Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].C(=O)(O)[O-].[K+:14]>O>[OH2:3].[C:1]([O-:9])(=[O:8])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[K+:14]
Reactant: O=C(O)C[C@H](O)C(=O)O
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: O=C(O)C[C@H](O)C(=O)[O-]
Temperature: 10 °C
Reaction time: 4 h
Yield: 152.1 %

Procedure:
134.1 g (one mole) of L-malic acid and 120 g (1.20 moles) of potassium bicarbonate are dissolved at 60° C. in 200 ml of water. The solution (pH 4.4) is concentrated under reduced pressure to make the total volume thereof about 200 ml. The concentrated solution is cooled to 10° C., and the mixture obtained (i.e., the mixture of the concentrated solution and crystals precipitated) is stirred at the same temperature for 4 hours. After stirring, the mixture had a pH of 6.0. The crystalline precipitates are collected by filtration. 144.6 g of monopotassium L-malate monohydrate are obtained as crystals. Yield: 76%
Reaction SMILES: O=O.[CH3:3][C:4]([CH3:16])=[C:5]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:6]([OH:8])=[O:7].[OH-].[Na+]>O>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C@@H:5]([CH:4]([CH3:16])[CH3:3])[C:6]([OH:8])=[O:7])=[CH:14][CH:13]=1
Reactant: CC(C)=C(C(=O)O)c1ccc(F)cc1
Agent: O=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)[C@@H](C(=O)O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.2 %

Procedure:
In a glove box (argon-atmosphere, O2 -content<1 ppm) a 10 ml measuring flask was charged with 16.9 mg (0.013 mmol) of ((S)-MeOBIPHEP-TS-Na)Ru(OCOF3)2 and filled to the graduation mark with 10 ml of degassed water. The suspension was stirred with a magnetic stirring bar for 15 min at room temperature. A clear yellow solution formed. In the glove box a 30 ml stainless steel autoclave fitted with a magnetic stirring bar was charged with 0.5 g (2.57 mmol) of 3-methyl-2-(p-fluorophenyl)crotonic acid, 4.93 ml of degassed water and 2.57 mmol (2.57 mmol) of a degassed aqueous 1N sodium hydroxide solution. To this suspension 2.0 ml of the above catalyst solution was added and the autoclave was then sealed, pressurized with 16 bar of argon and removed from the glove box. The autoclave was connected to a hydrogenation line, which was thoroughly flushed with hydrogen. The argon in the autoclave was replaced by 60 bar of hydrogen and the hydrogenation was carried out by stirring at 20° and 60 bar. After a reaction time of 21 h the autoclave was vented. The light yellow reaction mixture was transferred to a 50 ml separatory funnel, acidified at 20-25° by adding 2.7 ml of 1N aqueous hydrochloric acid and extracted with ether. The combined ether extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated to dryness by rotary evaporation. Distillation of the reddish residue at 160° and 0.1 mbar afforded 0.47 g of (R)-2-(4-fluorophenyl)-3-methylbutyric acid as a colorless oil, which solidified on standing at room temperature; ee 80%; purity>99 GC-area %.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH:5]([O:34][CH2:35][CH3:36])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:33])C.[Li+].[OH-]>>[CH2:35]([O:34][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:33])[C:4]([OH:37])=[O:3])[CH3:36]
Reactant: CCOC(=O)C(Cc1ccc(OCc2nc(-c3cc(OC)c(OC)c(OC)c3)oc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2nc(-c3cc(OC)c(OC)c(OC)c3)oc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], [rac]-2-ethoxy-3-{2-methyl-4-[5-methyl-2-(3,4,5-trimethoxy-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-ethoxy-3-{2-methyl-4-[5-methyl-2-(3,4,5-trimethoxy-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionic acid as colorless solid, which can be separated into its antipodes by methods known in the art, such as separation of the antipodes via diastereomeric salts by crystallization with optically pure amines such as e.g. (R) or (S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbens or a chiral eluent to give the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:26]2[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=2)[CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(O)CN(Cc2ccccc2)Cc2cccc(OC)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C2CN(Cc3ccccc3)Cc3cc(OC)ccc32)cc1
Temperature: 25 °C
Yield: 49.5 %

Procedure:
To a solution of 2-[benzyl-(3-methoxy-benzyl)-amino]-1-(4-methoxy-phenyl)-ethanol (16.23 g, 43.0 mmol, see Preparation 63) in CH2Cl2 (280 ml) was added TFA (40.0 g, 27.0 ml, 350 mmol). The mixture was refluxed overnight. The reaction mixture was allowed to cool to RT and poured onto ice-water containing sat. NaHCO3 (250 ml). The mixture was extracted with CH2Cl2 (3×150 ml) and the combined organics were dried over MgSO4, filtered, and concentrated in vacuo. Flash chromatography (SiO2, gradient elution 10-40% EtOAc/Hexanes) of the residue afforded the title product (7.67 g, 21.3 mmol, 50% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([CH2:21][C:22]([O:24][CH3:25])=[O:23])#[N:20]>N1CCCCC1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[C:21]([C:19]#[N:20])[C:22]([O:24][CH3:25])=[O:23])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: COC(=O)CC#N
Solvent: C1CCNCC1
Product: COC(=O)C(C#N)=Cc1ccc(OCc2ccccc2)c(OC)c1

Procedure:
A mixture of 4-(benzyloxy)-3-methoxybenzaldehyde (1.21 g, 0.005 mol), methyl cyanoacetate (0.50 g, 0.005 mol) methanol (10.0 mL) and piperidine (5 drops) is heated and stirred at reflux for 1 hour and cooled. The product, 3-(4-benzyloxy-3-methoxyphenyl)-2-cyano-2-propenoate is collected by filtration, washed with methanol and dried in air. The yield is 1.50 g (93%) of product having an absorption maximum at 364 nm in methylene chloride solution. The identity of the product is supported by mass spectrometry.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][NH:7][C@H:8]([CH3:31])[C@@H:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2].O(C1C=CC(C(CCC2C=CC=CC=2)C(O)C)=CC=1)C1C=CC=CC=1.[CH2:57]([O:64]C1C=C(C(CCC2C=CC=CC=2)C(O)C)C=CC=1OC1C=CC=CC=1)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>>[CH2:1]([O:3][C:4]([CH2:6][NH:7][CH:8]([CH3:31])[CH:9]([C:18]1[CH:19]=[CH:20][C:21]([O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:22]([O:64][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH:23]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CN[C@H](C)[C@H](CCc1ccccc1)c1ccc(Oc2ccccc2)cc1
Reactant: CC(O)C(CCc1ccccc1)c1ccc(Oc2ccccc2)c(OCc2ccccc2)c1
Agent: CC(O)C(CCc1ccccc1)c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)CNC(C)C(CCc1ccccc1)c1ccc(Oc2ccccc2)c(OCc2ccccc2)c1

Procedure:
The above identified compound was obtained by carrying out the same reaction as in Example 49(5) and (6) except that instead of (2RS,3SR)-3-(4-phenoxyphenyl)-5-phenylpentan-2-ol used as the starting material in Example 49(2), (2RS,3SR)-3-(3-benzyloxy-4-phenoxyphenyl)-5-phenylpentan-2-ol was used.
Reaction SMILES: COC[N:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([C:15]3[CH:19]=[CH:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29]C5CCCCO5)=[CH:22][N:21]=4)[N:16]=3)[CH3:14])=[CH:12][C:7]=2[S:6][C:5]1=[O:36].FC(F)(F)C(O)=O.C1COCC1.[OH-].[NH4+]>CCOC(C)=O>[OH:29][CH2:28][CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([N:17]2[CH:18]=[CH:19][C:15]([CH:13]([C:11]3[CH:10]=[CH:9][C:8]4[NH:4][C:5](=[O:36])[S:6][C:7]=4[CH:12]=3)[CH3:14])=[N:16]2)=[N:21][CH:22]=1
Reactant: COCn1c(=O)sc2cc(C(C)c3ccn(-c4ccc(OCCOC5CCCCO5)cn4)n3)ccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(c1ccc2[nH]c(=O)sc2c1)c1ccn(-c2ccc(OCCO)cn2)n1
Temperature: 72 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Dissolve 3-(methoxymethyl)-6-{1-[1-(5-{2-(tetrahydro-2H-pyran-2-yloxy)ethoxy}pyridine-2-yl)-1H-pyrazol-3-yl]ethyl}-3H-1,3-benzothiazol-2-one (140 mg, 274.18 μmoles) in trifluoroacetic acid (0.05 M; 73 mmoles; 5.5 mL) and heat at reflux (˜72° C.) under N2 for 2 hr. (orange color observed after about 10 min. and at 70° C.). Cool the reaction to room temperature and concentrate under reduced pressure. Dissolve the residue in THF (0.05 M; 67 mmoles, 5.5 mL), add 28% ammonium hydroxide (0.2 M; 9.9 mmoles; 1.4 mL), and stir at room temperature for ˜1 hr. Dilute with EtOAc (100 ml), wash with brine, dry over sodium sulfate, filter and concentrate. Purify by liquid chromatography on a 25 g silica gel column, eluting with a gradient of 60-80% EtOAc in hexanes to give 6-(1-{1-[5-(2-hydroxy-ethoxy)-pyridin-2-yl]-1H-pyrazol-3-yl}-ethyl)-3H-1,3-benzothiazol-2-one as a white foam (80 mg; 209 μmoles; 76% yield). LCMS (Low) rt 1.8 min., M+1=383.
Reaction SMILES: CC(CCCC1C=CC=CC=1)C(O)=O.[OH:15][CH2:16][C@H:17]([NH:24][C:25](=[O:37])[C@@H:26]([CH3:36])[CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[OH:15][CH2:16][C@H:17]([NH:24][C:25](=[O:37])[C@H:26]([CH3:36])[CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@@H](CCCc1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Agent: CC(CCCc1ccccc1)C(=O)O
Product: C[C@H](CCCc1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Yield: 33 %

Procedure:
(−)-(R)—N—((R)-2-Hydroxy-1-phenylethyl)-2-methyl-5-phenylpentanamide was prepared from (±)-2-methyl-5-phenylpentanoic acid (20mb(i)/20mc(i)) in the same manner as (S)—N—((R)-2-hydroxy-1-phenylethyl)-2-methyl-5-phenylpentanamide (19mb(i)) described above. Silica gel chromatography provided separation of the title compound from its diastereomer (19mb(i)) to provide the desired product (30.2 g, 33%) as a white solid; TLC Rf 0.33 (solvent system: 50:50 v/v ethyl acetate-heptane); HPLC retention time 13.25 minutes, Gemini 5μ C18 250×4.6 mm, at ultraviolet wavelength of 210 nm, 1 mL/min, 60:40:0.1 methanol-water-acetic acid, purity 99.36% (R), 0.64% (S); [α]Tλ=α/cl, [α]21.9D=−0.066/(0.01573 g/2 mL)(0.5)=−16.78° (c=0.7865, CHCl3).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH2:14]([O:13][C:11]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([N:19]3[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]3)=[N:7][CH:6]=2)[CH2:10][CH2:9]1)=[O:12])[CH3:15]
Reactant: CCOC(=O)C1(c2ccc(Cl)nc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CCOC(=O)C1(c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)CC1
Temperature: 130 °C

Procedure:
A mixture of ethyl 1-(6-chloropyridin-3-yl)cyclopropanecarboxylate (225.7 mg, 0.001000 mol) and tert-butyl piperazine-1-carboxylate (3.0 eq.) was heated at 130° C. for 6 h. After cooling, the mixture was flash chromatographed on a silica gel column to afford the desired product. LC/MS: 376.5 (M+H+).
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][N:15]=[C:14]([N:17](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:13]=3[CH:32]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.B(Br)(Br)Br>ClCCl>[NH2:17][C:14]1[C:13]2[CH:32]=[C:9]([C:8]3[C:3](=[O:2])[NH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=[CH:11][C:12]=2[O:16][N:15]=1
Reactant: COc1ncccc1-c1ccc2onc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1noc2ccc(-c3ccc[nH]c3=O)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
To a cold (−78° C.) solution of di-tert-butyl [5-(2-methoxypyridin-3-yl)-1,2-benzoxazol-3-yl]imidodicarbonate (0.235 g, 0.53 mmol) in dichloromethane (10 mL) was added boron tribromide (0.40 mL, 4.24 mmol). The mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated in vacuo and the resultant solid was suspended in acetic acid (3 mL), 48% w/w hydrobromic acid (1 mL) was added the mixture was stirred at ambient temperature 16 h, heated to 75° C., stirred for a further 6 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was taken up in water (100 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine (25 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford 3-(3-aminobenzo[d]isoxazol-5-yl)pyridin-2(1H)-one as a brownish-orange solid in 62% yield (0.08 g): 1H NMR (300 MHz, DMSO-d6) δ 11.87 (br s, 1H), 8.18 (d, J=1.2 Hz, 1H), 7.84 (dd, J=8.7, 1.8 Hz, 1H), 7.64 (dd, J=6.9, 2.1 Hz, 1H), 7.46-7.38 (m, 2H), 6.43 (br s, 2H), 6.32 (dd, J=6.7, 6.7 Hz, 1H); 13C NMR (75 MHz, DMSO-d6): 161.2, 161.1, 158.6, 138.6, 134.5, 130.9, 130.3, 129.6, 121.3, 116.7, 108.6, 105.4; MS (ES+) m/z 228.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:17](=[O:18])[N:16]([C:19]3[CH:24]=[C:23]([Cl:25])[C:22](=[O:26])[N:21]([CH3:27])[CH:20]=3)[CH:15]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:8]=2[N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=1Br)=[O:5])[CH3:2].[CH3:35][O:36][C:37]1[N:42]=[C:41]([O:43][CH3:44])[C:40](B(O)O)=[CH:39][N:38]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:17](=[O:18])[N:16]([C:19]3[CH:24]=[C:23]([Cl:25])[C:22](=[O:26])[N:21]([CH3:27])[CH:20]=3)[CH:15]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:8]=2[N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=1[C:40]1[C:41]([O:43][CH3:44])=[N:42][C:37]([O:36][CH3:35])=[N:38][CH:39]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c2c(n(C(C)C)c1Br)C(c1ccc(Cl)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: CCOC(=O)c1c2c(n(C(C)C)c1-c1cnc(OC)nc1OC)C(c1ccc(Cl)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-bromo-5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrole-3-carboxylic acid ethyl ester (Intermediate BM) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a white solid. tR=1.10 min (HPLC 3); ESI-MS: tR=1.05 min, [M+H]+ 626/628 (LC-MS 1); TLC: Rf=0.05 (EtOAc).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH3:11])=[N:8][CH:9]=1)([O-])=O.C([O-])=O.[NH4+]>C(O)C.[Pd]>[N:12]1([CH:10]([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH3:11])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CC(c1ccc([N+](=O)[O-])cn1)N1CCOCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(c1ccc(N)cn1)N1CCOCC1

Procedure:
Compound 36 (178 mg, 0.75 mmol) was added to Pd/C (20 mg) in ethanol (5 mL), followed by ammonium formate (237 mg, 3.76 mmol) and the reaction mixture heated to reflux for 1 h. The reaction mixture was filtered through celite and the filtrate evaporated. The residue was dissolved in dichloromethane (20 mL) and washed with saturated sodium bicarbonate (20 mL). The organic phase was passed through a hydrophobic frit and evaporated to give the title compound as a yellow oil (155 mg, quant.; LCMS, Rt=0.32 min (MeOH-FA method), m/z 208 (MH+).
Reaction SMILES: C(OC([N:6]1[CH2:21][CH2:20][C:10]2[C:11]3[CH:12]([O:18][CH3:19])[CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=O)C.[OH-].[K+].O.Cl>C(O)C>[CH3:19][O:18][CH:12]1[C:11]2[C:10]3[CH2:20][CH2:21][NH:6][CH2:7][CH2:8][C:9]=3[CH:17]=[CH:16][C:15]=2[CH2:14][CH2:13]1
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(OC)CC3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC1CCc2ccc3c(c21)CCNCC3
Temperature: 120 °C
Reaction time: 48 h
Yield: 48.6 %

Procedure:
The product from step (b) (52 mg, 0.18 mmol) was dissolved in ethanol (2 and placed in a pressure tube. To this solution was added KOH (0.20 g, 3.60 mmol) and water (0.5 ml). The tube was sealed and the contents stirred at 120° C. for 48 hours. The reaction mixture was then cooled to RT and acidified with 2N HCl to pH 3. The aqueous mixture was then washed with diethyl ether (3×). The aqueous phase pH was then adjusted to 12 by addition of 2M NaOH and extracted with DCM (3×). The combined DCM extracts were washed with brine, dried (Na2SO4), and solvent evaporated in vacuo to give the titled compound as a colorless oil (19 mg). 1H NMR (300 MHz, CDCl3) δ 7.02 (d, J=7.5 Hz, 1H); 6.98 (d, J=7.5 Hz, 1H); 4.92 (dd, J=5.4 Hz, 2.7 Hz, 1H); 3.35 (s, 3H); 3.15-2.76 (m, 10H); 2.24-2.12 (m, 2H); 1.99 (bs, 1H); MS: ESI (positive): 218 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:24][CH2:25][CH2:26][CH:27]2[O:31][C:30](=[O:32])[NH:29][C:28]2=[O:33])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:14][CH:15]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:24][CH2:25][CH2:26][CH:27]2[O:31][C:30](=[O:32])[NH:29][C:28]2=[O:33])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:14][CH:15]=1
Reactant: COc1cc(CCCC2OC(=O)NC2=O)ccc1OCc1coc(/C=C/c2ccccc2)n1
Solvent: C1CCOC1
Product: COc1cc(CCCC2OC(=O)NC2=O)ccc1OCc1coc(CCc2ccccc2)n1
Yield: 66.9 %

Procedure:
A mixture of 5-[3-[3-methoxy-4-[2-[(E)-styryl]-4-oxazolylmethoxy]phenyl]propyl]-2,4-oxazolidinedione (0.64 g), paradium-carbon (5%, 1.3 g) and tetrahydrofuran (THF) (35 ml) was subjected to catalytic hydrogenation under 1 atmospheric pressure at room temperature. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to yield 5-[3-[3-methoxy-4-[2-(2-phenylethyl)-4-oxazolylmethoxy]phenyl]propyl]-2,4-oxazolidinedione (0.43 g, 67%). The product was recrystallized from ethyl acetate-hexane to give colorless needles, m.p.122-123° C.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH3:7][N:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[S:9]([CH2:12][C:13](OC)=O)(=[O:11])=[O:10].BrC1[CH:25]=[CH:26][C:27]2[CH:38]=[CH:37][C:31]3=[N:32][CH:33]=[C:34]([Cl:36])[CH:35]=[C:30]3[C:29](=[O:39])[C:28]=2[CH:40]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:36][C:34]1[CH:35]=[C:30]2[C:29](=[O:39])[C:28]3[CH:40]=[C:13]([CH2:12][S:9]([N:8]([CH3:7])[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)(=[O:10])=[O:11])[CH:25]=[CH:26][C:27]=3[CH:38]=[CH:37][C:31]2=[N:32][CH:33]=1
Reactant: COC(=O)CS(=O)(=O)N(C)c1ccccc1
Reactant: O=c1c2cc(Br)ccc2ccc2ncc(Cl)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CN(c1ccccc1)S(=O)(=O)Cc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
Sodium tert-butoxide (47.4 g, 493 mmol) was added in one portion to a 1 L flask containing methyl {[methyl(phenyl)amino]sulfonyl}acetate (40.0 g, 164 mmol) and dissolved in dioxane (658 ml) at 0° C. After 15 min., 7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (52.7 g, 164 mmol) was added followed by palladium(II) acetate (1.846 g, 8.22 mmol) and tri-t-butylphosphonium tetrafluoroborate (7.16 g, 24.66 mmol). The resulting suspension was degassed by sparging with nitrogen for 30 min. Then, the mixture was heated to 90° C. in a pre-warmed bath and left to stir for 1 h. Then, the reaction flask was cooled to 50° C., 1M NaOH (500 mL) was added and the solution was stirred for 1 h. Then, the solution was diluted with saturated aqueous sodium hydrogen carbonate (800 mL) and extracted with dichloromethane (3×500 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc/Hexanes gradient) to afford the title compound as a pale yellow solid. 1H NMR (600 MHz, DMSO-D6) δ 8.99 (d, 1H); 8.47 (m, 1H); 8.17 (s, 1H); 7.81 (s, 2H); 7.47 (d, 1H); 7.32 (m, 5H); 7.21 (m, 1H); 4.75 (s, 2H); 3.24 (s, 3H). LRMS (APCI) calculated for C22H18ClN2O3S [M+H]+, 425.1; found 425.0.
Reaction SMILES: Cl[N:2]1C(=O)CCC1=O.CN1CC[O:15][B:14]([C:18]2[CH:19]=[C:20]([S:24]([O-:26])=[O:25])[CH:21]=[CH:22][CH:23]=2)[O:13]CC1.[Li+].[OH-].[NH4+]>C(Cl)Cl>[S:24]([C:20]1[CH:19]=[C:18]([B:14]([OH:15])[OH:13])[CH:23]=[CH:22][CH:21]=1)(=[O:26])(=[O:25])[NH2:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1CCOB(c2cccc(S(=O)[O-])c2)OCC1
Agent: [Li+]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
Step 2) N-Chlorosuccinimide (1.015 g, 7.6 mmol) was added to a suspension of the above prepared lithium 3-(6-methyl-[1,3,6,2]dioxazaborocan-2-yl)-benzenesulfinate (2 g, 7.27 mmol) in CH2Cl2 (14 mL) and the mixture was stirred for 2 h at rt.Ai solution of 25% ammonium hydroxide (1.09 mL, 14.5 mmol) was added and the mixture was stirred again for 2 h at rt, then completely evaporated to give the title compound as an off-white solid (1.38 g, 94%) (according to Bioorg. Med. Chem. 2005, 13, 2305-2312). MS (ISP) 200.4 [(M−H)−].
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:20][C:18](=[O:19])[CH2:17][C@@H:16]([OH:21])[C@H:15]([CH3:22])[C@@H:14]([O:23][C@@H:24]2[O:29][C@H:28]([CH3:30])[C@@H:27](O[C@@H]3O[C@@H](C)[C@H](O)[C@@](O)(C)C3)[C@H:26]([N:42]([CH3:44])[CH3:43])[C@H:25]2[OH:45])[C@@H:13]([CH2:46][CH:47]=[O:48])[CH2:12][C@@H:11]([CH3:49])[C:9](=[O:10])[CH:8]=[CH:7][C:6]([CH3:50])=[CH:5][C@@H:4]1[CH2:51][O:52][C@@H:53]1[O:58][C@H:57]([CH3:59])[C@@H:56]([OH:60])[C@@H:55]([O:61][CH3:62])[C@H:54]1[O:63][CH3:64]>Cl>[CH3:1][CH2:2][CH:3]1[O:20][C:18](=[O:19])[CH2:17][CH:16]([OH:21])[CH:15]([CH3:22])[CH:14]([O:23][CH:24]2[O:29][CH:28]([CH3:30])[CH2:27][CH:26]([N:42]([CH3:44])[CH3:43])[CH:25]2[OH:45])[CH:13]([CH2:46][CH:47]=[O:48])[CH2:12][CH:11]([CH3:49])[C:9](=[O:10])[CH:8]=[CH:7][C:6]([CH3:50])=[CH:5][CH:4]1[CH2:51][O:52][CH:53]1[O:58][CH:57]([CH3:59])[CH:56]([OH:60])[CH:55]([O:61][CH3:62])[CH:54]1[O:63][CH3:64]
Reactant: CC[C@H]1OC(=O)C[C@@H](O)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)[C@@H](O[C@H]3C[C@@](C)(O)[C@@H](O)[C@H](C)O3)[C@H](N(C)C)[C@H]2O)[C@@H](CC=O)C[C@@H](C)C(=O)C=CC(C)=C[C@@H]1CO[C@@H]1O[C@H](C)[C@@H](O)[C@@H](OC)[C@H]1OC
Agent: CCC1OC(=O)CC(O)C(C)C(OC2OC(C)CC(N(C)C)C2O)C(CC=O)CC(C)C(=O)/C=C/C(C)=C\C1COC1OC(C)C(O)C(OC)C1OC
Agent: CC[C@H]1OC(=O)C[C@@H](O)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)[C@@H](O[C@H]3C[C@@](C)(O)[C@@H](O)[C@H](C)O3)[C@H](N(C)C)[C@H]2O)[C@@H](CC=O)C[C@@H](C)C(=O)/C=C/C(C)=C/[C@@H]1CO[C@@H]1O[C@H](C)[C@@H](O)[C@@H](OC)[C@H]1OC
Agent: Cl
Product: CCC1OC(=O)CC(O)C(C)C(OC2OC(C)CC(N(C)C)C2O)C(CC=O)CC(C)C(=O)C=CC(C)=CC1COC1OC(C)C(O)C(OC)C1OC

Procedure:
4 g (0.004 mole) of tylosin base are stirred in 80 ml of 0.2 N hydrochloric acid for 4 hours at ambient temperature. The reaction mixture obtained is washed with dichloromethane, the aqueous phase is separated and its pH adjusted to 8.0. The aqueous phase is extracted with twice 120 ml of dichloromethane and the organic phases are combined, dried over sodium sulphate and evaporated. The residue consists of demycarosyltylosin.