Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:8]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:10](=[O:19])[C@@H:9]2[CH2:20][CH2:21][C@@H:22]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[OH:23])[CH:5]=[CH:6][CH:7]=1.[OH:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:11]2[C@H:8]([C:4]3[CH:3]=[C:2]([C:35]4[CH:36]=[CH:37][C:32]([OH:31])=[CH:33][CH:34]=4)[CH:7]=[CH:6][CH:5]=3)[C@@H:9]([CH2:20][CH2:21][C@@H:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[OH:23])[C:10]2=[O:19])=[CH:13][CH:14]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2cccc(Br)c2)N1c1ccc(F)cc1
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2cccc(-c3ccc(O)cc3)c2)N1c1ccc(F)cc1
Yield: 62.5 %

Procedure:
(3R,4S)-4-(3-Bromophenyl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (42 mg, 0.089 mmol) was coupled with 4-hydroxyphenyl boronic acid (18 mg, 0.13 mmol) under standard Suzuki conditions illustrated by Example 42. Purified by chromatography (silica gel, 10% to 90% ethyl acetate-hexane) to afford (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4′-hydroxybiphenyl-3-yl)azetidin-2-one (27 mg, 63% yield); Rf 0.31 (1:1 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.54-7.37 (m, 6H), 7.32-7.22 (m, 4H), 7.04-6.87 (m, 6H), 5.24 (br s, 1H), 4.72 (t, J=6.0 Hz, 1H), 4.67 (d, J=2.4 Hz, 1H), 3.17 (ddd, J=5.3, 2.5, 2.4 Hz, 1H), 2.26 (br s, 1H), 2.09-1.88 (m, 4H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:10][C:11]#C.[F-].[Cs+].[CH2:15](OCC)C>CCN(C1C=CC=CC=1)CC>[Br:1][C:2]1[C:3]2[O:9][C:10]([CH3:11])=[CH:15][C:4]=2[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: C#CCOc1cc(F)ccc1Br
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(CC)c1ccccc1
Product: Cc1cc2c(F)ccc(Br)c2o1
Yield: 89 %

Procedure:
A suspension of 57 g (250 mmol) of 1-bromo-4-fluoro-2-prop-2-ynyloxy-benzene and 53 g (350 mmol) of caesium fluoride in 400 ml of diethylaniline was heated at reflux in a metal bath for 4 hours. After cooling to room temperature 1500 ml of diethyl ether were added thereto and the insoluble constituents were filtered off. The diethyl ether phase was washed three times with 600 ml of 1N hydrochloric acid, dried over sodium sulfate and concentrated in a vacuum. The crude product obtained was purified by column chromatography on silica gel (hexane). 51.4 g (89%) of 7-bromo-4-fluoro-2-methylbenzofuran were obtained as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([CH:9]1[CH2:13][CH2:12][N:11]([CH3:14])[C:10]1=[O:15])=[O:8].[C:17]([C:20]1[S:24][C:23](B(O)O)=[CH:22][CH:21]=1)(=[O:19])[CH3:18].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:17]([C:20]1[S:24][C:23]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:16]=2)[C:7]([CH:9]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10]2=[O:15])=[O:8])=[CH:22][CH:21]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)c1ccc(B(O)O)s1
Reactant: CN1CCC(C(=O)c2cncc(Br)c2)C1=O
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)c1ccc(-c2cncc(C(=O)C3CCN(C)C3=O)c2)s1
Temperature: 85 °C
Yield: 50 %

Procedure:
A mixture of 3-(5-bromonicotinoyl)-1-methylpyrrolidin-2-one 3 (1 equiv), 5-Acetyl-2-thiopheneboronic acid (1.2 equiv), 1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium(II) complex with DCM (0.1 equiv) and 2M Na2CO3 (4 equiv) in toluene/1,4-dioxane (4:1, 15 volumes) was degassed and filled with nitrogen. Then the reaction mixture was heated to 85° C. and maintained for 2 h. After completion of the reaction filtered through Celite bed and washed with ethyl acetate. The combined organic layer was dried over with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude residue which was purified by silica-gel column chromatography using 2% MeOH/DCM as an eluent to afford 50% yield of titled compound.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH:17]([OH:26])[CH2:18][CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[C:1]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([OH:26])[CH2:18][CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccc(C#CC(O)CCc2cccnc2)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C(c1ccccc1)c1ccc(CCC(O)CCc2cccnc2)cc1
Reaction time: 18 h

Procedure:
Prepared according to the method as described in Example 55g) from (±)-1-(4 -benzoylphenyl)-5-(3-pyridyl)pent-1-yn-3-ol (0.6 g) in ethanol (10 ml), hydrogenated at 1.5 atmospheres for 18 hours using palladium on carbon (10%, 0.05 g). The residue was purified by column chromatography over silica with dichloromethane:ethanol (95:5) to give the title compound as an off white gum (0.387 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([OH:23])[CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21].ClC1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[O:23][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=1
Reactant: CCOC(=O)c1cc(Cl)ccn1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(Oc2ccc([N+](=O)[O-])c(F)c2)ccn1
Temperature: 120 °C
Reaction time: 4 h
Yield: 40.3 %

Procedure:
To ethyl 4-chloropyridine-2-carboxylate (19.4 g) were added 3-fluoro-4-nitrophenol (24.7 g) and chlorobenzene (7.0 ml), followed by heating and stirring under a nitrogen atmosphere at 120° C. for 4 hr. The reaction mixture was allowed to cool down to room temperature. Ethyl acetate (400 ml) and a saturated aqueous solution of sodium hydrogencarbonate (400 ml) were added thereto, followed by stirring at room temperature for 27 hr. Stirring was stopped and the aqueous layer was separated. To the organic layer was added again a saturated aqueous solution of sodium hydrogencarbonate, followed by stirring at room temperature for 2 days. Stirring was stopped and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate (300 ml). The organic layers were combined and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:1, 1:1, then ethyl acetate). Fractions containing the target compound were concentrated to provide the titled compound as a brown oil (12.9 g, 40.2%).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6][CH2:5]1.[NH:18]1[C:26]2[CH2:25][CH2:24][CH2:23][C:22](=[O:27])[C:21]=2[CH:20]=[CH:19]1.[OH-].[Na+].C(OCC)(=O)C>CS(C)=O.ClCCl>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][N:18]2[C:26]3[CH2:25][CH2:24][CH2:23][C:22](=[O:27])[C:21]=3[CH:20]=[CH:19]2)[CH2:5][CH2:6]1
Reactant: O=C1CCCc2[nH]ccc21
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccccc1N1CCN(CCn2ccc3c2CCCC3=O)CC1
Temperature: 0 °C

Procedure:
A mixture of 1-(2-Chloroethyl)-4-(2-methoxyphenyl)piperazine (7.30 g) was dissolved in DMSO (30 mL), then slowly added to 1,5,6,7-tetrahyro-indol-4-one (30.1 mmol) which was pretreated with sodium hydroxide (31.6 mmol) in DMSO (15 mL) for 0.5 h with slight heat. The reaction was left under heat and was monitored by TLC (ethyl acetate: dichloromethane, 1:1). After completion (8 h), the reaction mixture was poured in ice water (300 mL) and extracted with dichloromethane twice, dried with sodium sulfate and solvent removed under vacuum. Flash chromatography (ethyl acetate: dichloromethane, 1:4) yielded an oil, NEO-377 (7.25 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[CH2:13]([O:15][C:16]([N:18]1[CH2:33][CH2:32][C:22]2[C:23]3[C:24](=[O:31])[CH2:25][CH2:26][C:27]=3[C:28]([I:30])=[CH:29][C:21]=2[CH2:20][CH2:19]1)=[O:17])[CH3:14]>C1COCC1>[CH2:13]([O:15][C:16]([N:18]1[CH2:33][CH2:32][C:22]2[C:23]3[C:24]([OH:31])([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)[CH2:25][CH2:26][C:27]=3[C:28]([I:30])=[CH:29][C:21]=2[CH2:20][CH2:19]1)=[O:17])[CH3:14]
Reactant: CCOC(=O)N1CCc2cc(I)c3c(c2CC1)C(=O)CC3
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)N1CCc2cc(I)c3c(c2CC1)C(O)(c1cccnc1)CC3
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 3-bromopyridine (0.11 ml, 1.13 mmol) in THF (5 ml) under Ar at −78° C., n-BuLi (2.5 M in hexane, 0.45 ml, 1.13 mmol) was added. The mixture was stirred at −78° C. for 20 minutes, followed by dropwise addition of Intermediate 1 (0.15 g, 0.38 mmol) in THF (5 ml). The mixture was stirred for 2 h at −78° C., allowed to warm to room temperature, and quenched by slow addition of aqueous saturated NH4Cl (50 ml). The mixture was extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried (Na2SO4), and solvent evaporated in vacuo to give the sub-title compound as tan oil that was used without further purification. MS: ESI (positive): 479 (M+1).
Reaction SMILES: [N:1]1([C:7]2[NH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10][N:11]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:15][O:14][C:12]([C:9]1[NH:8][C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:16])[CH2:3][CH2:2]2)=[N:11][N:10]=1)=[O:13]
Reactant: COC(=O)c1nnc(N2CCNCC2)[nH]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nnc(N2CCN(C(=O)OC(C)(C)C)CC2)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of methyl 5-(piperazin-1-yl)-4H-1,2,4-triazole-3-carboxylate (1.0 g, 4.44 mmols) in DCM (10 mL) was added (BOC)2O (0.970 g, 4.44 mmol), DMAP (0.050 g, 0.41 mmol), DIEA (3.9 mL, 22.4 mmol). The reaction was stirred at RT overnight. Reaction concentrated and ISCO purification (0-5% MeOH in DCM) to obtain tert-butyl 4-(5-(methoxycarbonyl)-4H-1,2,4-triazol-3-yl)piperazine-1-carboxylate (0.580 g).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[O:32]1[C:36]2[CH2:37][NH:38][CH2:39][CH2:40][C:35]=2[C:34]([OH:41])=[N:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:38]5[CH2:39][CH2:40][C:35]6[C:34]([OH:41])=[N:33][O:32][C:36]=6[CH2:37]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:30])[F:31])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: Oc1noc2c1CCNC2
Product: O=C1N=C(N2CCc3c(O)noc3C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(3-hydroxy-4,7-dihydroisoxazolo[5,4-c]pyridin-6(5H)-yl)-1,3-thiazol-4(5H)-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 4,5,6,7-Tetrahydro-isoxazolo[5,4-c]pyridin-3-ol following general procedure C.
Reaction SMILES: CN.[OH2:3].Cl.Cl[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12](Cl)=[O:13])[CH:7]=1>C1(C)C=CC=CC=1>[N:9]1[CH:10]=[CH:11][CH:6]=[CH:7][C:8]=1[C:12]([OH:13])=[O:3]
Reactant: O=C(Cl)c1cc(Cl)ccn1
Reactant: O
Agent: CN
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccn1
Temperature: -5 °C

Procedure:
A reaction vessel is laden with methylamine as a 40% aqueous solution (117 kg, 1507 mol of methylamine). Water (97.5 kg) is added and the solution is cooled to −5° C. A solution of the crude 4-chloropyridine-2-carbonyl chloride hydrochloride (approx. 330 kg, including toluene, obtained from 60 kg of 2-picolinic acid by the process detailed in stage 1/method 1a) in toluene is added to such a degree that the temperature of the reaction mixture does not exceed 30° C. After stirring further at 20° C. for 1 h, the insoluble constituents are filtered out of the reaction mixture. After the phases have been separated, the organic phase is washed with water (90 kg). For better phase separation, 5 kg of sodium chloride are added. The majority of the toluene is distilled out of the organic phase under reduced pressure (final vacuum 40 mbar at jacket temperature 95° C.). The crude 4-chloro-N-methylpyridine-2-carboxamide is thus obtained as an orange- to dark brown-colored oil and is used in the next stage without further purification.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:7][C:8]=1[CH3:9])[NH2:2].C(N(CC)CC)C.[C:23](Cl)(=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCOCC1>[CH3:9][C:8]1[C:3]2[N:4]([C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:2][N:1]=2)[N:5]=[C:6]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH:7]=1
Reactant: Cc1cc(N2CCOCC2)nnc1NN
Reactant: O=C(Cl)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCOCC2)nn2c(-c3ccccc3)nnc12

Procedure:
1.48 Grams of 3-hydrazino-4-methyl-6-morpholinopyridazine and 1.8 grams of triethylamine are dissolved in 200 milliliters of dioxane. 3.5 Grams benzoyl chloride are added to the resulting mixture, and the mixture is heated at the boiling temperature under reflux for 3 hours. The mixture is evaporated to dryness, and the 8-methyl-6- -morpholino-3-phenyl-s-triazolo[4,3-b]pyridazine product is obtained as a residue. The product is washed with water, recrystallized from ethanol and found to melt at a temperature of 271°-273° C. 3.6 Grams of the product are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][CH:14]([CH:18]=[CH:19][CH3:20])[CH2:15][CH2:16][OH:17]>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:17][CH2:16][CH2:15][CH:14]([CH3:13])[CH:18]=[CH:19][CH3:20])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC=CC(C)CCO
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CC=CC(C)CCOC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of freshly crystallized 4-nitrobenzoyl chloride (10.1 g, 54.5 mmol) in CH2Cl2 (ml 20) was added dropwise to a solution of 3-methyl-hex-4-en-1-ol (5.4 g, 47.5 mmol) and TEA (8.6 ml, 61.8 mmol) in CH2Cl2 (ml 50) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 1 h and poured in ice/water (100 g). The CH2Cl2 was separated and the water phase was extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product was distilled at 171-173° C. 4 mmHg to give the title compound as yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([CH:20]=[O:21])[C:5]2[CH:6]=[CH:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1.[CH3:24][Mg+].[Br-]>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([CH:20]([OH:21])[CH3:24])[C:3]=1[O:22][CH3:23]
Reactant: COc1c(F)cc2c(ccn2S(=O)(=O)c2ccccc2)c1C=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1c(F)cc2c(ccn2S(=O)(=O)c2ccccc2)c1C(C)O
Reaction time: 0.33 h

Procedure:
A solution of crude 6-fluoro-5-methoxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (72.3 mg, 217 μmol) in THF (2 mL) was treated with MeMgBr (310 μL of a 1.4 M solution in Toluene/THF, 2 eq) at rt and stirred for 20 min (50% conversion). After 20 min another 2 eq Grignard solution were added and stirring continued for 15 min. The reaction mixture was quenched with sat. NH4Cl, extracted with EtOAc (3×), the combined org. phases were washed with brine, dried and the solvent removed in vacuo to give a yellow-brownish foam (81.9 mg), 56% pure according to LC/MS. This material was purified by prep. HPLC (25-55% MeCN/50 mM NH4HCO3) to yield the title compound as an off-white solid (26.5 mg, 9% over 4 steps). MS (ESI+) for C17H16FNO4S m/z 332 (M-OH)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][N:23]3C(=O)C4C(=CC=CC=4)C3=O)[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.ClCCl>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][NH2:23])[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc(CN3C(=O)c4ccccc4C3=O)co2)cc1OCc1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2nc(CN)co2)cc1OCc1ccccc1

Procedure:
A 9 g quantity of the 2-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]isoindolin-1,3-dione obtained in Reference Example 6 was suspended in 200 ml of ethanol, and 3.1 ml of hydrazine monohydrate was added. The mixture was heated and refluxed for 3 hours. After cooing the reaction mixture, 200 ml of dichloromethane was added and the mixture was stirred. Insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH silica, product of Fuji Sylisia Chemical Ltd., dichloromethane:methanol=20:1) to give 4.5 g of pale yellow powdery [2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-yl]methylamine.
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[O:18][CH2:19]2)[C@H:14]([Cl:28])[C@H:13]3O)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O>[C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[O:18][CH2:19]2)[C:14]([Cl:28])=[CH:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@H](O)[C@@H](Cl)C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Yield: 77.6 %

Procedure:
A mixture of 70 mg of 17α-acetoxy-6β-chloro-7α-hydroxy-2-oxa-4-pregnene-3,20-dione, 400 mg of p-toluenesulfonyl chloride, 1 ml of 4-dimethylaminopyridine and 0.9 ml of pyridine was heated under reflux for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 50% hydrochloric acid and then with a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by TLC [developing solvent: chloroform/acetone (19/1)] to give 52 mg of 17α-acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20-dione. The 1H-NMR spectrum of this compound was the same as that of the compound produced in Example 1.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([N:10]2[C:14]([CH:15]([CH3:17])[CH3:16])=[N:13][N:12]=[N:11]2)[CH:7]=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=2)[CH:5]=1.[Li+].[OH-]>CO.O.C1COCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([N:10]3[C:14]([CH:15]([CH3:17])[CH3:16])=[N:13][N:12]=[N:11]3)[CH:7]=2)[C:3]([OH:25])=[O:2])=[N:19][CH:20]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cn2)cc(-n2nnnc2C(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nnnn1-c1cc(C(=O)O)cc(-c2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
3-(5-Chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-benzoic acid methyl ester (1.84 g, 5.14 mmol) was dissolved in a mixture of MeOH (15 mL), water (2 mL) and THF (2 mL), and LiOH 308 mg, 12.86 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours and then partitioned between water and 1N aqueous HCl. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure to give 1.70 g of 3-(5-chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-benzoic acid, Mp=179.5-181.2° C., MS (M+H)=344.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[Br:13][CH2:14][CH2:15][CH2:16][NH2:17]>C(Cl)Cl.[OH-].[Na+]>[Br:13][CH2:14][CH2:15][CH2:16][NH:17][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCBr
Reactant: O=C(Cl)OCc1ccccc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCBr)OCc1ccccc1
Yield: 105.3 %

Procedure:
Benzylchloroformate (8.6 ml, 60 mmol) was added to a stirred mixture of 3-bromopropylamine hydrobromide (6.6 g, 30 mmol) in methylene chloride (100 ml) and 3N sodium hydroxide solution (100 ml) at 0° C. After stirring two phase reaction mixture at room temperature for overnight, organic layer was separated and washed with water twice (30 ml×2). After drying with MgSO4, the volatile solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc:Hx=1:4) to obtain desire compound (8.6 g, 98%) as colorless oil.
Reaction SMILES: ClC(OCC(C)C)=O.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([NH:16][C:17]1([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=O.C(N(CC)CC)C>O1CCCC1>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[O:25][C:23](=[O:24])[C:17]2([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[N:16]=1
Reactant: O=C(NC1(C(=O)O)CCCCC1)c1ccco1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OC(c2ccco2)=NC12CCCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
6.0 g (44 mmol) of isobutyl chloroformate was added dropwise to a solution of 10 g (42 mmol) of 1-[(2-furanylcarbonyl)amino]cyclohexanecarboxylic acid obtained in Reference example 14 and 6.1 ml (44 mmol) of triethylamine in tetrahydrofuran (80 ml), and the mixture was stirred at room temperature for 1 hour. The precipitated crystal was removed by filtration and the filtrate was concentrated. The obtained crystal was washed with water to give 8.95 g (97%) of the title compound.
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.CCCCCCC.C(OCC)(=O)C>CS(C)=O>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)#[N:2]
Reactant: [C-]#N
Reactant: Clc1nc2ccccc2s1
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: N#Cc1nc2ccccc2s1
Temperature: 80 °C
Reaction time: 5 h
Yield: 57.1 %

Procedure:
A suspension of potassium cyanide (1.50 g, 23.0 mmol) in dimethylsulfoxide (DMSO, 100 mL) was prepared in a 1-L 3-necked flask fitted with a reflux condenser, a heating mantle and an internal temperature probe. The 2-chlorobenzothiazole (2.6 g, 2.0 mL, 15.3 mmol) was added to the reaction flask via pipet and the reaction was heated at 80° C. (internal temperature). The reaction was monitored periodically by TLC (9:1 heptane-ethyl acetate). After 5 hours the reaction appeared to be about 50% complete. After 17 hours the reaction was judged complete by TLC analysis. The reaction mixture was allowed to cool to room temperature and was then extracted with ether (5×100 mL). The extracts were dried over sodium sulfate and concentrated to give a yellow-orange solid. The crude solid was purified on silica gel (100 g) using 9:1 heptane-ethyl acetate. Fractions containing product were pooled and concentrated to give 1.4 g (57%) of the desired product as a yellow-orange solid. The structure was confirmed by 1H NMR analysis in DMSO-d6.