Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17](=[O:27])[CH:18]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[CH3:19]>CS(C)=O>[O:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH:21]1[O:20][CH:18]([C:17]1([C:11]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=2[F:9])[CH2:4][O:27]1)[CH3:19]
Reactant: C[S+](C)(C)=O
Reactant: CC(OC1CCCCO1)C(=O)c1ccc(F)cc1F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(OC1CCCCO1)C1(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.7 %

Procedure:
To dimethyl sulfoxide (650 ml) was added, at room temperature, 60% sodium hydride in oil (15.2 g) by portions during 10 minutes. The mixture was stirred for 10 minutes at room temperature, to which was added by portions trimethylsulfoxonium iodide (83.7 g) during one hour. To the resultant mixture was added dropwise during one hour a solution of 2',4'-difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (86.5 g) in dimethyl sulfoxide (150 ml). The mixture was stirred for 3 hours at room temperature, then the reaction mixture was poured into ice-water (1.5 l), which was subjected to extraction 5 times with ethyl acetate (300 ml). The ethyl acetate layer was washed with water (300 ml) for four times, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to leave 2-[1-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl]-2-(2,4-difluorophenyl)oxirane (83.4 g) as a pale yellow oily product.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH:27][CH2:28][CH:29]([CH2:31]O)[OH:30].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CCOCC>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:31][CH:29]([OH:30])[CH2:28][OH:27])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: OCC(O)CO
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1
Temperature: 120 °C

Procedure:
A mixture of 722 mg of 4-(n-hexadecylamino)benzoic acid, 736 mg of glycerol, and 412 mg of p-toluene sulfonic acid is heated for 4 hours at 120° C., allowed to cool, and then is treated with ether and 2% aqueous sodium carbonate solution. Filtration affords a white solid which is recrystallized from chloroform to yield 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate, mp 112° C.
Reaction SMILES: [CH2:1]1[S:5][C@@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]C2C([N+]([O-])=O)=CC=CC=2)=O)[C@H:3]2[NH:22][C:23]([NH:25][C@@H:2]12)=[O:24].[CH3:26][O:27][CH:28]([O:31][CH3:32])[CH2:29][NH2:30].CCN(CC)CC>CC#N>[CH3:26][O:27][CH:28]([O:31][CH3:32])[CH2:29][NH:30][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][C@H:4]1[C@@H:3]2[C@@H:2]([NH:25][C:23]([NH:22]2)=[O:24])[CH2:1][S:5]1
Reactant: O=C1N[C@H]2[C@H](CS[C@H]2CCCCC(=O)Oc2ccccc2[N+](=O)[O-])N1
Reactant: COC(CN)OC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(CNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
To a suspension of D-(+)-biotin 2-nitrophenyl ester (365 mg, 1.00 mmol) in MeCN (20 mL) was added aminoacetaldehyde dimethyl acetal (130 μL, 1.20 mmol) and Et3N (170 μL, 1.20 mmol). The suspension was gently heated until a solution was obtained; the solution was then stirred for 16 h at ˜25° C. The reaction mixture was evaporated to dryness under reduced pressure and the material left was purified by silica gel chromatography using a gradient of MeOH (0→10%) in CH2Cl2 as the eluent. Fractions containing the product were collected and evaporated to dryness under low pressure affording 9 (300 mg, 910 μmol) as a solid in a yield of 91%. 1H NMR (300 MHz, DMSO-d6): δ 7.87 (t, J=5.8 Hz, 1H), 6.43 (s, 1H), 6.37 (s, 1H), 4.32 (t, J=5.5 Hz, 1H), 4.28 (d, J=5.5 Hz, 1H), 4.12 (ddd, J=7.6, 4.4, 1.8 Hz, 1H), 3.25 (s, 6H), 3.13 (t, J=5.7 Hz, 2H), 2.82 (dd, J=12.3, 12.3 Hz, 1H), 2.56 (d, J=12.3 Hz, 1H), 2.07 (t, J=7.4 Hz, 2H), 1.66-1.22 (m, 7H). 13C NMR (75 MHz, DMSO-d6): δ 172.2, 162.6, 102.0, 61.0, 59.1, 55.4, 53.1, 40.2, 39.8, 34.9, 28.1, 28.0, 25.2. +ESI-HRMS: Calcd for C14H25N3O4S [M+H]+ 332.1639. found 332.1641.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[CH:11][C:10]=1[CH:24]([OH:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:34].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[CH:11][C:10]=1[CH:24]([O:30][CH3:34])[CH2:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: COc1ccc(F)c(-c2ccc(OCc3ccccc3)c(C(O)CC(C)(C)C)c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)c(-c2ccc(OCc3ccccc3)c(C(CC(C)(C)C)OC)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-(benzyloxy)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-3-yl)-3,3-dimethylbutan-1-ol (425 mg) prepared in Example 14, step C, in DMF (3.0 mL) was added 60% sodium hydride (100 mg), and the mixture was stirred at room temperature for 30 min. Iodomethane (443 mg) was added dropwise and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a crude product. This compound was used for the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:19][C:20]#[N:21])[CH2:16][CH:15]([C:17]#[N:18])[CH2:14]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[N+:22]([C:25]1[CH:38]=[CH:37][C:28]([O:29][CH2:30][CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:27][CH:26]=1)([O-])=O>>[C:20]([CH2:19][C:13]1([N:11]2[CH:12]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:22][C:25]4[CH:38]=[CH:37][C:28]([O:29][CH2:30][CH2:31][N:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)=[CH:27][CH:26]=4)[N:7]=3)[CH:9]=[N:10]2)[CH2:16][CH:15]([C:17]#[N:18])[CH2:14]1)#[N:21]
Reactant: O=[N+]([O-])c1ccc(OCCN2CCCC2)cc1
Reactant: N#CCC1(n2cc(-c3ccnc(Cl)n3)cn2)CC(C#N)C1
Product: N#CCC1(n2cc(-c3ccnc(Nc4ccc(OCCN5CCCC5)cc4)n3)cn2)CC(C#N)C1

Procedure:
The cis- and trans-isomers of the titled compound were prepared as a racemic mixture according to the procedure described in example 306, using 3-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)-cyclobutanecarbonitrile and 1-[2-(4-nitrophenoxy)ethyl]pyrrolidine as starting materials. First isomer retention time 1.055 min, LCMS (M+H) 469.4. Second peak retention time 1.072 min, LCMS (M+H) 469.4.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:15])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])=[C:5]([CH3:16])[O:4][N:3]=1.C(O[CH:20]=[C:21]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])C.C(O)C>C(Cl)Cl>[CH2:25]([O:24][C:22](=[O:23])[C:21](=[CH:20][NH:15][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:16])[CH:8]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:26]
Reactant: COc1ccc(N)cc1-c1c(C)noc1C
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(=CNc1ccc(OC)c(-c2c(C)noc2C)c1)C(=O)OCC
Temperature: 130 °C
Yield: 86 %

Procedure:
[3-(3,5-Dimethyl-4-isoxazolyl)-4-(methyloxy)phenyl]amine (for a preparation see Intermediate 2) (39 g, 179 mmol) was dissolved in diethyl [(ethyloxy)methylidene]propanedioate (38.6 g, 179 mmol) and heated to 130° C., giving a steady effervescence as ethanol boiled off. The solution was heated for 1 h, then cooled to room temperature and evaporated in vacuo to give a brown oil. The product was dissolved in DCM (100 ml) and loaded onto a 750 g silica column, then eluted with 0-100% EtOAc/cyclohexane to give diethyl({[3-(3,5-dimethyl-4-isoxazolyl)-4-(methyloxy)phenyl]amino}methylidene)propanedioate (59.5 g, 153 mmol, 86% yield) as pale yellow crystalline solid. LCMS (formate) Rt 1.15 min, MH+ 389.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:12])([CH3:11])[C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1[C:3]([CH3:12])([CH3:11])[C:4]2[C:5]([N:10]=1)=[N+:6]([CH2:14][CH2:13][CH2:19][S:16]([O-:18])(=[O:17])=[O:15])[CH:7]=[CH:8][CH:9]=2
Reactant: O=S1(=O)CCCO1
Reactant: CC1=Nc2ncccc2C1(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1=Nc2c(ccc[n+]2CCCS(=O)(=O)[O-])C1(C)C
Temperature: 60 °C
Yield: 138.7 %

Procedure:
A mixture of 9 g of 2,3,3-trimethyl-3H-pyrrolo[2,3-b]pyridine and 20.6 g of 1,3-propanesultone is heated at 60° C. for 3 h. The reaction mixture is then dissolved in 100 mL of acetonitrile, and 300 mL of ethyl acetate is added. The resulting sticky solid is again stirred in 300 mL of ethyl acetate to yield 22 g of the product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]([NH2:14])=[S:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][CH2:16][C:17]([CH2:19]Cl)=O>C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[S:13][CH:19]=[C:17]([CH2:16][Cl:15])[N:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCNC(N)=S
Reactant: O=C(CCl)CCl
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCNc1nc(CCl)cs1
Yield: 23.4 %

Procedure:
A solution of N-(2-t-butyloxycarbonylaminoethyl)thiourea (1.00 g, 4.54 mol) in ethanol (22 mL) was added 1,3-dichloroacetone (2.60 g, 20.47 mmol) at room temperature. After 2 hours the reaction mixture was concentrated under reduced pressure. The residue was triturated with ether and filtered to afford the solid precipitate of title product (1.40 g), which was used for next step without further purification. 1H NMR (CDCl3) δ 1.40 (s, 9H), 3.35 (m, 4H), 4.38 (s, 2H), 5.00 (br s, 1H), 6.40 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[O:18]1[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]1>>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][NH:10][C:24]([CH:21]1[CH2:22][CH2:23][O:18][CH2:19][CH2:20]1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)C1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)c1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](CNC(=O)C1CCOCC1)c1ccccc1
Yield: 99.8 %

Procedure:
Using general procedure E, ((R)-2-amino-1-phenyl-ethyl)-carbamic acid tert-butyl ester (616 mg, 2.61 mmol) and tetrahydro-pyran-4-carboxylic acid (339 mg, 2.61 mmol) afforded ((R)-1-phenyl-2-[(tetrahydro-pyran-4-carbonyl)-amino]ethyl)-carbamic acid tert-butyl ester (908 mg, 99%).
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[F:19][C:20]1[CH:21]=[C:22]2[CH:28]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[NH:26][C:23]2=[N:24][CH:25]=1.[N:34]1[CH:39]=[CH:38][C:37]([CH2:40]O)=[CH:36][CH:35]=1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[N:34]1[CH:39]=[CH:38][C:37]([CH2:40][N:26]2[C:23]3=[N:24][CH:25]=[C:20]([F:19])[CH:21]=[C:22]3[CH:28]=[C:27]2[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:36][CH:35]=1
Reactant: OCc1ccncc1
Reactant: CCOC(=O)c1cc2cc(F)cnc2[nH]1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(F)cnc2n1Cc1ccncc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
9.18 g (36.02 mmol) of 1,1′-(azodicarbonyl)dipiperidine are added, in a quarter of an hour, to a solution, stirred at 20° C., of 5 g (24.02 mmol) of ethyl 5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (Example 21.3), 3.97 g (36.02 mmol) of (pyridin-4-yl)methanol and 7.5 g (36.02 mmol) of tributylphosphine in 150 ml of toluene. The reaction mixture is stirred at 20° C. for 16 hours, filtered over a celite buffer, concentrated under reduced pressure and then taken up in 100 ml of dichloromethane. The organic solution is washed twice with 50 ml of a 5% aqueous solution of potassium carbonate and then once with 50 ml of water, dried over sodium sulphate and concentrated under reduced pressure. The product obtained is chromatographed on a silica column, elution being carried out with a mixture of heptane and ethyl acetate. 4.5 g of the expected ester are thus isolated.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@H:8]([NH:9][C:10](=[O:46])/[C:11](=[N:25]\[O:26][C:27]2([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH2:29][CH2:28]2)/[C:12]2[N:13]=[C:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[S:15][CH:16]=2)[C:7](=[O:47])[NH:6]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.CO>[NH2:1][CH2:4][C@@H:5]1[C@H:8]([NH:9][C:10](=[O:46])/[C:11](=[N:25]\[O:26][C:27]2([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH2:29][CH2:28]2)/[C:12]2[N:13]=[C:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[S:15][CH:16]=2)[C:7](=[O:47])[NH:6]1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2CN=[N+]=[N-])cs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2CN)cs1
Reaction time: 12 h
Yield: 55.9 %

Procedure:
To a solution of benzhydryl 1-(((Z)-(2-(((2R,3S)-2-(azidomethyl)-4-oxoazetidin-3-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (689 mg, 1.04 mmol) in THF (10 mL) and MeOH (1.3 mL) was added Ph3P (301 mg, 1.15 mmol). After 12 h, the reaction mixture was concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 0-100%) to afford the title compound (369 mg, 56%). LCMS: Rt=0.88 min, m/z=635.1 (M+1), Method 2m_acidic.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[S:9][C:10]=1[CH:11]([OH:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][N:13]=1.CO>ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[S:9][C:10]=1[C:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][N:13]=1)=[O:20]
Reactant: COc1ccc(C(O)c2sc(NC(=O)OC(C)(C)C)nc2-c2ccco2)nc1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(C(=O)c2sc(NC(=O)OC(C)(C)C)nc2-c2ccco2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Compound 296 (697 mg, 1.73 mmol) was dissolved in dichloromethane (10 mL), and DMP (848 mg, 2.00 mmol) was added thereto, followed by stirring at room temperature for 1 hour. Methanol (10 mL) was added to the reaction mixture, followed by stirring for 10 minutes, and the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1) to afford the entitled Compound 297 (632 mg, 91%).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:44])[C@H:7]([CH:41]([CH3:43])[CH3:42])[CH2:8][C@H:9]([OH:40])[C@@H:10]([N:37]=[N+]=[N-])[CH2:11][C@@H:12]([CH:34]([CH3:36])[CH3:35])[CH:13](OC(=O)C(C)C)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH2:22][CH2:23][O:24][CH2:25][O:26][CH3:27])[CH:15]=1)[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[CH2:1]([NH:5][C:6](=[O:44])[C@H:7]([CH:41]([CH3:43])[CH3:42])[CH2:8][C@H:9]([OH:40])[C@@H:10]([NH2:37])[CH2:11][C@@H:12]([CH:34]([CH3:35])[CH3:36])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH2:22][CH2:23][O:24][CH2:25][O:26][CH3:27])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](C[C@@H](C(C)C)C(OC(=O)C(C)C)c1ccc(OC)c(CCOCOC)c1)N=[N+]=[N-])C(C)C
Agent: [Pd]
Solvent: CO
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@@H](N)C[C@H](Cc1ccc(OC)c(CCOCOC)c1)C(C)C)C(C)C

Procedure:
50 mg of 5(S)-azido-4(S)-hydroxy-8(R,S)-isobutyroxy-2(S),7(S)-diisopropyl-8-[4-methoxy-3-(2-methoxymethoxyethyl)-phenyl]-octanoic acid (N-butyl)amide are hydrogenated in 10 ml of methanol in the presence of 50 mg of 10% Pd/C at room temperature and under normal pressure. The reaction mixture is filtered and concentrated by evaporation. The residue is purified by means of FC (2 g of silica gel, dichloromethane/methanol=9:1). The title compound is obtained: Rf (dichloromethane/methanol=9:1)=0.19; HPLC Rt =13.42 minutes; FAB-MS (M+H)+ =509.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([CH3:28])[O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([OH:27])[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16])(C(C)(C)C)(C)C.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37].C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:29][C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[O:27][C:25]1[CH:24]=[C:14]([CH:13]=[C:12]([O:11][C@@H:10]([CH3:28])[CH2:9][OH:8])[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: COc1ccc(B(O)O)cc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2cc(O[C@@H](C)CO)cc(C(=O)Nc3ccn(C)n3)c2)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 30.9 %

Procedure:
A solution of 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (0.30 g, 0.74 mmol), 3-fluoro-4-methoxyphenylboronic acid (255 mg, 1.5 mmol), copper (II) acetate (0.202 g, 1.11 mmol), triethylamine (0.517 mL, 3.71 mmol) and freshly activated 4 Å molecular sieves (1 g) in DCM (40 mL) was stirred at ambient temperature and under ambient atmosphere for 2 days. The reaction mixture was filtered through celite, washed with DCM (2×10 mL), the DCM removed in vacuo. The residue was partitioned between ethyl acetate and a saturated solution of sodium bicarbonate, the organic layer washed with brine, dried (MgSO4) and concentrated in vacuo. 3.5M Hydrochloric acid (0.5 mL) was added to a solution of the residual oil dissolved in methanol (5 mL) and stirred at RT for 20 minutes, then the solution neutralised with saturated sodium bicarbonate. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was chromatographed on silica, eluting with ethyl acetate, to give the desired compound (95 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[Br:18]N1C(=O)CCC1=O>C(#N)C>[Br:18][C:15]1[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(CNC(=O)OC(C)(C)C)c1
Solvent: CC#N
Product: COc1ccc(Br)c(CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Methoxybenzylamine (23 g) was dissolved in 150 ml of tetrahydrofuran, and a solution of 32 g of t-butyl dicarbonate in tetrahydrofuran (50 ml) was added thereto. The mixture was stirred at room temperature for 1 hour, and then the solvent was evaporated. The residue was dissolved in ethyl acetate and successively washed with 1N hydrochloric acid and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated to give t-butyl N-(3-methoxybenzyl)carbamate. The resulting t-butyl N-(3-methoxybenzyl)carbamate was then dissolved in 250 ml of acetonitrile, 30 g of N-bromosuccinimide was added thereto under ice-cooling, the mixture was stirred at room temperature for 3 hours, and then the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with water and then with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by a silica gel column, to give 36 g of the title compound in the 2:1 hexane-diethyl ether fraction.
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:21][C:10]2=[C:11]3[C:16](=[C:17]([CH3:19])[CH:18]=[C:9]2[CH2:8]1)[NH:15][C:14](=[O:20])[CH:13]=[CH:12]3)(=O)=O.[I:22]([O-])(=O)=O.[Na+]>CN(C)C=O>[I:22][CH2:6][CH:7]1[O:21][C:10]2=[C:11]3[C:16](=[C:17]([CH3:19])[CH:18]=[C:9]2[CH2:8]1)[NH:15][C:14](=[O:20])[CH:13]=[CH:12]3
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(COS(C)(=O)=O)C2
Reactant: [O-][I+2]([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CI)C2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methanesulfonyloxymethyl-5-methyl -2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (931 mg) in dimethylformamide (20 ml), sodium iodate (4.5 g) was added, and the mixture was stirred at 100° C. for 2 hours. After completion of the reaction, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: chloroform) to obtain 1 g (assayed quantitatively) of the target compound as a light yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([C:14](=O)[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:35](C(OCC)=O)[C:36]([O:38]CC)=[O:37]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7](=[O:8])[O:9][C:35]([C:36]([OH:38])=[O:37])=[C:14]2[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: COc1cc(C(=O)O)c(C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(-c3cc(OC)c(OC)c(OC)c3)c(C(=O)O)oc(=O)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4,5-dimethoxy-2-(3,4,5-trimethoxybenzoyl)benzoic acid (5 g) in dimethylformamide (50 ral) ard added potassium carbonate (3.72 g) and diethyl bromomalonate (2.48 ml), and the mixture is stirred at room temperature overnight. The mixture is evaporated to remove dimethylformamide, and thereto is added chloroform and water. The chloroform layer is separated, and thereto are added dioxane (80 ml) and conc. hydrochloric acid (80 ml). The mixture is heated under reflux for three hours. The reaction mixture is cooled, and the precipitated crystals are collected by filtration washed with acetone, and dried to give 6,7-dimethoxy-4-(3,4,5-trimethoxyphenyl)isocoumarin-3-carboxylic acid (2.85 g) as listed in Table 57.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17][CH2:18][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17][CH2:18][O:19][S:38]([C:35]1[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=1)(=[O:40])=[O:39])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC(c1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC(c2ccccc2)c2cc(Br)ccc2OCc2ccccc2)cc1
Reaction time: 18 h
Yield: 93.6 %

Procedure:
A cooled (5° C.) solution of (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropan-1-ol (108.0 g) in dichloromethane (300 ml) was treated with pyridine (79.4 ml) and then p-toluenesulphonyl chloride (60.6 g) in dichloromethane (200 ml). After 18 hrs. at room temperature the solvent was removed in vacuum and the residue was extracted with diethyl ether. The extract was washed with hydrochloric acid, water, and dried over anhydrous sodium sulphate to give (±)-toluene-4-sulphonic acid 3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl ester as a light yellow oil after concentration under reduced pressure (140.3 g, 93.6% yield), tlc: (1) 0.66. NMR (CDCl3): 21.67, 33.67, 39.69, 68.58, 70.28, 113.21, 113.76, 126.47, 127.84, 128.10, 128.25, 128.41, 128.51, 129.81, 130.26, 130.42, 132.91, 134.39, 136.41, 142.16, 155.07.