Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2](C)/[CH:3]=[N:4]/[NH:5][C:6](=O)[CH2:7][C@H:8]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][CH2:22][C@H:23]([O:25][CH2:26][CH3:27])[CH3:24])=[CH:16][CH:15]=2)[C@@H:11]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]3[O:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:34]=3[CH:44]=2)[CH2:10][N:9]1S(C1C=CC(C)=CC=1)(=O)=O.CN.C(O)(=O)C.C([O-])(O)=O.[Na+]>C(#N)C>[CH2:26]([O:25][C@H:23]([CH3:24])[CH2:22][O:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:12]2[CH2:13][C@H:8]([CH2:7][C:6]3[N:2]([CH3:1])[CH:3]=[N:4][N:5]=3)[NH:9][CH2:10][C@@H:11]2[O:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]3[O:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:34]=3[CH:44]=2)=[CH:15][CH:16]=1)[CH3:27]
Reactant: CCO[C@H](C)COCc1ccc([C@H]2C[C@H](CC(=O)N/N=C/N(C)C)N(S(=O)(=O)c3ccc(C)cc3)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Agent: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCO[C@H](C)COCc1ccc([C@H]2C[C@H](Cc3nncn3C)NC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Temperature: 100 °C

Procedure:
Into a solution of 1.0 mmol of [(2R,4R,5R)-4-[4-((R)-2-ethoxy-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl) -piperidin-2-yl]-acetic acid [1-dimethylamino-meth-(E)-ylidene]- hydrazide in 2 ml of acetonitrile is condensed ca. 1 ml of gaseous methylamine, at RT. Acetic acid (2 mL) is carefully added, then the reaction system is sealed, and heated at 100° C. for 4 h. The reaction mixture is cooled to RT, poured into saturated aqueous NaHCO3, and extracted with EtOAc (3×). The combined organic extracts are dried over Na2SO4, concentrated under reduced pressure, and purified by flash chromatography (SiO2 60 F), to afford the title compound, which is identified based on its Rf value.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1.[NH2:13][NH2:14]>C1COCC1>[NH2:1][C:2]1[C:7]([S:8]([NH:13][NH2:14])(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cc1S(=O)(=O)Cl
Reactant: NN
Solvent: C1CCOC1
Product: NNS(=O)(=O)c1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Amino-5-bromopyridine-3-sulfonyl chloride (94 mg, 0.35 mmol) was taken into THF (2 mL) followed by addition of anhydrous hydrazine (40 uL, 1.4 mmol) and the mixture was stirred for 10 minutes at room temperature. The mixture was concentrated and dried to give 2-amino-5-bromopyridine-3-sulfonohydrazide as a white solid, which was then taken into ethanol (2 mL) followed by addition of sodium acetate (320 mg, 3.9 mmol) and ethyl iodide (140 uL, 1.75 mmol). The mixture was refluxed for 12 h then cooled to room temperature and concentrated. The residue was partitioned with ethyl acetate and water and the organic phase washed with brine then dried over sodium sulfate, filtered and concentrated to give 5-bromo-3-(ethylsulfonyl)pyridin-2-amine (67 mg, 72%) as a yellow oil. MS (EI) for C7H9N2SO2Br: 265, 267 (MH+).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[N:16][C:15]([C:18]([F:21])([F:20])[F:19])=[N:14]2)=[C:9]([CH3:22])[CH:8]=1>C(OCC)(=O)C>[CH3:6][C:7]1[CH:8]=[C:9]([CH3:22])[C:10]([N:13]2[CH:17]=[N:16][C:15]([C:18]([F:20])([F:21])[F:19])=[N:14]2)=[CH:11][C:12]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C)c1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(S(=O)(=O)Cl)cc1-n1cnc(C(F)(F)F)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
In a 25-ml eggplant flask provided with a magnetic stirrer were placed 2.5 g (22 mol) of chlorosulfonic acid and then 1.8 g (7.4 mmol) of 1,3-dimethyl-4-(3-trifluoromethyl-1H-1,2,4-triazol-1-yl)benzene. The mixture was stirred at 70° C. for 2 hours. The mixture was cooled to room temperature and then added onto ice in small portions. Thereto was added 30 ml of ethyl acetate to give rise to phase separation. The aqueous phase was extracted with 30 ml of ethyl acetate. The ethyl acetate phase was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. Then, vacuum distillation was conducted to distill off ethyl acetate to obtain a title compound as 2.5 g of brown oil. Yield: 99%
Reaction SMILES: [CH3:1][O:2][C:3](=[O:55])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:36][C:35]2[CH:34]=[C:33]3[C:28]([O:29][C@@H:30]([C:39]4[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=4)[C:31](=[O:38])[N:32]3[CH3:37])=[CH:27][C:26]=2[CH2:25][N:24]1[C@H:46]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:47][CH3:48])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Cl:56][C:57]1[CH:58]=[C:59]([CH:62]=[CH:63][C:64]=1[Cl:65])[CH2:60]Br.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:55])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:36][C:35]2[CH:34]=[C:33]3[C:28]([O:29][C@@H:30]([C:39]4[CH:40]=[CH:41][C:42]([O:45][CH2:60][C:59]5[CH:62]=[CH:63][C:64]([Cl:65])=[C:57]([Cl:56])[CH:58]=5)=[CH:43][CH:44]=4)[C:31](=[O:38])[N:32]3[CH3:37])=[CH:27][C:26]=2[CH2:25][N:24]1[C@H:46]([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[CH2:47][CH3:48])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(O)cc1)O3
Reactant: Clc1ccc(CBr)cc1Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.5 %

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (0.259 mmol) was dissolved in 2 mL of DMF and 3,4-dichlorobenzyl bromide (1.30 mmol) and potassium carbonate (1.30 mmol) were added. The mixture was stirred at room temperature for 6 hours and was poured onto ethyl acetate and saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated. The residue was purified over silica (hexanes-ethyl acetate-MeOH, 7-3-0.1) to provide (S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (96 mg, LC/MS: m/z 895). 1H NMR (400 MHz, d6 acetone): 7.89-7.77 (m, 5H), 7.56 (m, 2H), 7.49 (m, 2H), 7.34 (m, 1H), 7.30-7.18 (m, 7H), 6.97 (s, 1H), 6.84 (m, 2H), 6.78 (m, 2H), 6.71 (s, 1H), 5.65 (s, 1H), 4.88 (m, 2H), 4.73 (m, 1H), 3.71 (s, 3H), 3.68 (m, 1H), 3.53 (d, 1H), 3.47 (m, 1H), 3.41 (s, 3H), 3.34 (d, 1H), 3.10 (m, 1H), 3.02 (m, 1H), 2.83-2.71 (m, 2H), 1.90-1.66 (m, 2H), 0.54 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:16]2[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1.[Cl:23][C:24]1[C:25]([C:38](O)=[O:39])=[N:26][C:27]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:28][CH:29]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:25]([C:38]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[N:10]=[CH:9][CH:8]=[C:7]3[O:6][C:5]2[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)=[O:39])=[N:26][C:27]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:34])[CH3:35])=[CH:28][CH:29]=1
Reactant: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)ccnc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cccc(C(F)(F)F)c4)ccnc23)n1
Yield: 38.4 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(3-(trifluoromethyl)phenoxy)quinolin-8-amine (Intermediate-11, 100 mg, 0.327 mmol), 3-chloro-6-(pivalamidomethyl)picolinic acid (Intermediate-3, 180 mg, 0.66 mmol), oxalyl chloride (125 mg, 0.99 mmol), DMF (1 drop) and DIPEA (126 mg, 0.98 mmol) in CH2Cl2 (5 mL) to afford 70 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 11.86 (s, 1H), 8.91 (d, J=6.9 Hz, 1H), 8.81 (d, 1H), 8.35 (br t, 1H), 8.12 (d, J=7.8 Hz, 1H), 8.06 (d, J=9.1 Hz, 1H), 7.80-7.70 (m, 5H), 7.47 (d, J=7.8 Hz, 1H), 6.83 (d, J=4.8 Hz, 1H), 4.50 (d, J=6.0 Hz, 2H), 1.16 (s, 9H); MS [M+H]+: 557.26.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:14]([C:15](OCC)=[O:16])=[CH:13][C:12]3[CH:20]=[CH:21][S:22][C:11]=3[S:10]2(=[O:24])=[O:23])[CH:6]=[CH:7][CH:8]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:14]([CH2:15][OH:16])=[CH:13][C:12]3[CH:20]=[CH:21][S:22][C:11]=3[S:10]2(=[O:24])=[O:23])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1=Cc2ccsc2S(=O)(=O)N1c1cccc(OC)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: COc1cccc(N2C(CO)=Cc3ccsc3S2(=O)=O)c1
Yield: 72.5 %

Procedure:
A solution of the product of Step C (5.64 g, 15.45 mmol) in anhydrous THF (150 mL) was treated with DIBAL (66 mmol) in a manner essentially analogous to that described in Example 15, Step D to provide the desired product as a white solid (3.62 g, 73%): mp 141°-143° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:22]([CH2:24][NH2:25])[OH:23]>>[OH:23][CH2:22][CH2:24][NH:25][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCCO
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cn1
Product: COc1ccc(N(C)c2nc(NCCO)nc3ccccc23)cn1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine (12 mg, 0.040 mmol) and ethanolamine (28 μl) by a procedure similar to Example 10 and was isolated as off white solid (8 mg, 66%). 1H NMR (CDCl3): 8.03 (brd, J=3.0 Hz, 1H), 7.47-7.35 (m, 3H), 6.91 (brd, J=8.7 Hz, 1H), 6.78-6.73 (m, 2H), 5.56 (brs, 1H), 3.94 (s, 3H), 3.93-3.90 (m, 2H), 3.70-3.56 (m, 2H), 3.48 (s, 3H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:20][CH3:21])(=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Br[CH2:23][C:24]#[C:25][CH3:26].Cl>O1CCCC1>[CH2:23]([CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:9]([O:20][CH3:21])=[O:19])[C:24]#[C:25][CH3:26]
Reactant: CCCCCCCCCC(=O)OC
Reactant: CC#CCBr
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC#CCC(CCCCCCCC)C(=O)OC
Temperature: -78 °C

Procedure:
A solution of 0.055 mol of lithium diisopropylamide (LDA) in 100 ml tetrahydrofuran (THF) was cooled to −78° C. under an inert atmosphere, and 0.055 mol of methyl decanoate in THF was added dropwise with stirring. The mixture was allowed to warm over one hour to −20° C., then cooled again to −78° C. A solution of 1-bromo-2-butyne (0.050 mol) in THF (20 ml) was added dropwise, and the mixture allowed to warm to room temperature overnight. Aqueous 6N HCl (100 ml) was added, and the product extracted with ethyl ether, dried with anhydrous sodium sulfate, concentrated, and distilled in vacuo to provide methyl 2-(2-butynyl)decanoate as an oil.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[I:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.C(=O)=O.CC(C)=O>O.O1CCCC1>[I:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
To a mixture of 41.8 g of diethyl malonate and 100 ml of tetrahydrofuran, 11.0 g of 60% sodium hydride was added, and the resulting mixture was stirred at room temperature for 1 hour. The mixture was added gradually dropwise to a mixture of 69.5 g of 4-iodobenzoyl chloride and 300 ml of tetrahydrofuran under cooling with dry ice-acetone. The reaction mixture was stirred for 3 hours, and then 300 ml of water was added. The tetrahydrofuran was removed from the reaction mixture by evaporation under reduced pressure, and the reaction mixture was extracted with diethyl ether. The extract was dried over magnesium sulfate, filtered and concentrated at atmospheric pressure. The resulting residue was recrystallized in diethyl ether-hexane to give 28.5 g of the title compound as colorless crystals.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:47][O:48][C:49]([C:51]1[N:52]([CH2:69][C:70]2[CH:75]=[CH:74][C:73]([C:76]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:77])=[CH:72][CH:71]=2)[C:53](=[O:68])[C:54]2[C:59]([C:60]=1[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[CH:58][C:57](Br)=[CH:56][CH:55]=2)=[O:50].[CH2:83]([NH2:90])[C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH3:47][O:48][C:49]([C:51]1[N:52]([CH2:69][C:70]2[CH:75]=[CH:74][C:73]([C:76]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:77])=[CH:72][CH:71]=2)[C:53](=[O:68])[C:54]2[C:59]([C:60]=1[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[CH:58][C:57]([NH:90][CH2:83][C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1)=[CH:56][CH:55]=2)=[O:50]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: NCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)c2cc(NCc3ccccc3)ccc2c(=O)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 0.08 h

Procedure:
To toluene (40 ml) were added palladium(II) acetate (27 mg) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (240 mg) at room temperature, and the mixture was stirred for 5 min. under a nitrogen stream. To the reaction mixture were added 6-bromo-2-(4-tert-butoxycarbonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (2.0 g) and benzylamine (0.6 ml) at room temperature and the mixture was stirred for 10 min. under a nitrogen stream. Further, to the reaction mixture was added sodium tert-butoxide (480 mg) at room temperature and the mixture was heated under reflux under a nitrogen atmosphere for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane-hexane:ethyl acetate=1:1) to give the title compound (1.8 g).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12](C2C=C(OC)C(Cl)=C(CC3C=CC(OCC)=CC=3)C=2)[O:11][C@@H:10]1[CH2:50][O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:59]([O:62][C:63]1[CH:68]=[C:67](Br)[CH:66]=[C:65]([CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[C:64]=1[Cl:77])[CH:60]=[CH2:61]>>[CH2:59]([O:62][C:63]1[CH:68]=[C:67]([C@H:12]2[C@H:13]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:10]([CH2:50][O:51][CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[O:11]2)[CH:66]=[C:65]([CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[C:64]=1[Cl:77])[CH:60]=[CH2:61]
Reactant: C=CCOc1cc(Br)cc(Cc2ccccc2)c1Cl
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cc(OC)c2Cl)cc1
Product: C=CCOc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc(Cc2ccccc2)c1Cl

Procedure:
Similar procedure with preparation of 76 proceeded except for using compound 168 to obtain the compound 169.
Reaction SMILES: [OH:1][C@H:2]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH2:25][OH:26])[CH:19]=1)[CH2:3][NH:4][C@H:5]([CH3:17])[CH2:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12]C)=[O:11].[OH-].[Li+].Cl>O1CCCC1>[OH:1][C@H:2]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH2:25][OH:26])[CH:19]=1)[CH2:3][NH:4][C@H:5]([CH3:17])[CH2:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1cccc(C[C@@H](C)NC[C@H](O)c2ccc(O)c(CO)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](Cc1cccc(C(=O)O)c1)NC[C@H](O)c1ccc(O)c(CO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 119.3 %

Procedure:
To a solution of methyl 3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzoate (Preparation 60) (5.12 g, 14.24 mmol) in tetrahydrofuran (35 ml), was added aqueous lithium hydroxide solution (1M, 29 ml, 29 mmol) and the solution left to stir at room temperature for 18 hours. Aqueous hydrochloric acid (1M, 29 ml, 29 mmol) was added and the tetrahydrofuran/water removed in vacuo to give the title compound as an off-white solid (5.87 g) that was used without further purification. 1H NMR (400 MHz, CD3OD): δ=7.86-7.84 (1H, d), 7.82 (1H, s), 7.37-7.30 (3H, m), 7.17-7.15 (1H, dd), 6.79-6.77 (1H, d), 4.89-4.85 (1H, m), 4.65 (2H, s), 3.60-3.50 (1H, m), 3.21-3.15 (3H, m), 2.84-2.78 (1H, dd), 1.25-1.23 (3H, d) ppm. LRMS (electrospray): m/z [M+H]+ 346, [M+Na]+ 368, [M−H]− 344. CHN analysis: found C, 50.29; H, 6.07; N, 3.07. C19H23NO5+2.0LiCl+1.3H2O requires C, 50.31; H, 5.69; N, 3.09.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:9][CH:10]([CH3:14])[C:11](O)=[O:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([O:8][C:11](=[O:12])[CH:10]([SH:9])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(S)C(=O)O
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(S)C(=O)OCc1ccccc1

Procedure:
Into a 100 ml reaction flask equipped with thermometer, reflux condenser, hot plate (equipped with magnetic stirring apparatus) and spin bar are placed 21.6 grams benzyl alcohol; 29.6 grams of 2-mercaptopropionic acid; and 0.5 grams of para-toluene sulphonic acid.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=3[NH:10][C:11](=[O:14])[CH2:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:14]=[C:11]1[N:10]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:13][CH2:12]1
Reactant: CCOC(=O)CCCCCBr
Reactant: O=C1CN=C(c2ccccc2)c2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCN1C(=O)CN=C(c2ccccc2)c2ccccc21
Yield: 62.5 %

Procedure:
Title compound 362 (400 mg, 1.69 mmol), ethyl 6-bromohexanoate (0.3 mL, 1.69 mmol) and potassium carbonate (584 mg, 4.23 mmol) were mixed in DMF (20 mL) and the reaction mixture was heated to 80 oC for 24 hours. The DMF was removed and the residue was partitioned between water and ethyl acetate. The 2 layers were split and the aqueous layer was extracted with 2 other portions of ethyl acetate. The combined organic layers were washed with brine, dried, filtered and evaporated. The crude product was purified by flash chromatography (2:1 to 1:2, hexanes:ethyl acetate) to afford title compound 363 (400 mg, 63%) as a clear oil.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][C@@H:15]3[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][S:32]([CH2:35][CH2:36][CH2:37][C:38]([F:44])([F:43])[C:39]([F:42])([F:41])[F:40])(=[O:34])=[O:33])=[CH:22][CH:21]=3)([CH3:13])[C:11](=O)[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.[CH3:46][O-].[Na+].[Cl-].[NH4+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH2:46]=[C:11]1[CH2:10][CH2:9][C@H:8]2[C@H:7]3[C@H:16]([C@@H:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][S:32]([CH2:35][CH2:36][CH2:37][C:38]([F:43])([F:44])[C:39]([F:40])([F:42])[F:41])(=[O:33])=[O:34])=[CH:22][CH:21]=4)[CH2:14][C@:12]12[CH3:13])[C:17]1[CH:18]=[CH:19][C:2]([OH:1])=[CH:3][C:4]=1[CH2:5][CH2:6]3
Reactant: C[C@]12C[C@H](c3ccc(OCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: C[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: C=C1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3[C@@H](c3ccc(OCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)cc3)C[C@]12C
Reaction time: 16 h
Yield: 16 %

Procedure:
500 mg of the product obtained in Example 73 is added to a mixture containing 815 mg of methyltriphenylphosphonium bromide, 5 cm3 of dioxan and 125 mg of sodium methylate. Agitation is carried out for 16 hours at ambient temperature, 100 cm3 of an aqueous solution of ammonium chloride is added, followed by extracting with methylene chloride, drying, eliminating the solvent under reduced pressure and chromatographing the residue on silica (eluant: cyclohexane-ethyl acetate 7-3). 80 mg of expected product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]([OH:9])[C:6]([OH:8])=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([CH3:26])([CH3:25])[NH2:24])=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([NH:24][C:6](=[O:8])[CH:5]([OH:9])[C:4]2[CH:10]=[CH:11][CH:12]=[C:2]([Cl:1])[CH:3]=2)([CH3:25])[CH3:26])=[CH:17][CH:16]=1
Reactant: COc1ccc(CCC(C)(C)N)cc1
Reactant: O=C(O)C(O)c1cccc(Cl)c1
Product: COc1ccc(CCC(C)(C)NC(=O)C(O)c2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared from 3-chloromandelic acid (2.1 g) and 3-(4-methoxyphenyl)-1,1-dimethylpropanamine (1.9 g) by an analogous procedure to that described in Description 12 and used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:19])=[C:13]([CH:18]=1)[C:14]([O:16]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C@@H:21]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:22][OH:23]>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[OH:23][CH2:22][C@@H:21]([NH:20][C:14](=[O:16])[C:13]1[CH:18]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=[CH:11][C:12]=1[OH:19])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1O
Reactant: N[C@H](CO)Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(N[C@H](CO)Cc1ccccc1)c1cc(OCc2ccccc2)ccc1O
Reaction time: 72 h
Yield: 50 %

Procedure:
In a flask equipped with a reflux condenser and a magnetic stirring bar are dissolved the methyl 5-benzyloxy-2-hydroxybenzoate and one equivalent of 2-(S)-amino-3-phenyl-1-propanol in dry dimethyl formamide. The flask is immersed in an oil bath at 75° C. and left to stir for 72 hours. The solvent is evaporated and the residue is isolated-through the use of a silica gel column using a mixture of ethyl acetate and hexane as eluent. In this fashion is obtained in 50% yield, N-{(S)-1-hydroxy-3-phenyl-2-propyl}-5-benzyloxy-2-hydroxybenzamide.