on silica gel with n-heptane:ethyl acetate=20:1 as eluent. 1.1 g of methyl (Z)-3-phenylacrylate are obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](=[O:10])[CH3:9])[CH:3]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH:8]([OH:10])[CH3:9])[CH:3]=1
Reactant: CC(=O)c1cc(Cl)ncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
1-(6-Chloro-4-pyrimidinyl)ethanone (Intermediate 18A, 1.0 g, 6.39 mmol) was dissolved in ethanol (21 mL), treated with sodium borohydride (0.242 g, 6.39 mmol) and the resulting mixture was stirred at room temperature under argon for 2 hours. The solvent was removed under reduced pressure and the residue was diluted with water and extracted with ethyl acetate (×3). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure to give the title compound as a yellow oil (808 mg);
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:20])[C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:21].Br[C:23]1[CH:24]=[C:25]([CH:29]=[O:30])[CH:26]=[N:27][CH:28]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:30][CH2:29][C:25]1[CH:24]=[C:23]([C:7]2[C:6]([CH3:20])=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[C:3](=[O:21])[CH2:4]3)[CH:28]=[N:27][CH:26]=1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc2c1CC(=O)N2C
Reactant: O=Cc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1c(-c2cncc(CO)c2)ccc2c1CC(=O)N2C
Temperature: 120 °C

Procedure:
To 1,4-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (85 mg, 0.30 mmol) was added (5-bromo-pyridin-3-yl)-methanal (CAS#37669-64-0, 61 mg, 0.33 mmol), 1,2-dimethoxyethane (3.0 mL), and 2 M aqueous sodium carbonate (0.370 mL, 0.74 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (135 mg, 0.015 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 3 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was partially purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 7.5%). Further purification was accomplished via reverse phase HPLC (10 to 40% acetonitrile/Water w/0.1% NH4OH) to furnish 5-(5-hydroxymethyl-pyridin-3-yl)-1,4-dimethyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 269.1288 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.14 (s, 3H), 3.15 (s, 3H), 3.56 (s, 2H), 4.60 (s, 2H), 5.35 (br. s., 1H), 6.93 (d, J=7.8 Hz, 1H), 7.18 (d, J=8.1 Hz, 1H), 7.65 (t, J=2.1 Hz, 1H), 8.40 (d, J=2.3 Hz, 1H), 8.50 (d, J=2.0 Hz, 1H).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:5]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:6]=2[S:7][C:8]=1[CH:9]=[O:10].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>CN(C)C=O>[CH3:16][O:15][C:13]1[C:12]([O:17][CH3:18])=[CH:11][C:6]2[S:7][C:8]([CH:9]=[O:10])=[C:4]([O:27][C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[C:5]=2[CH:14]=1
Reactant: COc1cc2sc(C=O)c(Cl)c2cc1OC
Reactant: COc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2c(C=O)sc3cc(OC)c(OC)cc23)cc1

Procedure:
1.1 equivalents of sodium hydride and then 0.033 mol of the product obtained in Step D are added at room temperature and under an inert atmosphere to a solution of 0.036 mol of 4-methoxyphenol in 250 ml of dimethylformamide. After 12 hours' reaction, the reaction mixture is concentrated under reduced pressure. The residue is then diluted in ethyl acetate, washed with water and then with an aqueous NaCl solution, dried over calcium sulphate, filtered and concentrated under reduced pressure. Chromatography over silica gel (dichloromethane/ethyl acetate: 98/2) enables 8.6 g of the expected product to be isolated.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)([OH:3])=[O:2]>[Pd].CO>[CH3:13][O:12][C:10]([CH2:9][CH2:8][C:7]1[CH:14]=[CH:15][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1)=[O:11]
Reactant: COC(=O)C=Cc1ccc(C(=O)O)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A mixture of methyl 4-carboxycinnamate (1.5 g) and 10% palladium on carbon (300 mg) in methanol (5 ml) was stirred for 2 hours at ambient temperature under hydrogen atmosphere. Insoluble material was filtered off, and the filtrate was concentrated in vacuo to give 4-[2-(methoxycarbonyl)ethyl]benzoic acid (1.3 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCc1ccc2c(c1)OCO2
Yield: 82.6 %

Procedure:
3-benzo-1,3-dioxol-5-ylacrylic acid (2 g) was hydrogenated in ethanol (50 ml) over 5% Pd-C under a pressure of hydrogen at 10 psi for 40 mins to give 3-benzo-1,3-dioxol-5-ylpropionic acid (1.67 g, 80% yield) as a solid, m.p. 86.1°-88.3° C. (Lit m.p. 87-88° C.)10.