Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O/[CH:4]=[CH:5]/[C:6]([NH:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:7])C.[OH-].[Na+]>>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:9]1[CH:4]=[CH:5][C:6](=[O:7])[NH:8]1
Reactant: CCO/C=C/C(=O)NNc1ccccn1
Agent: [Na+]
Agent: [OH-]
Product: O=c1ccn(-c2ccccn2)[nH]1

Procedure:
(2E)-3-Ethoxy-N′-pyridin-2-ylprop-2-enohydrazide (8.5 g, 41 mmol) was stirred with concentrated 37% HCl (20 mL) for 3 h. The resulting reaction mixture was adjusted to pH 7 using 1N NaOH (aq) and a precipitate formed. The reaction mixture then extracted with EtOAc (3×50 mL)and washed with brine. The combined organic phase was dried over Na2SO4, concentrated in vacuo purified using liquid chromatography on silica gel eluting with EtOAc (100%) to afford 1-pyridin-2-yl-1,2-dihydro-3H-pyrazol-3-one as a yellow solid. 1H NMR (CD3Cl, 300 MHz) δ 12.00 (br, 1H), 8.43˜8.39 (m, 2H), 7.85 (ddd, 1H), 7.64 (d, 1H), 7.16 (ddd, 1H), 5.99 (d, 1H). MS (ESI) 162 (M++H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](SC)=[N:6]2.CC1N=C(C2C=CC=CC=2)N2C=1C=NC(S(C)(=O)=O)=N2.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:47][C:44]1[CH:45]=[CH:46][C:41]([O:40][CH3:39])=[CH:42][CH:43]=1)=[N:6]2
Reactant: CSc1ncc2c(C)nc(-c3ccccc3)n2n1
Reactant: COc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1nc(-c2ccccc2)n2nc(S(C)(=O)=O)ncc12
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncc3c(C)nc(-c4ccccc4)n3n2)cc1
Yield: 23.2 %

Procedure:
A mixture of 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (Intermediate 72) (75 mg, 0.26 mmol), p-anisidine (32 mg, 0.26 mmol) and p-toluenesulfonic acid (5 mg, 0.03 mmol) in tetrahydrofuran (5 mL) was stirred at reflux overnight. The mixture was then reduced under vacuum, and purified by chromatography on silica gel eluting with 40% ethyl acetate in petrol to give a solid which was purified further by trituration with diethyl ether to afford 5-methyl-N-[4-(methyloxy)phenyl]-7-phenylimidazo[5,1-f][1,2,4]triazin-2-amine (20 mg) as a yellow solid. MS m/z 332 (M+1).
Reaction SMILES: O=[C:2]([CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH2:3][C:4]([O:6]CC)=O.[CH3:15][C:16]1[C:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[C:23]=2[CH3:32])=[C:19]([NH2:33])[NH:18][N:17]=1>C(O)(=O)C>[CH3:15][C:16]1[C:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[C:23]=2[CH3:32])=[C:19]2[N:33]=[C:2]([CH:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[CH:3]=[C:4]([OH:6])[N:18]2[N:17]=1
Reactant: Cc1n[nH]c(N)c1Cc1cccc(C(F)(F)F)c1C
Reactant: CCOC(=O)CC(=O)C1CCOCC1
Solvent: CC(=O)O
Product: Cc1nn2c(O)cc(C3CCOCC3)nc2c1Cc1cccc(C(F)(F)F)c1C
Temperature: 140 °C
Reaction time: 8 h

Procedure:
To a suspension of ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (98 mg, 0.49 mmol) in acetic acid (2 mL) was added 3-methyl-4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-5-amine (125 mg, 0.46 mmol), prepared as described in Example 1, step a, in microwave reaction vessel. It was sealed and heated with microwave reactor at 140° C. for 40 minutes. The reaction mixture was cooled, diluted with acetic acid (2 mL) and stood for overnight. Precipitate was observed, filtered. Solid was washed with cooled methanol. Solid was dried. The titled compound was obtained. (75 mg, 38%) LC/MS: MS (ES+) m/e 406 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.80 (m, 4H) 2.05 (s, 3H) 2.46 (s, 3H) 2.75 (s, 1H) 3.37 (td, J=11.68, 2.40 Hz, 2H) 3.95 (d, J=14.40 Hz, 2H) 3.99 (s, 2H) 5.57 (s, 1H) 7.00 (d, J=7.33 Hz, 1H) 7.28 (t, J=7.45 Hz, 1H) 7.55 (d, J=7.58 Hz, 1H) 11.59 (d, J=1.01 Hz, 1H).
Reaction SMILES: C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[N:30]1[CH:35]=[C:34]([C:36]([NH:38][C:39]2([C:42]([OH:44])=O)[CH2:41][CH2:40]2)=[O:37])[CH:33]=[N:32][CH:31]=1.[Br:45][C:46]1[CH:60]=[CH:59][C:49]([O:50][C:51]2[CH:58]=[CH:57][C:54]([CH2:55][NH2:56])=[CH:53][CH:52]=2)=[C:48]([Cl:61])[CH:47]=1>CN(C=O)C>[Br:45][C:46]1[CH:60]=[CH:59][C:49]([O:50][C:51]2[CH:58]=[CH:57][C:54]([CH2:55][NH:56][C:42]([C:39]3([NH:38][C:36]([C:34]4[CH:33]=[N:32][CH:31]=[N:30][CH:35]=4)=[O:37])[CH2:40][CH2:41]3)=[O:44])=[CH:53][CH:52]=2)=[C:48]([Cl:61])[CH:47]=1
Reactant: NCc1ccc(Oc2ccc(Br)cc2Cl)cc1
Reactant: O=C(NC1(C(=O)O)CC1)c1cncnc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1(C(=O)NCc2ccc(Oc3ccc(Br)cc3Cl)cc2)CC1)c1cncnc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
7 μL (0.05 mmol) of triethylamine and 8.4 mg (0.03 mmol) of TBTU were added to a solution of 5.4 mg (0.03 mmol) of 1-[(pyrimidin-5-carbonyl)-amino]-cyclo-propanecarboxylic acid (from 1b) in 1 mL DMF and stirred for 5 min at RT. Then 8 mg (0.03 mmol) of 4-(4-bromo-2-chloro-phenoxy)-benzylamine was added and the mixture was stirred overnight at ambient temperature. The reaction mixture was purified by chromatography (reversed phase).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[NH:23]([C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: Nc1ccc2ccc(Nc3ccccc3)nc2n1
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)Nc2ccc3ccc(Nc4ccccc4)nc3n2)cc1
Temperature: 4 °C
Yield: 41 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with 4-methoxybenzoic acid (6.1 g), N,N'-carbonyldiimidazole (6.5 g) and 2-amino-7-anilino-1,8-naphthyridine (7 g). The product obtained by precipitation in water (12 g) is dissolved in boiling ethanol (140 cc). After cooling for 1 hour at 4° C., the crystallized solid is separated by filtration, washed with ethanol (10 cc), and dried at 45° C. under reduced pressure (0.07 kPa). N-(7-Anilino-1,8-naphthyridin-2-yl)-4-methoxybenzamide (4.5 g), m.p. 245° C., is obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[OH-].[K+].Cl.[CH:18]12[NH:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][CH2:19]2>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:24]2[CH:18]3[CH2:23][CH2:22][CH:21]2[CH2:20][CH2:19]3)=[CH:3][C:4]=1[C:11]([F:14])([F:13])[F:12])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Reactant: C1CC2CCC1N2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N2C3CCC2CC3)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
To 4-fluoro-1-nitro-2-(trifluoromethyl)benzene (8) dissolved in 3 vol DCM, tetrabutylammoniumbromide (0.05 eq) and 50 wt % KOH (3.6 eq) were added. 7-azabicyclo[2.2.1]heptane hydrochloride (9) was then added at 0-5° C. The reaction was warmed to ambient temperature. The reaction was monitored by HPLC, and when the substrate was <1% AUC, the reaction was considered complete, and the layers are separated. The organic layer was washed with 1M HCl, and the aqueous layer was discarded. The organic layer was then washed once with water, once with brine, and evaporated. The resulting material was recrystallized from cyclohexane at reflux. The solid was filtered, washed with cyclohexane, and dried in a vacuum oven at 45° C. under a nitrogen atmosphere to provide 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(NCC)C.CCN=C=NCCCN(C)C.Cl.[C:37]([N:44]([CH2:52][C:53]1[N:54]=[CH:55][C:56]([C:59](O)=[O:60])=[N:57][CH:58]=1)[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1)([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:37]([N:44]([CH2:52][C:53]1[N:54]=[CH:55][C:56]([C:59]([NH:16][C@H:15]([C:17]([OH:19])=[O:18])[CH2:14][CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])=[O:60])=[N:57][CH:58]=1)[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1)([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1cnc(C(=O)O)cn1
Reactant: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1cnc(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)O)cn1
Reaction time: 1 h

Procedure:
The compound obtained in Example 8-6 (160 mg) was dissolved in DMF (3.2 ml) and diethylamine (0.32 ml) was added. After one hour, the reaction solution was concebtrated and the residue obtained was dissolved in DMF (1 ml). Then, WSCI hydrochloride (73 mg), DMAP (31 mg), and a solution of the compound obtained in Example 13-3 in DMF (1 ml) were sequentially added. After 15 hours, the reaction solution was concentrated. After the addition of chloroform and 1 mol/l hydrochloric acid, the residue was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was crude-purified by silica gel column chromatography (4 g, chloroform/ethyl acetate=1/2) to obtain the title compound (95.2 mg) as colorless syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:21](O)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:25][O:26][C:27]1[CH:31]=[C:30]([CH2:32][NH2:33])[O:29][N:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:17])[F:18])=[CH:12][N:11]=[C:10]([C:21]([NH:33][CH2:32][C:30]3[O:29][N:28]=[C:27]([O:26][CH3:25])[CH:31]=3)=[O:22])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(CN)on1
Reactant: C[C@H](Oc1cnc(C(=O)O)cc1-c1ccc(Cl)cc1)C(F)(F)F
Agent: Cl
Product: COc1cc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(O[C@@H](C)C(F)(F)F)cn2)on1

Procedure:
The title compound was synthesized in analogy to Example 1, using (S)-4-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)picolinic acid (example AR) and 3-methoxy-5-isoxazolemethanamine hydrochloride as starting materials. MS: 456.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([C:13]1[C:18]([F:19])=[C:17](F)[N:16]=[C:15]([F:21])[C:14]=1[F:22])[C:3]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][C:32]=1[OH:39])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C.C(OCC)(=O)C>[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][C:32]=1[O:39][C:17]1[C:18]([F:19])=[C:13]([N:2]([CH3:1])[C:3]2([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]2)[C:14]([F:22])=[C:15]([F:21])[N:16]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)C1(N(C)c2c(F)c(F)nc(F)c2F)CCCC1
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1(N(C)c2c(F)c(F)nc(Oc3cc(C#N)ccc3OCc3ccccc3)c2F)CCCC1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To a solution of 4-(N-methyl-N-(1-ethoxycarbonylcyclopent-1-yl)amino)-2,3,5,6-tetrafluoropyridine (0.89 g, 2.8 mmol) in acetonitrile (30 mL) was added 2-benzyloxy-5-cyanophenol (0.63 g, 2.8 mmol) and cesium carbonate (1.2 g, 3.6 mmol). The resultant mixture was stirred at 60° C. for 1 day. The mixture was then cooled to ambient temperature and poured into 100 mL of water and 100 mL of ethyl acetate. The aqueous layer was separated and extracted with another 100 mL of ethyl acetate. The combined organic extracts were washed with 1M aqueous KOH solution (100 mL), brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford a yellow oil. Purification by flash chromatography on silica gel afforded 0.87 g (60% yield) of 4-benzyloxy-3-[(4-(N-methyl-N-(1-ethoxycarbonylcyclopent-1-yl)amino)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile, a compound of formula (G), as a clear, colorless oil: NMR (CDCl3) 7.6-7.1 (m, 8), 5.2 (s, 2), 4.2 (q, 2), 3.1 (s, 3), 2.3-1.6 (m, 8), 1.3 (t, 3) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=O)[CH2:5][Cl:6].[BH4-].[Na+].Cl.[O:16]1CCOCC1>O>[OH:16][C:2]1([Cl:1])[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][CH:3]1[CH2:4][CH2:5][Cl:6]
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: C1COCCO1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: OC1(Cl)C=C(Cl)C=CC1CCCl
Reaction time: 2 h

Procedure:
To a solution of 52 g (0.23 m) of 2,4-dichlorophenacyl chloride in 200 ml of dioxane is added 9 g (0.24 m) of sodium borohydride dissolved in 60 ml of water dropwise at 50°. The addition is set at such a rate that the reaction temperature does not exceed 50°. After the addition, the reaction mixture is stirred at 50° for 11/2 hours. Excess sodium borohydride is carefully decomposed by slow addition of 10% hydrochloric acid. The organic product is extracted into ether and the combined ether extracts are washed with water, saturated sodium bicarbonate solution, and dried over MgSO4. Solvent is evaporated to give 49 g of product.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:9]([CH:11]2[CH2:13][CH2:12]2)[OH:10])=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8]>ClCCl.O=[Mn]=O>[CH3:1][C:2]1[C:3]([C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1c(Cl)ccnc1C(O)C1CC1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1c(Cl)ccnc1C(=O)C1CC1
Yield: 98.2 %

Procedure:
A solution of (3-methyl-4-chloro-pyridin-2-yl)-cyclopropyl-methanol (7.01 g, 35.5 mmol) in dichloromethane (80 mL) was treated with MnO2 (30.8 g, 355 mmol) at room temperature overnight. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated to dryness, affording the title compound (6.82 g, 98%). ESI-MS m/z: 196 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ ppm: 8.41 (d, J=5.4 Hz, 1H), 7.42 (d, J=5.4 Hz, 1H), 2.96-3.04 (m, 1H), 2.57 (s, 3H), 1.20-1.28 (m, 2H), 1.14-1.09 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:9][C:6]([CH:7]=O)=[C:5]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[CH:4]=1.[C:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=1)(=[O:29])[CH3:28]>>[CH3:1][O:2][C:3]1[C:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:9][C:6](/[CH:7]=[CH:28]/[C:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=2)=[O:29])=[C:5]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[CH:4]=1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COCCOCCOCCOc1cc(OC)c(-c2cccs2)cc1C=O
Product: COCCOCCOCCOc1cc(OC)c(-c2cccs2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Yield: 82 %

Procedure:
The title compound was prepared by condensing 4-methoxy-2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-5-thiophen-2-yl-benzaldehyde (Ex-68B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 137–138° C., 82% yield. 1H-NMR (300 MHz, DMSO-d6) δ 8.20–8.23 (m, 3H), 8.09 (d, 2H, J=8.3 Hz), 8.01 (m, 2H), 7.66 (d, 1H, J=3.6 Hz), 7.52 (d, 1H, J=5.1 Hz), 7.13 (dd, 1H, J=5.1, 3.6 Hz), 6.88 (s, 1H), 4.37 (t, 2H, J=3.6 Hz), 4.01 (s, 3H), 3.89 (t, 2H, J=3.6 Hz), 3.64–3.67 (m, 2H), 3.53–3.56 (m, 2H), 3.47–3.50 (m, 2H), 3.36–3.95 (m, 2H), 3.19 (s, 3H). MS (ESI) m/z=527 ([M+H]+, 100%). Anal. Calcd. for C28H30O8S: C, 63.86; H, 5.74; S, 6.09. Found: C, 64.08; H, 5.77; S, 6.09.
Reaction SMILES: [Mg].BrCC[C@H](C)CCCC(C)C.BrC[C@@H](C)CCOC1CCCCO1.[CH3:26][C@H:27]([CH2:37][CH2:38][CH2:39][C@H:40]([CH3:47])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:28][CH2:29][O:30]C1CCCCO1>O1CCCC1>[CH3:26][C@H:27]([CH2:37][CH2:38][CH2:39][C@H:40]([CH3:47])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:28][CH2:29][OH:30]
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCOC1CCCCO1
Agent: CC(C)CCC[C@@H](C)CCBr
Agent: C[C@H](CBr)CCOC1CCCCO1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCO
Reaction time: 3 h

Procedure:
A Grignard solution is prepared in the manner described above in Example 10 from 0.3 g (12.4 mmol) of magnesium and 2.54 g (11.5 mmol) of (R)-1-bromo-3,7-dimethyloctane in 10 ml of absolute tetrahydrofuran. To this solution are added dropwise at 0° 1.45 g (5.57 mmol) of 2-[(S)-4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran followed by 0.3 ml. of a 0.1 molar solution of Li2CuCl4 in tetrahydrofuran. This reaction mixture is stirred at 0° for 3 hours. The working-up as well as the hydrolysis of the tetrahydro-2-{[(3R,7R)-3,7,11-trimethyldodecyl]-oxy}-2H-pyran obtained to (3R,7R)-3,7,11-trimethyl-1-dodecanol is effected in the manner described above in Example 10. The yield of (3R,7R)-3,7,11-trimethyl-1-dodecanol amounts, after bulb-tube distillation at 90°-95°/0.05 Torr, to 0.5 g (43% based on 2-[ (S)-4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran); [α]D20 = +3.9° (c = 1.05, n-octane).
Reaction SMILES: C([O:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][O:13][CH2:14][C@@H:15]1[CH2:19][C@H:18]([F:20])[CH2:17][N:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[C:24]([O:23][C:21]([N:16]1[CH2:17][C@@H:18]([F:20])[CH2:19][C@H:15]1[CH2:14][O:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1COC/C=C\COCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1COCCCCO
Reaction time: 14 h
Yield: 68.6 %

Procedure:
In ethanol (200 ml) were suspended (Z)-(2S,4S)-2-(4-benzyloxy-2-butenyloxymethyl)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine (4.58 g, 12.1 mmol) and 20% palladium hydroxide (4.0 g). The resulting suspension was subjected to catalytic hydrogenation at room temperature under normal pressure for 14 hours. The catalyst was then filtered off and the filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 100 g), whereby from chloroform/acetone (10/1) eluate fractions, the title compound (2.42 g, 67%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(=O)c1cccc(C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(=O)c1cccc(CBr)c1
Yield: 95.2 %

Procedure:
3′-Methylpropiophenone (2.38 g; 16.1 mmol), N-bromosuccinimide (2.78 g; 16.1 mmol), and benzoyl peroxide (0.20 g) were added to carbon tetrachloride (60 ml), and the mixture was heated under reflux for 3 hours. The mixture was brought to room temperature, and insoluble matter was filtered off. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1), to thereby yield 3.48 g of the target compound as pale yellow oily, matter (yield: 95.2%). 1H-NMR (CDCl3, ppm); 1.23 (3H, t, J=1.89 Hz), 3.01 (2H, q, J=1.89 Hz), 4.53 (3H, s), 7.42˜7.70 (2H, m), 7.79˜8.13 (2H, m).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([OH:13])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][Cl:25]>CN(C)C=O>[Cl:25][CH2:24][CH2:23][CH2:22][CH2:21][N:10]1[CH:11]=[CH:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]1=[O:13]
Reactant: ClCCCCBr
Reactant: Oc1nccc(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1nc(-c2ccccc2)ccn1CCCCCl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.84 g (4.20 mmol) of 4-phenylpyrimidin-2-ol from Example 24.2 was stirred in 8.4 ml of N,N-dimethylformamide (DMF) and 0.58 g (4.20 mmol) of K2CO3 at room temperature for 1 hour. Then 0.72 g (4.20 mmol) of 1-bromo-4-chlorobutane was added dropwise, the reaction mixture was stirred at room temperature for 12 hours, and the reaction mixture was filtered and concentrated. The residue was then taken up in toluene and concentrated, and the residue was again taken up in toluene and concentrated. The resulting residue was stirred with pentane and filtered. Yield: 0.74 g.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][C:10]([O:12][C@H:13]1[CH2:32][C@@:31]2([CH3:33])[C@@H:24]([CH2:25][CH2:26][C@@H:27]2[C:28](=[O:30])[CH3:29])[C@H:23]2[C@H:14]1[C@:15]1([CH3:35])[C@@H:20]([CH2:21][CH2:22]2)[CH2:19][C:18](=[O:34])[CH2:17][CH2:16]1)=[O:11]>O.O.Cl.Cl.Cl[Ir](Cl)(Cl)Cl>[Cl:8][CH2:9][C:10]([O:12][C@H:13]1[CH2:32][C@@:31]2([CH3:33])[C@@H:24]([CH2:25][CH2:26][C@@H:27]2[C:28](=[O:30])[CH3:29])[C@H:23]2[C@H:14]1[C@:15]1([CH3:35])[C@@H:20]([CH2:21][CH2:22]2)[CH2:19][C@H:18]([OH:34])[CH2:17][CH2:16]1)=[O:11]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3[C@@H](OC(=O)CCl)C[C@]12C
Agent: Cl[Ir](Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@@H](OC(=O)CCl)C[C@]12C
Yield: 84.8 %

Procedure:
Chloroiridic acid reagent (10 ml) was neutralised to pH7 with triethylamine (1.1 ml), and to it was added 11β-chloroacetoxy-5α-pregnane-3,20-dione (880 mg). The solution was refluxed for 4 hours, and then cooled and diluted with water. The oily precipitate was extracted into ether/ethyl acetate, and the organic layer was washed with water, dried over sodium sulphate and evaporated to a yellow foam (875 mg) which was purified by preparative TLC in ethyl acetate/petrol (1/1) to give title compound (750 mg) as a white foam, [α]D +100° (c 0.62%).
Reaction SMILES: C([O:5][C:6](=[O:70])[C@H:7]([CH2:62][C:63]([O:65]C(C)(C)C)=[O:64])[NH:8][C:9](=[O:61])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:60])[CH2:18][CH2:19][S:20][CH2:21][CH:22]([O:42][C:43](=[O:59])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:23][O:24][C:25](=[O:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>>[C:43]([O:42][CH:22]([CH2:23][O:24][C:25](=[O:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:21][S:20][CH2:19][CH2:18][C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][C@H:7]([C:6]([OH:70])=[O:5])[CH2:62][C:63]([OH:65])=[O:64])=[O:61])=[CH:11][CH:12]=1)=[O:60])(=[O:59])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](CC(=O)O)C(=O)O)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To (4-(6,7-bis(palmitoyloxy)-4-thiaheptanoylamino)benzoyl)aspartic acid di-t-butyl ester as obtained in Example 21 (197 mg), trifiuoroacetic acid (5 ml) was added, followed by stirring at room temperature for 4 hours. The mixture was concentrated to yield the title compound (170 mg, yield 97%) as a colorless crystal.