Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH3:35][C:36]1[CH:37]=[CH:38][C:39]([O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])=[C:40]([CH2:42][OH:43])[CH:41]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:43][CH2:42][C:40]4[CH:41]=[C:36]([CH3:35])[CH:37]=[CH:38][C:39]=4[O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@H](C)Oc1ccc(C)cc1CO
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4cc(C)ccc4O[C@@H](C)CC=C)nn23)CC1
Reaction time: 5 h
Yield: 22.3 %

Procedure:
(S)-Ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.45 g, 0.770 mmol) was dissolved in 1 mL DMF to this was added (S)-(5-methyl-2-(pent-4-en-2-yloxy)phenyl)methanol (0.191 g, 0.924 mmol) as a solution in 1 mL DMF. NaH-60% wt/wt in oil (47 mg, 1.16 mmol) was added and the reaction mixture was stirred for 5 hours. The reaction was quenched with 1N HCl then transferred to a separatory funnel where the product was extracted with ethyl acetate. The organic solution was dried over Na2SO4. After filtration the solvent was removed under vacuum and the product purified by silica gel chromatography using a Biotage apparatus to isolate the title compound as an oil (114 mg). 1H NMR (400 MHz, CDCl3) δ 1.21-1.24 (15H, overlapping s and m), 1.32 (3H, d), 1.65-1.8 (4H, br m), 2.35 (3H, s), 2.50 (2H, m), 2.61 (3H, s), 3.0-3.5 (4H, very broad m), 3.75 (2H, s), 4.21 (2H, m), 4.45 (1H, m), 4.66 (2H, br s), 4.77 (2H, s), 5.06-5.22 (4H, overlapping m), 5.32 (1H, s), 5.85-6.2 (2H, overlapping m), 6.59 (1H, s), 6.71 (1H, s), 6.77 (1H, d), 7.34 (1H, d).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=O)[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1.O>N1C=CC=CC=1>[N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[S:26])[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: S=C1Nc2cccnc2Nc2ccccc21
Temperature: 100 °C

Procedure:
A mixture of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (3.00 g, 14 mmol) and Lawesson's reagent (6.51 g, 16 mmol) in pyridine (40 mL) was heated to 100° C. for 18 hours. After cooling to room temperature the mixture was poured into water and stirred. The precipitate was collected on a filter paper and dried. The crude product (yellow solid) was carried on to the next step without further purification (96%). 1H NMR (DMSO-d6) 400 MHz δ: 11.99 (s, 1H), 8.37, (s, 1H), 7.98 (dd, J=4.6, 1.7 Hz, 1H), 7.96 (dd, J=8.0, 1.7 Hz, 1H), 7.44 (dd, J=7.7, 1.4 Hz, 1H), 7.35 (td, J=7.7, 1.7 Hz, 1H), 7.06 (dd, J=8.0, 1.2 Hz, 1H), 7.01 (dd, J=8.0, 4.6 Hz, 1H), 6.95 (td, J=8.0, 1.2 Hz, 1H); LC/MS [M+H]: 228.
Reaction SMILES: C[O:2][C:3]([C:5]1[C@@H:6]2[N:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:9]([CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][C:22]3[C:27]([Cl:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=3[Cl:30])=[CH:14][CH:13]=1)[CH2:8][CH2:7]2)=[O:4].[OH-].[Na+]>CCO>[C:35]([O:34][C:32]([N:31]1[C@H:9]2[CH2:8][CH2:7][C@@H:6]1[C:5]([C:3]([OH:4])=[O:2])=[C:11]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][O:21][C:22]3[C:23]([Cl:30])=[CH:24][C:25]([CH3:29])=[CH:26][C:27]=3[Cl:28])=[CH:16][CH:17]=1)[CH2:10]2)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)C1=C(c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C[C@@H]2CC[C@H]1N2C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Cl)c(OCCOc2ccc(C3=C(C(=O)O)[C@H]4CC[C@@H](C3)N4C(=O)OC(C)(C)C)cc2)c(Cl)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Compound C2 (3.82 g, 6.80 mmol) was dissolved in EtOH (100 mL). The sol. was heated to 70° C., and aq. 1M NaOH (80 mL, 80 mmol) was added. The mixture was stirred at 80° C. for 3 h, and allowed to cool to rt. The solvents were partially removed under reduced pressure, and the residue was poured into a separatory funnel filled with EtOAc. Aq. 1M HCl was added until the aq. phase was acidic, and the phases were shaken and separated. The aq. layer was extracted with EtOAc (2×), and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the crude title compound mixed with (rac.)-(1R*,5S*)-3-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-8-aza-bicyclo[3.2.1]oct-3-ene-2,8-dicarboxylic acid 8-tert-butyl ester (3.45 g, 93%) that was used further without purification. LC-MS: tR=1.13 min; ES+: 548.25.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][O:17][CH3:18])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Si:11]([CH3:14])([CH3:13])[CH3:12])[CH3:2].[CH3:19]I>>[CH2:1]([N:3]([CH2:16][O:17][CH3:18])[C:4](=[O:15])[C:5]1[C:6]([Si:11]([CH3:13])([CH3:12])[CH3:14])=[CH:7][CH:8]=[CH:9][C:10]=1[CH3:19])[CH3:2]
Reactant: CCN(COC)C(=O)c1ccccc1[Si](C)(C)C
Reactant: CI
Product: CCN(COC)C(=O)c1c(C)cccc1[Si](C)(C)C

Procedure:
The compound of Example 50 (1.33 g, 5.0 mmol) and MeI (2.8 g, 20 mmol) were combined according to General Method B. The resulting reaction was partitioned between ethyl acetate and sat aq NaHCO3. The organic phase was washed with brine, dried (MgSO4), and concentrated to afford a quantitative yield of the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.ClCCl.[Cu]Cl>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[O:25][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Oc1cccc(Cl)c1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: O=C(Nc1cc2ccc(Oc3cccc(Cl)c3)cc2cn1)C1CC1
Temperature: 180 °C
Reaction time: 1.65 h
Yield: 28 %

Procedure:
A mixture of N-(7-Bromoisoquinolin-3-yl)cyclopropanecarboxamide (89 mg, 0.30 mmol), 3-chlorophenol (115.2 mg, 0.90 mmol), 2,2,6,6-tetramethylheptane-3,5-dione (27.6 mg, 0.15 mmol), copper(I) chloride (30 mg, 0.30 mmol) and cesium carbonate (292.5 mg, 0.90 mmol) in 1-methyl-2-pyrrolidinone (2.5 mL) was stirred under microwave irradiation at 180° C. for 99 minutes under nitrogen. The mixture was diluted with dichloromethane and filtered through a pad of Celite. The filer cake was washed with dichloromethane and the combined filtrates were concentrated and purified by prep-HPLC to give the product (28.5 mg, 13%). LCMS (ESI): RT (min)=1.237, M+H+=338.8, method=A; 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.06 (s, 1H), 8.41 (s, 1H), 8.02 (t, J=0.8 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.53 (dd, J=1.6, 8.4 Hz, 1H), 7.38-7.31 (m, 5H), 2.09-1.99 (m, 1H), 0.83-0.79 (m, 4H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][CH2:22][N:23]3[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)(O)[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]3=[O:39])[CH2:18][CH:19]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([BH3-])#N.[Na+].CN(C)CCN(C)C.[C:52]([OH:57])(=[O:56])[C:53]([OH:55])=[O:54]>C(Cl)Cl.O1CCCC1.C(C(C)=O)C>[C:52]([OH:57])(=[O:56])[C:53]([OH:55])=[O:54].[C:33]1([CH:31]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:39])[N:23]2[CH2:22][CH2:21][CH2:20][N:17]2[CH2:16][CH:15]=[C:14]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:19][CH2:18]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C1c2ccccc2C(O)(c2ccccc2)N1CCCN1CC=C(c2ccccc2)CC1
Agent: CN(C)CCN(C)C
Agent: O=C(O)C(=O)O
Agent: [BH3-]C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(c2ccccc2)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 2 h
Yield: 41.3 %

Procedure:
60 cc of trifluoroacetic acid is added in the course of 45 minutes to 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1pyridyl)propyl]-3-phenyl-3-hydroxy-1-isoindolinone (12.4 g) and sodium cyanoborohydride (3.8 g) cooled to a temperature close to -25° C. Agitation is continued for 2 hours at a temperature close to 20° C. The solution is diluted with methylene chloride (150 cc) then washed with saturated aqueous sodium bicarbonate solution (130 cc). The aqueous phase is extracted with methylene chloride (4×100 cc). The organic extracts are combined, washed with 1N hydrochloric acid solution (3×50 cc), dried over anhydrous magnesium sulphate, treated with animal charcoal, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in tetrahydrofuran (150 cc). Tetramethylethylenediamine (4.5 cc) is added and the solution heated to a temperature close to 65° C. for 1 hour. After cooling to a temperature close to 20° C., the solution is diluted with methylene chloride (300 cc), washed with distilled water (5×50 cc). The organic extract is dried over anhydrous magnesium sulphate, filtered and evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The residue obtained is poured onto neutral alumina (750 g) contained in a column of 6 cm diameter. Elution is carried out with a mixture of ethyl acetate and cyclohexane (40-60 by volume) (2000 cc) and the corresponding eluates are eliminated. Elution is then carried out with ethyl acetate (3000 cc) and the corresponding eluates are evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The residue obtained is dissolved in methyl ethyl ketone (30 cc). A solution of oxalic acid (0.7 g) in methyl ethyl ketone (10 cc) is added and agitation continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration and recrystallized from boiling acetonitrile (240 cc). 1.6 g of 3-phenyl-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalate are obtained, melting at 198° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4](=[O:13])[N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:6]=1.[CH3:14][N:15]([CH3:24])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.N1CCCCC1>C(O)C.O>[CH3:14][N:15]([CH3:24])[C:16]1[CH:23]=[CH:22][C:19](/[CH:20]=[C:3]2/[C:4](=[O:13])[N:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[N:6]=[C:2]/2[CH3:1])=[CH:18][CH:17]=1
Reactant: CC1=NN(c2ccccn2)C(=O)C1
Reactant: CN(C)c1ccc(C=O)cc1
Solvent: CCO
Solvent: O
Solvent: C1CCNCC1
Product: CC1=NN(c2ccccn2)C(=O)/C1=C/c1ccc(N(C)C)cc1

Procedure:
1.3 g (7.42 mmol) of 5-methyl-2-(2-pyridinyl)-2,4-dihydro-3H-pyrazol-3-one and 1.68 g (11.13 mmol) of 4-(dimethylamino)benzaldehyde are stirred under reflux with the addition of 3 ml of piperidine in absolute ethanol for 2 hours. The mixture is then diluted with water and the orange-red precipitate is filtered off, then washed with water and dried under reduced pressure.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[O:9][N:8]=1)C>Cl.C1COCC1>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:10]2[O:9][N:8]=[C:7]([CH2:6][CH2:5][CH:4]=[O:3])[N:11]=2)=[CH:17][CH:16]=1
Reactant: CCOC(CCc1noc(-c2ccc(OC)cc2)n1)OCC
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(CCC=O)no2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(3,3-diethoxypropyl)-5-(4-methoxyphenyl)-1,2,4-oxadiazole (1.0 g, 3.0 mmol) in 2N HCl (10 mL) and THF (10 mL) was stirred at room temperature overnight. The reaction mixture was extracted with EtOAc (3×). The organic layers were washed with water, dried over Na2SO4, filtered and concentrated to give the desired product. LCMS calculated for C12H13N2O3 (M+H): 233.1. Found: 233.1.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[CH3:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10]>C1(C)C=CC=CC=1>[CH3:12][O:11][C:9]([C:8]([CH:3]1[CH2:4][CH2:5][C:1](=[O:6])[CH2:2]1)([C:13]([O:15][CH3:16])=[O:14])[CH3:7])=[O:10]
Reactant: COC(=O)C(C)C(=O)OC
Reactant: O=C1C=CCC1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C(=O)OC)C1CCC(=O)C1
Temperature: 30 °C
Reaction time: 48 h
Yield: 50.8 %

Procedure:
Under an atmosphere of argon, 11.0 mg (0.02 mmol, S/C=50) of Ru[(S,S)-Msdpen] (hexamethylbenzene), 84 μL (1.0 mmol) of 2-cyclopentenone, 133 μL (1.0 mmol) of dimethyl methylmalonate, and 1 mL of toluene were placed in a 20 mL Schlenk tube and stirred at 30° C. for 48 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 116 mg (51% yield) of the title compound. The optical rotation [α]D25 was +87.2(c 1.00, CHCl3). The optical purity was measured by HPLC (CHIRALPAK AS manufactured by Daicel Chemical Industries, Ltd., hexane:2-propanol=80:20, flow rate 1.5 mL/min, detection at 210 nm) and it was found to be 97% ee.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:34])[NH:28]2>>[Cl:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:11]([NH:22][C:23]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]3[C:24]=1[CH:25]=[CH:26][C:27](=[O:34])[NH:28]3)[C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH2:9][C:8]2([CH3:19])[CH3:18]
Reactant: Nc1ccc(F)c2[nH]c(=O)ccc12
Reactant: COc1c(Cl)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Product: COc1c(Cl)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1ccc(F)c2[nH]c(=O)ccc12

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 250 g of 4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 137 mg of 5-amino-8-fluoroquinolin-2(1H)-one. The title compound is obtained analogously to Example 3 by reaction of the imine that is formed with 1.4 ml of titanium tetrachloride solution (1 M in dichloromethane).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:14][C:15](=O)[C:16]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)C1C=CC=CC=1.C(OCC)(=O)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>CCOCC>[CH2:25]([O:24][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH3:23])[C:16]=1[CH2:15][OH:14])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1cccc(OCc2ccccc2)c1C(=O)OCc1ccccc1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1cccc(OCc2ccccc2)c1CO
Reaction time: 2 h
Yield: 109.2 %

Procedure:
In a nitrogen stream, to a suspension of lithium aluminum hydride (0.88 g, 23.14 mmol) in ether (35 mL), a solution of 2-benzyloxy-6-methoxybenzoic acid benzyl ester (6.2 g, 17.80 mmol) in ether (20 mL) was added at room temperature over 15 minutes. The reaction mixture was stirred for two hours under heating to reflux. Ethyl acetate (2 mL) was added dropwise to the reaction mixture under cooling with ice and then a saturated Rochelle salt aqueous solution (20 mL) was added dropwise thereto and the mixture was stirred at room temperature for 20 hours. The reaction mixture was subjected to Celite filtration and to the filtrate was added a saturated Rochelle salt aqueous solution (15 mL) and the mixture was extracted with ether. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous sodium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ether: n-hexane (1:1)] to obtain the title compound (4.75 g, 100%).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:20][C:21]1([C:24]([OH:28])([C:26]#[CH:27])[CH3:25])[CH2:23][CH2:22]1>>[F:19][C:3]1[C:2]([C:27]#[C:26][C:24]([OH:28])([C:21]2([CH3:20])[CH2:23][CH2:22]2)[CH3:25])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)C1(C)CC1
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)C1(C)CC1
Yield: 8 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(1-methylcyclopropyl)but-3-yn-2-ol to give the titled compound as a light brown solid (7.8 mg, 8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[OH:19].Br[CH:21]([CH:27](Br)[CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:18])[C:10]3[CH2:17][CH2:16][CH2:15][CH2:14][C:11]=3[C:12]2=[O:13])=[CH:4][C:3]=1[O:19][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][CH3:28]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)c(O)c1
Reactant: CCOC(=O)C(Br)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC=C(Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl)C(=O)OCC
Reaction time: 6 h

Procedure:
A mixture of 4.0 g. of N-(4-chloro-3-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide, 4.7 g. of ethyl 2,3-dibromobutyrate, 2.4 g. of potassium carbonate and 35 ml. of acetone was refluxed with stirring for 6 hours and the precipitated salt was separated by a filtration. The filtrate was concentrated under a reduced pressure and 2N-HCl was added to the residue to obtain a crude crystal. The product was washed with water and dried and purified by a chromatography on a column of silica gel (developing solvent: ethyl acetate:n-hexane of 3:7) to obtain 5.2 g. of Compound No. 158 shown in Table 1.
Reaction SMILES: C([Li])CCC.[Si:6]([O:13][CH:14]([C:44]1[N:45]=[CH:46][O:47][CH:48]=1)[CH2:15][CH:16]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH:17]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH:18]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH3:19])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH:49]([C:51]1[O:55][CH:54]=[N:53][CH:52]=1)=[O:50].Cl>CCCCCC.C1COCC1.O>[O:55]1[C:51]([CH:49]([C:46]2[O:47][CH:48]=[C:44]([CH:14]([O:13][Si:6]([C:9]([CH3:10])([CH3:11])[CH3:12])([CH3:7])[CH3:8])[CH2:15][CH:16]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:38])[CH3:39])[CH:17]([O:28][Si:29]([C:32]([CH3:33])([CH3:34])[CH3:35])([CH3:31])[CH3:30])[CH:18]([O:20][Si:21]([C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:23])[CH3:22])[CH3:19])[N:45]=2)[OH:50])=[CH:52][N:53]=[CH:54]1
Reactant: O=Cc1cnco1
Reactant: CC(O[Si](C)(C)C(C)(C)C)C(O[Si](C)(C)C(C)(C)C)C(CC(O[Si](C)(C)C(C)(C)C)c1cocn1)O[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC(O[Si](C)(C)C(C)(C)C)C(O[Si](C)(C)C(C)(C)C)C(CC(O[Si](C)(C)C(C)(C)C)c1coc(C(O)c2cnco2)n1)O[Si](C)(C)C(C)(C)C
Temperature: -50 °C
Reaction time: 3 h

Procedure:
Butyllithium (n-Buli, 0.32 g, 5 mmol) in hexane is added to a -50° C. Solution of 4-[1,3,4,5-tetra(t-butyldimethylsilyloxy)hexyl]oxazole (6, 3.4 g, 5 mmol) in THF (50 mL). The resulting solution stirred at -50° C. for three hours. A solution of 5-formyloxazole (0.53 g, 5.5 mmol - Preparation 20) in THF (7 mL) is added, and the mixture allowed to warm to room temperature while stirring for 12 hours. The resulting mixture is added to water, acidified with HCl and extracted three times with ether. The organic layer is washed with aqueous Na2SO3 and brine, dried over Na2SO4, and evaporated to yield 2-[1-(oxazol-5-yl)-1-hydroxymethyl]-4-[1,3,4,5-tetra(t-butyldimethylsilyloxy)hexyl]oxazole (7).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[N:27]=[C:28]([C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)[S:29][C:30]=1[CH2:31][NH:32][C:33]1[CH:38]=[CH:37][C:36]([C@@H:39]2[CH2:41][C@H:40]2[C:42](O)=[O:43])=[CH:35][CH:34]=1.[N:55]1[CH:60]=[CH:59][C:58]([CH2:61][NH2:62])=[CH:57][CH:56]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:25][C:26]1[N:27]=[C:28]([C:45]2[CH:46]=[CH:47][C:48]([C:51]([F:54])([F:52])[F:53])=[CH:49][CH:50]=2)[S:29][C:30]=1[CH2:31][NH:32][C:33]1[CH:34]=[CH:35][C:36]([C@@H:39]2[CH2:41][C@H:40]2[C:42]([NH:62][CH2:61][C:58]2[CH:59]=[CH:60][N:55]=[CH:56][CH:57]=2)=[O:43])=[CH:37][CH:38]=1
Reactant: NCc1ccncc1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CNc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CNc1ccc([C@@H]2C[C@H]2C(=O)NCc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
HATU (0.14 g, 0.37 mmol) and racemic-(trans)-2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}cyclopropanecarboxylic acid (I-2m) (0.12 g, 0.28 mmol) in DMF (10 mL) were stirred at RT for 45 min, then (4-pyridinylmethyl)amine (0.36 g, 3.33 mmol) was added. The solution was stirred at RT for 16 h, then saturated NaHCO3 solution (50 mL) and ethyl acetate (50 mL) were added. The organic layer was separated, washed with saturated NaHCO3 solution (50 mL), water (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated. The crude material was partially dissolved in dichloromethane (10 mL) and diethyl ether was added (10 mL). The white solid was filtered, washed with diethyl ether, and dried to give the title compound as a white powder (0.094 g, 64%). 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=5.1 Hz, 2H), 7.97 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.2 Hz, 2H), 7.20 (d, J=4.7 Hz, 2H), 6.96 (d, J=8.1 Hz, 2H), 6.60 (d, J=8.4 Hz, 2H), 5.99 (t, J=5.7 Hz, 1H), 4.49 (t, J=5.9 Hz, 2H), 4.45 (s, 2H), 4.02 (bs, 1H), 2.49 (s, 3H), 2.49-2.45 (m, 1H), 1.63-1.53 (m, 2H), 1.25-1.21 (m, 1H). ES-MS m/z 523.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=O)=[CH:15][CH:14]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([CH2:29]C#N)[CH:26]=[CH:27][CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4=[N:19][O:21][C:29]([C:25]5[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH:24]=5)=[C:17]4[CH:18]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#CCc1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccc(Cl)cc2)cc1
Product: Fc1cccc(-c2onc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cc23)c1

Procedure:
The title compound, light yellow solid (46 mg, 35%), MS (ISP) m/z=390.2 [(M+H)+], mp 184° C., was prepared in accordance with the general method of example 1 from 1-(4-chloro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate H) (100 mg, 353 μmol) and commercially available 2-(3-fluoro-phenyl)-acetonitrile.