Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:10][CH:11]=[C:12]([CH2:14][CH2:15][O:16]S(C)(=O)=O)[CH:13]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:10][CH:11]=[C:12]([CH2:14][CH2:15][OH:16])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCc1ccc(OCc2ccccc2)c(-c2ccc(F)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OCCc1ccc(OCc2ccccc2)c(-c2ccc(F)cc2)c1
Yield: 69.6 %

Procedure:
5-(4-fluorophenyl)-4-benzyloxy-2-mesyloxyethylbenzene (2.5 g, 6.24 mmol) was dissolved in methanol (80 mL). To this was added sodium hydroxide (300 mg, 7.5 mmol) dissolved in water (20 mL). The solution was heated to reflux and heating maintained for 24 hours, when an additional equivalent of sodium hydroxide was added, and reflux maintained for an additional 16 hours. The mixture was cooled, acidified with 1N HCl, and extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford an orange solid which was triturated with hexane to yield 5-(4-fluorophenyl)-4-benzyloxy-2-hydroxyethylbenzene (1.4 g) as an off-white powder. NMR (DMSO-d6): 1.11, t, (3H); 2.50, q (2H); 3.34, s (3H); 5.02, s (2H); 6.60, d (1H); 6.98, s (1H); 7.16, t (2H); 7.35, m (5H); 7.50, dd (2H); 9.44, s (1H). Mass Spec (GCMS): 322 (M).
Reaction SMILES: Br[C:2]1[C:7]([O:8][C@H:9]([CH2:11][CH:12]=[CH2:13])[CH3:10])=[CH:6][C:5]([F:14])=[CH:4][C:3]=1[F:15].FC1C(F)=CC([B:24]2[O:31][C:30](=[O:32])[CH2:29][N:28]([CH3:33])[CH2:27][C:26](=[O:34])[O:25]2)=C(O[C@H](CC=C)C)C=1>>[F:15][C:3]1[CH:4]=[C:5]([F:14])[CH:6]=[C:7]([O:8][C@H:9]([CH2:11][CH:12]=[CH2:13])[CH3:10])[C:2]=1[B:24]1[O:31][C:30](=[O:32])[CH2:29][N:28]([CH3:33])[CH2:27][C:26](=[O:34])[O:25]1
Reactant: C=CC[C@H](C)Oc1cc(F)c(F)cc1B1OC(=O)CN(C)CC(=O)O1
Reactant: C=CC[C@H](C)Oc1cc(F)cc(F)c1Br
Product: C=CC[C@H](C)Oc1cc(F)cc(F)c1B1OC(=O)CN(C)CC(=O)O1
Yield: 58 %

Procedure:
Prepared from (S)-2-bromo-1,5-difluoro-3-(pent-4-en-2-yloxy)benzene in 58% yield following the same procedure as (S)-2-(4,5-difluoro-2-(pent-4-en-2-yloxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione. 1H NMR (400 MHz, DMSO-d6) 6.84 (d, J=11.5 Hz, 1H), 6.67-6.59 (m, 1H), 5.89-5.78 (m, 1H), 5.16-5.02 (m, 2H), 4.71-4.60 (m, 1H), 4.35 (dd, J=17.2, 5.6 Hz, 2H), 4.05-3.92 (m, 2H), 2.65 (s, 3H), 2.46-2.36 (m, 1H), 2.25 (dt, J=14.3, 6.9 Hz, 1H), 1.17 (d, J=6.0 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2([C:22]#[N:23])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[H][H]>C(O)C.[Pd]>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([C:9]2([C:22]#[N:23])[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(C#N)c2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(CN)c2)CC1
Reaction time: 3 h
Yield: 63.4 %

Procedure:
To a mixture of 0.31 g (1 mmole) of 4-(3-cyanophenyl)-1-tert-butoxycarbonyl-piperidine-4-carbonitrile in 30 ml of absolute ethanol was added 0.08 ml (1 mmole) of conc. hydrochloric acid followed by 30 mg of 5% Pd/C. The mixture was agitated in a Parr shaker for 3 hours at 30 lbs. of pressure of hydrogen. The mixture was filtered through celite and the filtrate was evaporated. The residue was treated with ether and was stirred for 30 minutes and was filtered. The filter cake was treated with aqueous sodium carbonate and was extracted with dichloromethane to give 0.2 g of product: 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.38-1.60(m, 9H), 1.88-2.18(m, 4H), 3.05-3.30(m, 4H), 3.79-4.0(m, 2H), 7.22-7.85(m, 4H); MS (ESI) m/e 316 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH:15]([OH:26])[C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)=[CH:7][CH:6]=1.[OH-].[Na+].O>CO>[OH:26][CH:15]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)[CH2:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:27])[C:3]([OH:28])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1ccc(OCCCC(O)c2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCCC(O)c2ccc3ccccc3c2)cc1
Yield: 36.2 %

Procedure:
As in Example 19, a stirred solution of rac-4-[4-hydroxy-4-(2-naphthalenyl)butoxy]-alpha-oxobenzeneacetic acid methyl ester (0.172 g) in warm methanol (2.5 mL) was treated with 1N sodium hydroxide (1 mL) and then water (25 mL) was added. After the methanol was removed in vacuo, the mixture was acidified with 1N hydrochloric acid (1.2 mL) and extracted with dichloromethane (1×50 mL, 1×10 mL). The dried (MgSO4) extracts were concentrated and the residual gummy solid (~0.17 g) was crystallized from acetone-hexane to give 0.06 g of rac-4-[4-hydroxy-4-(2-naphthalenyl) butoxy]-alpha-oxobenzeneacetic acid as a colorless solid, mp 108°-110° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][N:7]1[CH:15]=[N:14][C:13]2[C:8]1=[N:9][CH:10]=[N:11][C:12]=2[NH2:16])=[N+]=[N-].[H][H]>[Pd].CO>[NH2:1][CH2:4][CH2:5][CH2:6][N:7]1[CH:15]=[N:14][C:13]2[C:8]1=[N:9][CH:10]=[N:11][C:12]=2[NH2:16]
Reactant: [H][H]
Reactant: [N-]=[N+]=NCCCn1cnc2c(N)ncnc21
Agent: [Pd]
Solvent: CO
Product: NCCCn1cnc2c(N)ncnc21
Yield: 76 %

Procedure:
A mixture of 9-(3-azidopropyl)adenine (0.5 g, 2.3 mM) and 5% palladium on carbon (0.5 g) in methanol was reacted with hydrogen gas at room temperature for 22 hours. The catalyst was removed by filtration, the solvent removed to give 9-(3-aminopropyl)adenine as a white solid in 76% yield. 1H NMR (DMSO-d6): δ=1.80 (m, 2H, CH2), 2.45 (m, 2H, CH2), 3.35 (S, 2H, NH2), 4.20 (m, 2H, CH2), 7.20 (s, 2H, NH2), 8.10 (s, 2H, CH). MS (ED+): 193.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[N:15]=[C:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH2:26][CH3:27])[CH:3]=1.[NH:28]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH:17]1([N:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:28]5[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[CH:3][C:4]=4[O:25][CH2:26][CH3:27])=[N:13][C:12]=3[C:14]([CH3:23])=[N:15]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CNCCNC1
Reactant: CCOc1cc(Br)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Product: CCOc1cc(N2CCCNCC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Yield: 62 %

Procedure:
The same reaction procedure as in Example 16 was performed, except that the compound obtained in Example 116 was used in place of the compound obtained in Example 15, and homopiperazine was used in place of N-methylpiperazine. In this manner, 97 mg (62%) of the captioned compound was obtained.
Reaction SMILES: C([O:5][C:6](=[O:16])[CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH3:14])[C:9]1=[O:15])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:14][N:10]1[CH2:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]([OH:16])=[O:5])[C:9]1=[O:15]
Reactant: CN1CCCN(CC(=O)OC(C)(C)C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCCN(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 1012.6 %

Procedure:
To a solution of 0.090 g (0.39 mmol) of tert-butyl (3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)acetate from step B above in 4 mL of anhydrous dichloromethane was added 1 mL of TFA. The resulting mixture was stirred at ambient temperature for 6 h then evaporated to dryness in vacuo to afford the title compound as an off-white gum (0.68 g, 99%). LC-MS: m/z (ES) 173 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH2:17]O)[CH:14]=[CH:15][CH:16]=3)[N:6]2[N:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:55]>O1CCCC1>[CH2:28]([N:24]1[CH:23]=[C:22]2[C:26]([CH:27]=[C:19]([C:8]3[CH:9]=[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][Br:55])[CH:12]=4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:20]=[CH:21]2)=[N:25]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrC(Br)(Br)Br
Reactant: Nc1ncnn2c(-c3cccc(CO)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncnn2c(-c3cccc(CBr)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 90.1 %

Procedure:
To a solution of {3-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]phenyl}methanol (575 mg, 1.29 mmol) and triphenylphosphine (507 mg, 1.93 mmol) in tetrahydrofuran (10 mL) was added carbon tetrabromide (512 mg, 1.55 mmol). The reaction was stirred at rt for 17 h. The mixture was partitioned between water (50 mL) and CH2Cl2 (50 mL). The layers were separated and the organic phase was washed with brine, dried (Na2SO4), and evaporated. The crude material was purified via ISCO® chromatography using a gradient of 50 to 75% ethyl acetate in hexanes to afford 592 mg (90%) of the desired product, which contained a minor impurity. ES-MS m/z 509.41 [M+H]+, HPLC RT (min) 3.31 min.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>COCCOC.O.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>[NH2:8][C:3]1[C:2]([C:13]2[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: Nc1ncccc1Br
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: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: Nc1ncccc1-c1ccc(O)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.967 g) was added to a suspension of 3-bromopyridin-2-amine (4.82 g), 4-hydroxyphenylboronic acid (5.00 g) and sodium carbonate (5.91 g) in DME (250 mL) and water (50.0 mL) and the mixture was stirred at 80° C. under nitrogen for 4 hr. Water and EtOAc were added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) and washed with IPE to give the title compound (2.80 g) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([F:11])=[C:6]([CH2:12][NH:13][C:14]([C@@H:16]2[CH2:20][C@@H:19]([F:21])[CH2:18][N:17]2[C:22](=[O:36])[CH2:23][N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([C:33](=[O:35])[CH3:34])=[CH:25]2)=[O:15])[CH:5]=1.O[Li].O>C1COCC1.CO.O>[C:33]([C:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:24]([CH2:23][C:22]([N:17]2[CH2:18][C@H:19]([F:21])[CH2:20][C@H:16]2[C:14]([NH:13][CH2:12][C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([Cl:10])[C:7]=2[F:11])[C:3]([OH:37])=[O:2])=[O:15])=[O:36])[CH:25]=1)(=[O:35])[CH3:34]
Reactant: COC(=O)c1cc(Cl)c(F)c(CNC(=O)[C@@H]2C[C@@H](F)CN2C(=O)Cn2cc(C(C)=O)c3ccccc32)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cc(C(=O)O)cc(Cl)c2F)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 3-[({(2S,4R)-1-[2-(3-acetyl-indol-1-yl)-acetyl]-4-fluoro-pyrrolidine-2-carbonyl}-amino)-methyl]-5-chloro-4-fluoro-benzoic acid methyl ester Example 523 (35.0 mg, 0.066 mmol) in THF-MeOH—H2O (ratio 2:1:1; 1 mL) was added LiOH.H2O (2.76 mg, 0.066 mmol). The reaction mixture was stirred at RT for 4 h. Volatiles were evaporated and the residue was taken up in water, Acidification to pH=1 by addition of a 6M HCl solution formed a precipitate which was filtered and dried at 50° C. in vacuo for 1 h to afford the title compound as a solid. MS: 518.0 [M+H]+; tR (HPLC conditions c): 4.26 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][C:8]=1[N+:17]([O-])=O)[CH3:2].CCO>[Fe].CC(O)=O>[CH2:1]([O:3][C:4]([C:5]1[NH:17][C:8]2[C:7]([CH:6]=1)=[CH:12][CH:11]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=2)=[O:21])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2ccc(C(C)(C)C)cc2[nH]1

Procedure:
A mixture of 3-(4-tert-butyl-2-nitro-phenyl)-2-oxo-propionic acid ethyl ester (prepared in Example XX; 9.1 g, 31 mmol), iron powder (15.3 g, 274 mmol). EtOH (70 mL), and glacial AcOH (70 mL) was refluxed for 2 hours. After cooling, the resulting mixture was evaporated. THF (100 mL) was added to the residue, and the suspension was filtered on florisil, eluting with a large amount of THF. The solvents were evaporated, and the residue was purified by flash silica gel chromatography (5%-30% EtOAc in hexanes as eluents). MS(APCI): 246 (M+H).
Reaction SMILES: C(OC([NH:11][CH2:12][CH:13]([NH:15][S:16]([C:19]1[C:20]2[CH:21]=[CH:22][N:23]=[CH:24][C:25]=2[CH:26]=[CH:27][CH:28]=1)(=[O:18])=[O:17])[CH3:14])=O)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[NH2:11][CH2:12][CH:13]([NH:15][S:16]([C:19]1[C:20]2[CH:21]=[CH:22][N:23]=[CH:24][C:25]=2[CH:26]=[CH:27][CH:28]=1)(=[O:18])=[O:17])[CH3:14]
Reactant: CC(CNC(=O)OCc1ccccc1)NS(=O)(=O)c1cccc2cnccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(CN)NS(=O)(=O)c1cccc2cnccc12
Yield: 97.9 %

Procedure:
In 50 ml of ethanol was dissolved 2.0 g of N-(2-benzyloxycarbonylamino-1-methylethyl)-5-isoquinolinesulfonamide obtained above, and to the solution was added 0.1 g of 5% palladium-carbon. Then the solution was stirred at a temperature of 15° C.~25° C. in a hydrogen (0.7 to 1.40 kg/cm2) for 3 hours. The palladium-carbon was separated from the reaction solution by filtration under the reduced pressure. After the methanol was distilled therefrom, the reaction solution was concentrated to dryness to give 1.30 g of N-(2-amino-1-methylethyl)-5-isoquinolinesulfonamide in a yield of 98%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:27]=[CH:26][C:7]([CH2:8][CH:9]2[S:13][C:12](=[O:14])[N:11]([CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)[C:10]2=[O:25])=[CH:6][CH:5]=1)[CH3:2]>C(O)(C(F)(F)F)=O.ClCCl>[NH2:17][CH2:16][CH2:15][N:11]1[C:10](=[O:25])[CH:9]([CH2:8][C:7]2[CH:26]=[CH:27][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[S:13][C:12]1=[O:14]
Reactant: CCOc1ccc(CC2SC(=O)N(CCNC(=O)OC(C)(C)C)C2=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(CC2SC(=O)N(CCN)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 5 (80 mg, 0.20 mmol) was dissolved in 50% TFA in dichloromethane (2 mL) and then stirred at room temperature for 1 h. The solvent was removed by evaporation and the residue was dissolved in dioxane (2 mL), and evaporated again. The solid was collected by filtration, washed with ethyl ether, and dried to afford compound 6 in 58.5% (48 mg) yield as a white solid.
Reaction SMILES: P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CCCC)CCCC)CCC.Br[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1.[C]=O.[H][H].C[CH2:47][O:48]CC>>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([CH:47]=[O:48])=[CH:35][CH:36]=1
Reactant: CCOCC
Reactant: COc1ccc(Br)cc1
Reactant: [H][H]
Agent: [C]=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN(CCCC)CCCC
Product: COc1ccc(C=O)cc1
Temperature: 150 °C

Procedure:
A mixture of 0.25 mmole PdBr2 [P(C6H5)3 ]2, 19 mmoles tri-n-butylamine and 17.2 mmoles p-bromoanisole was placed in a 45 ml pressure vessel and pressured to 1450 psig with a 1:2 mixture of carbon monoxide and hydrogen. The reaction mixture was heated to 150°C for 10 hrs. with magnetic stirring during which time the gas pressure dropped to 1100 psig. After cooling and venting the reaction mixture was diluted with ether, washed with dilute aqueous hydrochloric acid, dried over anhydrous magnesium sulfate and distilled under reduced pressure. There was obtained 1.97 g of p-methoxybenzaldehyde, b.p. 73°-75°C at 0.7 mm which is 84% of the theoretical amount.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[Br:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.[CH:18](=O)[CH3:19]>C1(C)C=CC=CC=1>[N:1]1([CH:18]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([Br:10])=[CH:12][CH:13]=2)[CH3:19])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC=O
Reactant: Nc1ccc(Br)cc1
Solvent: Cc1ccccc1
Product: CC(Nc1ccc(Br)cc1)n1nnc2ccccc21
Reaction time: 12 h
Yield: 82.6 %

Procedure:
To a suspension of benzotriazole (139 g, 1.16 mol) in toluene (2 L) in a 3 L, four neck flask under nitrogen atmosphere was added at room temperature a solution of 4-bromoaniline (200 g, 1.16 mol) in toluene (300 mL). Then, via a dropping funnel was added drop wise acetaldehyde (64.7 ml, 1.17 mol) in solution in toluene (200 mL). The reaction mixture becomes progressively homogenous and then gives a precipitate. The resulting mixture is stirred 12 hours under nitrogen atmosphere and then filtered. The precipitate is recrystallised in toluene to afford the title compound as a white solid (304 g, 82%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.1 (m, 3H) 4.9 (m, 0.66H) 5.15 (m, 0.33H) 6.5-6.9 (m, 3H) 7.2-8.2 (m, 7H)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN.C1C=CC2N(O)N=[N:28][C:26]=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.C(Cl)Cl>[CH3:26][NH:28][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (1.00 g, 3.98 mmol) in DMF (5 mL) and methylene chloride (5 mL) was added methylamine hydrochloride (403 mg, 5.97 mmol), HOBt (645 mg, 4.78 mmol), and Hunig's Base (1.73 mL, 9.95 mmol) and the resulting solution stirred at 0° C. for 10 minutes. EDCI (916 mg, 4.78 mmol) was added and the reaction stirred at 25° C. for 18 hours. The mixture was concentrated in vacuo, the resulting residue was diluted with ethyl acetate (45 mL), brine (10 mL), and 5% H3PO4 aqueous solution (10 mL), and the layers were separated. The organic layer was washed with 5% H3PO4 aqueous solution (10 mL), twice with saturated aqueous sodium bicarbonate solution (15 mL), water (15 mL), and brine (15 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a light colored solid. The crude material was taken on directly to the next step. (1.04 g, 99% yield) MS (ESI+) m/z=265 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[C:10]=2[F:18])[CH:7]=1.[Li][CH2:21]CCC.CCCCCC.C[Si](C)(C)[O:33][C@@H:34]1[C@@H:39]([O:40][Si](C)(C)C)[C@H:38]([O:45][Si](C)(C)C)[C@@H:37]([CH2:50][O:51][Si](C)(C)C)[O:36][C:35]1=[O:56]>C1(C)C=CC=CC=1.C1COCC1>[Cl:19][C:5]1[CH:4]=[CH:3][C:2]([C@@:35]2([O:56][CH3:21])[C@H:34]([OH:33])[C@@H:39]([OH:40])[C@H:38]([OH:45])[C@@H:37]([CH2:50][OH:51])[O:36]2)=[CH:7][C:6]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[C:10]=1[F:18]
Reactant: [Li]CCCC
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Reactant: COc1ccc(Cc2cc(Br)ccc2Cl)c(F)c1F
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1-[(5-bromo-2-chloro-phenyl)methyl]-2,3-difluoro-4-methoxy-benzene 2e (3.55 g, 10.2 mmol) was dissolved in 30 mL mixed solution (THF and toluene, v:v=1:2) and cooled to −78° C., followed by dropwise addition of a solution of nBuLi in n-hexane (4.9 mL, 12.26 mmol). After stirring for 1 hour at −78° C., a solution of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl)tetrahydropyran-2-one 2f (5.24 g, 11.22 mmol, prepared according to the method in WO2010048358) in toluene (30 mL) was added. The reaction mixture was stirred for 3 hours at −78° C. Thereafter, the reaction mixture was concentrated under reduced pressure after 30 mL saturated sodium carbonate solution were added. The residue was dissolved in 30 mL saturated sodium chloride solution and extracted with ethyl acetate (50 mL×3) and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system A to obtain the title compound (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 2g (1.31 g, white solid), yield: 27.9%. MS m/z (ESI): 429.1 [M−31]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH3:17])([C:12]([O:14]CC)=[O:13])[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Li+:18].[OH-]>C1COCC1.O>[Li+:18].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH3:17])([C:12]([O-:14])=[O:13])[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C(C)(C)Nc1ccc(Cl)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(Nc1ccc(Cl)c(Cl)c1)C(=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 50-mL round bottom flask equipped with a magnetic stirring bar was charged with ethyl N-(3,4-dichlorophenyl)-2-methylalaninate (790 mg, 2.9 mmol) and dissolved in 3 mL of THF. A solution of LiOH (132 mg, 5.8 mmol) dissolved in 1.0 mL of H2O was added and the mixture was stirred at room temperature for 24 h. The solvent was removed under reduced pressure. A total of 846 mg (90%) of N-(3,4-dichlorophenyl)-2-methylalanine as a yellow solid was recovered as the lithium salt, after drying under vacuum for 24 h. MS (ES) m/z 248 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[CH2:26](O)[CH2:27][CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[O:9]=[C:6]1[C:5]2[CH:10]=[CH:11][C:2]([O:1][CH2:26][CH2:27][CH3:28])=[C:3]([CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)[C:4]=2[O:8][CH2:7]1
Reactant: CCCO
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCOc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 110 °C
Reaction time: 5 h
Yield: 35 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.522 g, 1.50 mmol), n-propanol (0.135 mL, 1.80 mmol) and triphenylphosphine (0.590 g, 2.25 mmol) in toluene (6 mL) was added with a 40% solution of diethyl azodicarboxylate in toluene (0.980 g, 2.25 mmol), and the mixture was stirred at 110° C. for 5 hours in a sealed tube. The reaction mixture was concentrated, and the resulting residue was subjected to silica gel column chromatography (chloroform/ethyl acetate) to obtain tert-butyl 4-[(3-oxo-6-propoxy-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.205 g, 35%).