Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]([C@H:12]([OH:17])[C@H:13]([CH3:16])[CH:14]=[CH2:15])=[C:10]2[C:5]([C:6]([CH2:19][CH2:20][CH3:21])=[CH:7][C:8](=[O:18])[O:9]2)=[C:4]2[O:22][C:23]([CH3:27])([CH3:26])[CH:24]=[CH:25][C:3]=12.N1C=CC=CC=1.[C:34]([Si:38](Cl)([CH3:40])[CH3:39])([CH3:37])([CH3:36])[CH3:35].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:1][C:2]1[C:11]([C@H:12]([O:17][Si:38]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:40])[CH3:39])[C@H:13]([CH3:16])[CH:14]=[CH2:15])=[C:10]2[C:5]([C:6]([CH2:19][CH2:20][CH3:21])=[CH:7][C:8](=[O:18])[O:9]2)=[C:4]2[O:22][C:23]([CH3:26])([CH3:27])[CH:24]=[CH:25][C:3]=12
Reactant: C=C[C@@H](C)[C@@H](O)c1c(O)c2c(c3c(CCC)cc(=O)oc13)OC(C)(C)C=C2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C[C@@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)c1c(O)c2c(c3c(CCC)cc(=O)oc13)OC(C)(C)C=C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.5 %

Procedure:
To a solution of 9 (1.44 g, 3.89 mmol) in dry CH2Cl2 (50 mL) at -20° C. was added pyridine (6 mL), DMAP (1.10 g, 9.00 mmol) and tert-butylchlorodimethylsilane (1.40 g, 9.28 mmol). The reaction mixture was stirred under nitrogen at room temperature for 1.5 h until disappearance of the starting material was observed. Water (15 mL) was then added, and the mixture was stirred for an additional 15 min. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2×15 mL). The combined organic layers were evaporated under reduced pressure at room temperature. The oil obtained was submitted to silica gel chromatography (solvent B) to obtain 10 (1.80 g, 95%) as a syrup: [α]D20 +26° (c 3.8, acetone); 1H NMR (CDCl3): δ -0.11, 0.08 (2s, 6H, --SiCH3), 0.80 [s, 9H, --C(CH3)3 ], 0.90 (d, 3H, J=6.90 Hz, --CHCH3), 0.96 (t, 3H, J=7.30 Hz, --CH2CH3), 1.39, 1.43 (2s, 6H, --C(CH3)2), 1.60 (m, 2H, --CH2CH3), 2.54 (m, 1H, --CHCH3), 2.80 (m, 2H, --CH2CH2CH3), 4.86-5.00 (m, 2H, --CH=CH2), 5.22 [d, 1H, J=6.85 Hz, --CHOSi(CH3)2 --], 5.46 (d, 1H, J=10.0 Hz, H-3), 5.68-5.87 (m, 1H, --CH=CH2), 5.83 (s, 1H, H-9), 6.59 (d, 1H, J=10.0 Hz, H-4), 9.20 (s, 1H, Ar--OH); 13C NMR (CDCl3): δ -0.42, -0.22, 13.90, 16.14, 17.95, 23.02, 25.58, 27.47, 27.90, 38.49, 44.45, 74.08, 77.49, 102.63, 106.65, 106.72, 110.00, 115.60, 116.51, 126.61, 139.63, 150.99, 151.69, 155.33, 158.33, 160.90; Anal. Calcd for C28H40O5Si: C, 69.38; H, 8.32. Found C, 68.55; H, 8.42. MS (negative-ion FAB): m/z 483 (M-1)-, 351, 297.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[O:13][CH:14]([CH2:16][CH3:17])[CH3:15].[Li+].[OH-]>C1COCC1.CO>[CH:14]([O:13][C:7]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=1[CH:5]=[CH:4][C:3]([OH:18])=[O:2])([CH2:16][CH3:17])[CH3:15]
Reactant: CCC(C)Oc1cc(F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(C)Oc1cc(F)ccc1C=CC(=O)O
Yield: 82.7 %

Procedure:
3-(2-sec-Butoxy-4-fluoro-phenyl)-acrylic acid methyl ester (105 mg) was reacted with 1N LiOH (5 ml) in THF and CH3OH for 2 hrs as described above to yield title compound (82 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=S)[NH:7][C:6]=2[CH:17]=1.[NH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>C(OCCO)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:7][C:6]=2[CH:17]=1
Reactant: NCc1cccnc1
Reactant: S=C1Nc2cc(Cl)ccc2Nc2ccccc21
Solvent: CCOCCO
Product: Clc1ccc2c(c1)N=C(NCc1cccnc1)c1ccccc1N2
Yield: 39.8 %

Procedure:
A solution of 0.39 g (1.5 mmol) of 8-chloro-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-thione (Hunziker F., et al., Helv. Chim. Acta, 50:1588 (1967)) in 10 mL of 2-ethoxyethanol was treated with 0.3 mL (2.99 mmol) of 3-(aminomethyl)pyridine and heated at reflux for 30 hours. The solvent was removed under reduced pressure and the residue mixed with EtOAc and filtered to give 200 mg of the product. The filtrate was chromatographed on silica gel, eluting with EtOAc to give an additional 200 mg of product. Total yield 400 mg (80% yield) of the product as a yellow solid, mp 230-234° C. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =335.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[F:21][CH:22]([F:29])[C:23]1[N:24]=[C:25]([NH2:28])[S:26][CH:27]=1>>[F:21][CH:22]([F:29])[C:23]1[N:24]=[C:25]([NH:28][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])[S:26][CH:27]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(F)c2)cc(C)n1
Reactant: Nc1nc(C(F)F)cs1
Product: Cc1cc(-c2cc(F)cc(F)c2)cc(C(=O)Nc2nc(C(F)F)cs2)n1

Procedure:
The title compound, was prepared from 4-(3,5-Difluorophenyl)-6-methyl-pyridine-2-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 4-Difluoromethyl-thiazol-2-ylamine instead of 3-chloroaniline to yield the final compound as a white solid, MS (ISP): m/e=382 [M]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10]C)=O)=[N:4][CH:5]=[CH:6][N:7]=1.[NH2:12][C@H:13]([C:18]([OH:20])=[O:19])[CH2:14][C:15]([OH:17])=[O:16].C(N(CC)CC)C>CS(C)=O>[O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]=[C:3]1[C:8]([NH:12][C@@H:13]([CH2:14][C:15]([OH:17])=[O:16])[C:18]([OH:20])=[O:19])=[O:10]
Reactant: COC(=O)c1nccnc1O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(O)C[C@H](NC(=O)c1ncc[nH]c1=O)C(=O)O
Temperature: 50 °C
Reaction time: 6 h
Yield: 17.4 %

Procedure:
In 4 mL of dimethyl sulfoxide is dissolved 0.4 g of methyl 3-hydroxy-2-pyrazinecarboxlate. Then, 0.27 g of L-aspartic acid and 0.85 mL of triethylamine are successively added to the solution, which is then stirred at 50° C. for 6 hours. The deposited crystals are filtered off, and the filtrate is concentrated under reduced pressure. Then, 2 mL of water and 0.2 mL of methanol are added to the resulting residue. The precipitate formed is collected by filtration to obtain 0.09 g of (2S)-2-{[(3-oxo-3,4-dihydro-2-pyrazinyl)-carbonyl]amino}-butanedioic acid.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[C:24]#[N:25])=[CH:13][CH:12]=2)[C:8]2[CH:26]=[CH:27][CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:30]=[N+:31]=[N-:32].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C)C=O.C(O)(=O)C.C(OCC)(=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[C:24]3[NH:32][N:31]=[N:30][N:25]=3)=[CH:15][CH:16]=2)[C:8]2[CH:26]=[CH:27][CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1nc2ccccc2n1Cc1ccc(-c2cc(Cl)ccc2C#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2cc(Cl)ccc2-c2nnn[nH]2)cc1

Procedure:
1.2 g of 2-n-butyl-1-{(5'-chloro-2'-cyanobiphenyl-4-yl)methyl}benzimidazole prepared in Preparation Example 8, 910 mg of sodium azide and 750 mg of ammonium chloride were heated while stirring in 50 ml of dimethylformamide as a reaction solvent at an internal temperature of 125° C. for 50 hr. After cooling, a dilute sodium hydroxide solution and ethyl acetate were added thereto for phase separation, thereby obtaining a watery phase. The watery phase was wealky acidified with acetic acid, extracted with chloroform and washed with water. The extract was dried over anhydrous magnesium sulfate, and the residue was subjected to silica gel chromatography (chloroform:etanol:acetic acid=98:2:0.2). A fraction of the intended title compound was concentrated and then recrystallized from ethyl acetate-isopropyl ethermethanol. The yield was 450 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:3]=1[C:4]([C:12]#[CH:13])([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H][H]>CO>[CH3:1][C:2]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:3]=1[C:4]([CH2:12][CH3:13])([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: C#CC(O)(c1ccccc1)c1cc(C)ccc1C
Solvent: CO
Product: CCC(O)(c1ccccc1)c1cc(C)ccc1C

Procedure:
10 g. of 5% palladium-on-calcium-carbonate catalyst are added to a solution of 94.5 g. of 2,5-dimethyl-α-ethynyl-benzhydrol in 900 ml. of methanol, and the mixture is hydrogenated until the uptake of the calculated amount of hydrogen (about 30 to 40 minutes). The catalyst is filtered off, the filtrate is evaporated, and the obtained crystalline residue is recrystallized from n-heptane. This way 80.7 g. of 2,5-dimethyl-α-ethyl-benzhydrol are obtained, m.p.: 38°-39° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([O:26]C)=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([N:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([OH:26])=[O:25])[CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)CC(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)CN(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(isobutyl(methyl)amino)quinoxaline-6-carboxylate (80 mg, 0.22 mmol) in methanol (20 mL) and water (1 mL) was added sodium hydroxide (34.8 mg, 0.87 mmol 1), and the reaction was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (10 mL), and adjusted to pH 5 with HCl (3N) to give the precipitate, which was collected by filtration to afford 2-(4-fluorophenyl)-3-(isobutyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (50.0 mg, 65%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:28]([OH:30])=[O:29])[CH2:20][NH:21]C(OCC=C)=O)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1([SiH3])C=CC=CC=1>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:21][CH2:20][C@@H:19]([C:28]([OH:30])=[O:29])[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17]
Reactant: C=CCOC(=O)NC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Product: NC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reaction time: 0.58 h

Procedure:
A mixture of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-3-[(2-propenyloxy)carbonyl]amino-L-alanine resin (Example 64; 2 g), tetrakis(triphenylphosphine)palladium(0) (509 mg, 0.45 mmol), and phenylsilane (21.9 mmol) in dichloromethane (20 Ml) was shaken for 35 min. The resin was washed with dichloromethane and methanol, then vortexed with dimethylformamide/water (1:1) at room temperature for 10 min, and washed again with dichloromethane and methanol to give 3-amino-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-alanine on Wang resin.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[CH3:27][O:28][C:29]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32]>C1COCC1>[CH3:27][O:28][C:29]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:30]=1[CH2:31][NH:32][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([I:11])[CH:9]=[CH:10][C:2]=1[Cl:1]
Reactant: O=C(O)c1cc(I)ccc1Cl
Reactant: COc1ccc(CN)c(OC)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: C1CCOC1
Product: COc1ccc(CNC(=O)c2cc(I)ccc2Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.2 %

Procedure:
2-Chloro-5-iodobenzoic acid (2 g, 7.08 mmol) in 25 mL THF was treated with 1,1′-carbonyldiimidazole (1.15 g, 7.08 mmol) at ambient temperature until CO2 evolution ceased (˜20 min). 2,4-Dimethoxybenzylamine (1.18 g, 7.08 mmol) was added and stirred at ambient temperature for 16 h. The reaction mixture was concentrated to dryness, partitioned between EtOAc and saturated NaHCO3, the organic phase isolated, dried over MgSO4, filtered and concentrated to give N-{[2,4-bis(methyloxy)phenyl]methyl}-2-chloro-5-iodobenzamide (3.00 g, 6.95 mmol) as a pale yellow oil that crystallized on standing. 1H NMR (300 MHz, CDCl3) d 7.95 (d, J=2.2 Hz, 1H), 7.62 (dd, J=8.5, 2.2 Hz, 1H), 7.25 (m, 1H), 7.10 (m, 1H), 6.63 (m, 1H), 6.45 (m, 2H), 4.55 (d, J=5.7 Hz, 2H), 3.83 (s, 3H), 3.80 (s, 3H). LCMS ES+ 431.82, 433.77 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[CH:16][CH:15]=2)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH:26]=C)[CH:4]=1)[CH3:2].I([O-])(=O)(=O)=[O:29].[Na+].C(#N)C.O>[Os]=O.CC(C)=O>[CH2:1]([C:3]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[CH:16][CH:15]=2)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH:26]=[O:29])[CH:4]=1)[CH3:2]
Reactant: C=Cc1cc(CC)c(Cc2ccc(-c3ccn(C)n3)cc2)cc1C(=O)OC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CC#N
Product: CCc1cc(C=O)c(C(=O)OC)cc1Cc1ccc(-c2ccn(C)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
A mixture of methyl 4-ethyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-2-vinylbenzoate (0.21 g), osmium oxide (fixed catalyst I) (0.08 g) and sodium periodate (0.64 g) in acetone (4.00 mL)-acetonitrile (4.00 mL)-water (4.00 mL) was stirred overnight at room temperature. The insoluble substance was removed by filtration, the filtrate was diluted with ethyl acetate, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.21 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]([F:29])([F:28])[C:11](=[O:27])[CH2:12][C:13]([CH3:26])([C:15]1[C:23]2[O:22][CH2:21][CH2:20][C:19]=2[CH:18]=[C:17]([S:24][CH3:25])[CH:16]=1)[CH3:14].O>CS(C)=O>[CH3:26][C:13]([C:15]1[C:23]2[O:22][CH2:21][CH2:20][C:19]=2[CH:18]=[C:17]([S:24][CH3:25])[CH:16]=1)([CH3:14])[CH2:12][C:11]1([C:10]([F:9])([F:28])[F:29])[CH2:2][O:27]1
Reactant: C[S+](C)(C)=O
Reactant: CSc1cc2c(c(C(C)(C)CC(=O)C(F)(F)F)c1)OCC2
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1cc2c(c(C(C)(C)CC3(C(F)(F)F)CO3)c1)OCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a suspension of trimethylsulfoxonium iodide (1.36 g) in anhydrous dimethylsulfoxide (7.7 mL) was added sodium hydride (60% dispersion in mineral oil, 246 mg). The resulting solution was stirred at room temperature for 30 minutes and was then added dropwise to a solution of 1,1,1-trifluoro-4-methyl-4-(5-methylsulfanyl-2,3-dihydrobenzofuran-7-yl)pentan-2-one (1.63 g) in anhydrous dimethylsulfoxide (6.5 mL). After 2 hours, water (100 mL) was added and the resulting mixture was extracted with three 100 mL portions of diethyl ether. The combined organic phases were washed twice with water, washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-5-methylsulfanyl-2,3-dihydrobenzofuran as a clear oil (1.64 g) which was used without further purification.
Reaction SMILES: [C:1]12([C:11]3[N:12]([CH2:22][C:23]([NH:25][C:26]([NH2:28])=[NH:27])=[O:24])[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:14][CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.[CH2:36]([S:38](Cl)(=[O:40])=[O:39])[CH3:37]>C(Cl)Cl>[C:1]12([C:11]3[N:12]([CH2:22][C:23](/[N:25]=[C:26](/[NH2:28])\[NH:27][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:24])[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:14][CH:15]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: N=C(N)NC(=O)Cn1c(-c2ccccc2)ccc1C12CC3CC(CC(C3)C1)C2
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N/C(N)=N\C(=O)Cn1c(-c2ccccc2)ccc1C12CC3CC(CC(C3)C1)C2
Reaction time: 0.21 h

Procedure:
A solution of 1 equivalent of N-[2-(2-adamantan-1-yl-5-phenyl-pyrrol-1-yl)-acetyl]-guanidine in 2.0 mL CH2Cl2 was cooled to 7° C. To the solution 1.0 equivalent of triethylamine was added. The reaction was stirred for 10-15 minutes, after which time ethylsulfonyl chloride was added. The reaction was concentrated and the residue is dissolved in a mixture of DMSO, MeOH and water (1.5 mL total) and purified by Gilson preparative HPLC system. HPLC conditions: YMC Pro C18 column, 20 mm×50 mm ID, 5 uM; 2 mL injection; Solvent A: Water (0.05% NH4OH buffer); Solvent B: acetonitrile (0.05% NH4OH buffer); Gradient: Time 0: 5% B; 2 min: 5% B; 12 min: 95% b, Hold 95% B 3 min; Flow rate 22.5 mL/min; Detection: 254 nm DAD. [M+H] 469, retention time 2.7 min.
Reaction SMILES: C([O:3][C:4](=[O:33])/[CH:5]=[CH:6]/[C@@:7]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([CH3:24])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=1)C.[OH-].[Li+].CCOC(C)=O.Cl>CO.C1COCC1.O>[C:29]([O:28][C:26]([NH:25][C@:7]([CH3:24])([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=1)/[CH:6]=[CH:5]/[C:4]([OH:33])=[O:3])=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CCCCCCCOc1ccc(CC[C@](C)(/C=C/C(=O)OCC)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(CC[C@](C)(/C=C/C(=O)O)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of (E)-(R)-4-tert-butoxycarbonylamino-6-(4-heptyloxy-phenyl)-4-methyl-hex-2-enoic acid ethyl ester (56 mg, 0.12 mMol) in methanol (0.5 ml), THF (0.5 ml) and water (0.5 ml) is added lithium hydroxide (14 mg, 0.61 mMol). The mixture is stirred at RT for 3.5 hours. The reaction mixture is then poured onto a biphasic mixture of AcOEt and HCl (aqueous, 1 M). The aqueous phase is extracted twice with AcOEt. The combined organic layers are washed with a small amount of NaHCO3 (saturated aqueous solution), dried (Na2SO4) and concentrated under reduced pressure to give the title compound. The crude product is sufficiently pure to be used in the next stage without further purification.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](O)=[O:41])=[CH:33][C:32]=2[CH3:43])=[C:28]([CH:44]([CH3:46])[CH3:45])[NH:27][N:26]=1)(=[O:3])[CH3:2].Cl.[NH2:48][C:49]([CH3:61])([CH3:60])[C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:41])[NH:48][C:49]([C:50]([O:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[O:51])([CH3:61])[CH3:60])=[CH:33][C:32]=2[CH3:43])=[C:28]([CH:44]([CH3:46])[CH3:45])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(N)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)NC(C)(C)C(=O)OCc3ccccc3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole (0.14 g) in N,N-dimethyl-formamide (3 mL) were added benzyl 2-amino-2-methylpropionate hydrochloride (57 mg), 1-hydroxybenzotriazole (31 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (60 mg) and triethylamine (0.087 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=40/1-20/1) to give the title compound (0.15 g).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14]2.[O:25]=[C:26]1[C:31]2[CH:32]=[C:33]([C:36](O)=[O:37])[CH:34]=[CH:35][C:30]=2[N:29]=[C:28]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:27]1>ClC(Cl)C>[CH3:8][O:9][C:10]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]([C:36]([C:33]2[CH:34]=[CH:35][C:30]3[N:29]=[C:28]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:27][C:26](=[O:25])[C:31]=3[CH:32]=2)=[O:37])[N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14]2
Reactant: COc1c(-c2ccccc2)cn2ccccc12
Reactant: O=C(O)c1ccc2nc(-c3ccccc3)oc(=O)c2c1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COc1c(-c2ccccc2)c(C(=O)c2ccc3nc(-c4ccccc4)oc(=O)c3c2)n2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
2.25 ml (16.12 mmol) of triethylamine and 3 g (13.44 mmol) of 1-methoxy-2-phenylindolizine (according to the method described in WO 03/084956) diluted in 20 ml of dichloroethane are added, under an inert atmosphere at ambient temperature, to 4.22 g (14.78 mmol) of 4-oxo-2-phenyl-4H-3,1-benzoxazine-6-carboxylic acid (described in WO 06/097625) in 100 ml of dichloroethane. After stirring overnight at ambient temperature, the reaction medium is filtered, and rinsed with dichloroethane. The filtrate is washed with water, dried over sodium sulphate, filtered, and concentrated under reduced pressure. The residue is filtered through a silica pâté, elution being carried out with dichloromethane. 4.4 g of a yellow solid are obtained.
Reaction SMILES: FC1C=CC(NC(=O)NC2C=CC(C3C=C4C(=CC=3)C(=O)N([C@@H](C(C)C)C(O)=O)C4)=CC=2)=CC=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44](=[O:70])[NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:53]=[C:54]4[C:58](=[CH:59][CH:60]=3)[C:57](=[O:61])[N:56]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[CH2:55]4)=[CH:48][CH:47]=2)=[CH:39][CH:38]=1>>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44](=[O:70])[NH:45][C:46]2[CH:47]=[CH:48][C:49]([C:52]3[CH:53]=[C:54]4[C:58](=[CH:59][CH:60]=3)[C:57](=[O:61])[N:56]([C@@H:62]([CH:67]([CH3:68])[CH3:69])[C:63]([OH:65])=[O:64])[CH2:55]4)=[CH:50][CH:51]=2)=[CH:39][CH:38]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(OC)cc4)cc3)ccc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Product: COc1ccc(NC(=O)Nc2ccc(-c3ccc4c(c3)CN([C@H](C(=O)O)C(C)C)C4=O)cc2)cc1
Yield: 95 %

Procedure:
The compound of example 249 was prepared analogous to compound of example 225 by hydrolysis of compound of example 248.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[OH:6][CH2:7][CH:8]([CH2:10]O)[OH:9].[OH-].[K+].C1(C=CC(O)=CC=1)O>S(=O)(=O)(O)O>[C:1]([O:5][CH2:10][CH:8]([CH2:7][OH:6])[OH:9])(=[O:4])[CH:2]=[CH2:3]
Reactant: OCC(O)CO
Reactant: C=CC(=O)O
Agent: O=S(=O)(O)O
Agent: Oc1ccc(O)cc1
Agent: [K+]
Product: C=CC(=O)OCC(O)CO

Procedure:
Using 0.3 g (0.003 mole) of sulfuric acid as a catalyst, 72 g (1 mole) of acrylic acid was reacted with 92 g (1 mole) of glycerol. The reaction mixture was neutralized with 0.34 g (0.006 mole) of potassium hydroxide, and 0.15 g (0.1 mass %) of hydroquinon was added as a stabilizer. Thus, glycerol monoacrylate (A1—1) was obtained.