Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23](Cl)[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:7].O=C1C(C(O)=O)=CC(C2C=CN=CC=2)=NN1.C(Cl)(=O)C(Cl)=O.ClC1C=CC=CC=1CN>C(N(CC)CC)C.CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:7]
Reactant: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)n[nH]c1=O
Agent: NCc1ccccc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cc(-c2ccncc2)n[nH]c1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1Cl)c1cc(-c2ccncc2)n[nH]c1=O

Procedure:
Working as in example 2 for the preparation of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide, but starting with 0.3 g of 3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxylic acid, 10 cm3 of dichloromethane, 0.02 cm3 of dimethylformamide, 0.12 cm3 of oxalyl chloride, 0.19 cm3 of 2-chlorobenzylamine and 0.19 cm3 of triethylamine, 0.25 g of N-(2-chlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a white solid melting above 260° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:23])[CH:18]=2)[C:13]=1[O:24]S(C(F)(F)F)(=O)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:23])[CH:18]=2)[C:13]=1[OH:24])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(Cl)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(Cl)ccc2c1O
Reaction time: 0.75 h

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(6-chloro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (1.521 g, 3.15 mmol) in anhydrous THF (30 mL) at 0° C. was added a 1M solution of tetrabutylammonium fluoride in THF (6.30 mL. 6.30 mmol) to give a bright yellow solution. The reaction mixture was stirred for 45 minutes and quenched with saturated ammonium chloride solution and stirred for 5 minutes. The product was extracted with ethyl acetate/hexane (1:1, 2×). The combined organic layer was dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C19H24ClO4: 349.1. Found: 349.1.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][CH3:7])[CH2:3][CH:4]=[CH2:5].C1C=C(Cl)C=C(C(OO)=[O:17])C=1>C(Cl)Cl>[CH3:1][C:2]([CH3:8])([CH2:6][CH3:7])[CH2:3][CH:4]1[CH2:5][O:17]1
Reactant: C=CCC(C)(C)CC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCC(C)(C)CC1CO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4,4-dimethylhex-1-ene (49.5 g, 442 mmol) in methylene chloride (1 L) at 0° C. was added m-CPBA (120 g, 535 mmol), and the reaction was stirred at rt for 16 h. The reaction mixture was filtered through Celite and the filtrate was washed with saturated sodium hydrogen sulfite (1×1 L), saturated sodium carbonate (2×1 L), dried over sodium sulfate and concentrated to give 2-(2,2-dimethylbutyl)oxirane, which was dissolved in methanol (400 mL). To this solution was added sodium azide (22.8 g, 351 mmol), ammonium chloride (18.8 g, 351 mmol) and water (100 mL). After heating at 80° C. overnight, the volatiles were removed and the residue was partitioned between water (300 mL) and ethyl acetate (300 mL). The organic layer was separated, dried over sodium sulfate and concentrated, and the residue was purified by passing through a silica gel pad (13 cm×10 cm) eluted with 1:9 ethyl acetate/hexanes to provide 1-azido-4,4-dimethylhexan-2-ol. 1H NMR (500 MHz, CDCl3) δ 3.88 (m, 1H), 3.29 (dd, J=12.2 Hz, J=3.7 Hz, 1H), 3.23 (dd, J=12.2 Hz, J=7.7 Hz, 1H), 1.90 (d, J=4.5 Hz, 1H), 1.40 (dd, J=14.7 Hz, J=8.2 Hz, 1H), 1.28 (m, 3H), 0.93 (m, 3H), 0.90 (s, 3H), 0.83 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])=[CH:4][CH:3]=1.[F:26][C:27]([Si](C)(C)C)([F:29])[F:28].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])([CH3:14])[C:27]([F:29])([F:28])[F:26])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:24])([F:23])[F:25])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(=O)c1cn(-c2ccc(Br)cc2)c(-c2ccccc2C(F)(F)F)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(O)(c1cn(-c2ccc(Br)cc2)c(-c2ccccc2C(F)(F)F)n1)C(F)(F)F
Temperature: 50 °C
Reaction time: 48 h
Yield: 38.9 %

Procedure:
To a solution of 1-[1-(4-bromophenyl)-2-(2-trifluoromethyl-phenyl)-1H-imidazol-4-yl]-ethanone (0.24 g, 0.59 mmol) and trifluoromethyl-trimethylsilane (0.10 mL, 0.68 mmol) in toluene (3 mL, anhyd) at 0° C. was added a 1.0M solution of tetrabutylammonium fluoride (TBAF) in THF (0.12 mL, 20 mol %, dried over 4 Å molecular sieves). After 24 h the reaction mixture was charged with additional trifluoromethyl-trimethylsilane (0.10 mL) and 1.0M TBAF (0.12 mL) and then heated at 50° C. After 48 h (total) the reaction mixture was allowed to cool to ambient temperature, quenched with H2O and extracted with DCM (2×30 mL). The combined extracts were dried (Na2SO4), concentrated and purified by chromatography (silica, EtOAc/Hex, 20:80 to 60:40) to yield the title compound (0.11 g, 39%) as a white solid. 1H-NMR (DCM-d2): δ 7.76 (d, 1H), 7.50-7.60 (m, 2H), 7.46 (d, 2H), 7.27 (m, 2H), 7.02 (d, 2H), 4.36 (s, 1H), 1.72 (s, 3H).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.[I-].[Na+].C(N(CC)CC)C.Cl[CH2:47][CH2:48][O:49][CH2:50][CH2:51][OH:52]>CN(C)C=O>[OH:52][CH2:51][CH2:50][O:49][CH2:48][CH2:47][N:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:36])=[O:5])[CH2:19][CH2:18][N:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([OH:31])=[O:30])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Reactant: OCCOCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)CN1CCN(CCOCCO)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,4,7,10-Tetraazacyclododecane-4,7,10-triacetic acid tri-t-butyl-ester (515 mg, 1 mmol) was dissolved in dimethylformamide (3 ml). Sodium iodide (15 mg, 0.1 mmol), triethylamine (233 mg, 2.5 mmol) and 2(2-chloroethoxy)ethanol (313 mg, 3.5 mmol) were added to the stirred mixture at ambient temperature. The mixture was stirred for 18 hours at ambient temperature. The temperature was then raised to 100° C. and kept there for 1 hour. The solvent was then evaporated and the residue dissolved in a mixture of dichloromethane (4.5 ml) and trifluoroacetic acid (4.5 ml). The mixture was stirred for 2 hours at ambient temperature and the solvent was then evaporated. The residue was dissolved in water (8 ml), and this aqueous solution was washed with ether (6×4 ml). The aqueous solution was acidified and the title compound was isolated as a hygroscopic white powder after evaporation of the water. Yield 325 mg (75%), FAB MS: 435(M+1). The structure was confirmed by 1HNMR and 13C NMR.
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[O:15][N:14]=[C:13]([CH3:16])[N:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:21][C@H:22]1[O:24][CH2:23]1)(=O)=O>>[CH2:21]([O:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[O:15][N:14]=[C:13]([CH3:16])[N:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C@H:22]1[O:24][CH2:23]1
Reactant: Cc1noc(-c2cc3c(O)cccc3o2)n1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Product: Cc1noc(-c2cc3c(OC[C@@H]4CO4)cccc3o2)n1
Yield: 28.3 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 5-(4-hydroxybenzo(b)furan-2-yl)-3-methyl-1,2,4-oxadiazole (3.3 g) and (S)-glycidyl nosylate (3.7 g), the title compound (1.1 g) was obtained as white crystals.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.[CH2:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:32])[CH2:30][NH2:31])[CH2:25][CH2:24]1)=[O:22])[CH2:17][CH2:18][CH3:19].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:16]([O:20][C:21]([N:23]1[CH2:24][CH2:25][N:26]([C:29](=[O:32])[CH2:30][NH:31][C:13]([C:4]2[CH:3]=[C:2]([OH:1])[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=2)=[O:15])[CH2:27][CH2:28]1)=[O:22])[CH2:17][CH2:18][CH3:19]
Reactant: Cc1ccc2c(O)cc(C(=O)O)nc2c1
Reactant: CCCCOC(=O)N1CCN(C(=O)CN)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4.0 g of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid and 7 g of 4-(2-Amino-acetyl)-piperazine-1-carboxylic acid butyl ester in 40 ml of DMF, 3.3 g of HOBT and 4.1 g of EDC was added and the reaction mixture was stirred for 4 h at RT. Then, the reaction mixture was diluted with water and extracted with DCM. The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The isolated crude product was used in the next reaction step. Yield: 4.5 g.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[CH:16]=[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])[C:14]([C:21]4[O:22][C:23]([NH:26][CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[N:24][N:25]=4)=[CH:13][N:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C1COCC1.CCN(C(C)C)C(C)C.[S:47](Cl)([CH3:50])(=[O:49])=[O:48]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[CH:16]=[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])[C:14]([C:21]4[O:22][C:23]([NH:26][CH:27]5[CH2:32][CH2:31][N:30]([S:47]([CH3:50])(=[O:49])=[O:48])[CH2:29][CH2:28]5)=[N:24][N:25]=4)=[CH:13][N:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(NC2CCNCC2)o1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(NC2CCN(S(C)(=O)=O)CC2)o1
Reaction time: 0.08 h

Procedure:
To a stirred solution of N2-(benzo[d]thiazol-6-yl)-N4-isopropyl-5-(5-(piperidin-4-ylamino)-1,3,4-oxadiazol-2-yl)pyridine-2,4-diamine (Example 131) (30 mg, 0.06 mmol) in DCM (4 mL): THF (4 mL), added DIPEA (0.09 mmol, 1.5 equiv.) and DMAP (0.006 mmol, 0.1 equiv.) and stirred for 5 min. Added mesyl chloride (0.5 mmol, 0.8 equiv.) dropwise at 0° C. Stirred the reaction mixture at 0° C. for 1 h, reaction temperature was brought to room temperature and stirred overnight. The reaction mixture was diluted with DCM. The DCM layer was washed with 10% NaHCO3 solution followed by water. The DCM layer was collected, dried over Na2SO4, filtered and concentrated. The material obtained was purified by prep HPLC to afford the title compound, N2-(benzo[d]thiazol-6-yl)-N4-isopropyl-5-(5-((1-(methylsulfonyl)piperidin-4-yl)amino)-1,3,4-oxadiazol-2-yl)pyridine-2,4-diamine. 1H NMR: 400 MHz, CD3OD: δ 1.34 (d, J=6.40 Hz, 6H), 1.66-1.75 (m, 2H), 2.10-2.14 (m, 2H), 3.027 (s, 3H), 3.30-3.36 (1H, merged with water peak), 3.56-3.60 (m, 1H), 3.78-3.82 (m, 1H), 4.00-4.05 (m, 2H), 6.17 (s, 1H), 7.53-7.57 (m, 1H), 7.98 (d, J=8.80 Hz, 1H), 8.38 (s, 1H), 8.43 (d, J=2.00 Hz, 1H), 9.08 (s, 1H). LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 μm; Solvent A=10% MeOH: 90% H2O: 0.1% TFA; Solvent B=90% MeOH: 10% H2O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time); retention time: 1.501 min; LCMS (ES-API), m/z 529.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 5.771 min; Purity: 99.7%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH:16]([S:18]([CH:21]=[CH2:22])(=[O:20])=[O:19])=[CH2:17]>CCO>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:22][CH2:21][S:18](=[O:20])(=[O:19])[CH2:16][CH2:17]2)=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CS(=O)(=O)C=C
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(N2CCS(=O)(=O)CC2)cc1
Temperature: 25 °C

Procedure:
A solution of 408 mg (4-Amino-phenyl)-carbamic acid tert-butyl ester and 254 mg Ethenesulfonyl-ethene in 4 mL EtOH were heated for 30 min at 140° C. under microwave irradiation (100 W, CEM Discover™ apparatus). Then, after cooling to RT the solvents were removed under reduced pressure and the residue was dried in vacuo. The crude product was subjected to the next reaction step.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:11][C:10]=1[C:20]([OH:22])=O)=O)(C)(C)C.[NH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>>[NH2:8][C:9]1[S:13][C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:11][C:10]=1[C:20]([NH:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2)nc1C(=O)O
Reactant: Nc1cccnc1
Product: Nc1sc(-c2ccccc2)nc1C(=O)Nc1cccnc1

Procedure:
Following the procedures as described in EXAMPLE 1 and starting with 5-(tert-butoxycarbonylamino)-2-phenylthiazole-4-carboxylic acid and 3-aminopyridine, the title compound was obtained as a white solid (21.0 mg, 42%). 1H NMR (400 MHz, DMSO) δ 9.78 (s, 1H), 8.99 (d, J=2.4, 1H), 8.30-8.18 (m, 2H), 7.95-7.88 (m, 2H), 7.59 (s, 2H), 7.53-7.32 (m, 4H). ESIMS m/z=297.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH2:15][NH:16][C:17]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)=[O:18])[C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].S(=O)(=O)(O)O.[CH3:35]O>>[CH3:35][O:13][C:12](=[O:14])[CH:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:15][NH:16][C:17]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)=[O:18]
Reactant: CO
Reactant: COc1ccc(CC(=O)NCC(C(=O)O)c2ccc(OC)c(OC)c2)cc1OC
Agent: O=S(=O)(O)O
Product: COC(=O)C(CNC(=O)Cc1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1

Procedure:
A solution of 23.3 g of 2-(3,4-dimethoxyphenyl)-3-{{[(3,4-dimethoxyphenyl)methyl]carbonyl}amino}propanoic acid and 15.5 ml of concentrated sulfuric acid in 300 ml of methanol was refluxed for 6 hours and evaporated to dryness. The residue was partitioned between ethyl acetate and dilute sodium bicarbonate solution and the organic layer was dried and evaporated to give 15.5 g of crude 2-(3,4-dimethoxyphenyl)-3-{{[(3,4-dimethoxyphenyl)methyl]carbonyl}amino}propanoic acid methyl ester. Crystallization from ethyl acetate provided the analytical sample, mp 92°-93°.
Reaction SMILES: [C:1]([CH:4]([CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])[C:5]([O:7][CH3:8])=[O:6])(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[OH:3][CH:1]([CH:4]([CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: C=CCCCC(C(C)=O)C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C=CCCCC(C(=O)OC)C(C)O
Reaction time: 1 h

Procedure:
5.00 g (27.1 mmol) of methyl 2-acetyl-6-heptenoate (Example 20A) are introduced into 50 ml of methanol and ice-cooled. 0.56 g (14.9 mmol) of sodium borohydride are added in portions and the mixture is stirred for a further 1 h. The batch is then evacuated from the solvent, taken up in diethyl ether and washed with 1 N hydrochloric acid. The organic phase is dried, concentrated and flash-chromatographed using the eluent petroleum ether/ethyl acetate 10/1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccccn3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccccn3)c1)=N2

Procedure:
The title compound was prepared from {5-ethoxy-2-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M39) (198 mg, 0.36 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (138 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[CH2:16][OH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.CI.[CH3:22]N(C)C=O.[H-].[Na+]>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[CH2:16][O:17][CH3:22])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CN1Cc2c(CO)ncn2-c2cccc(Cl)c2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COCc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A mixture of 2.22 g (8 mmol) of 7-chloro-4,5-dihydro-3-(hydroxymethyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one, 0.6 ml (10 mmoL) of methyl iodide and 20 ml of dry dimethylformamide is treated with 0.4 g (9 mmol) of sodium hydride (55 percent oil dispersion, washed with n-hexane) and the mixture is stirred at room temperature for 23 hours. The mixture is poured into 50 ml of water and extracted four times with methylene chloride. The methylene chloride solution is dried over magnesium sulphate and evaporated. The crude product is chromatographed on silica gel using methylene chloride containing 1% of methanol for the elution. By subsequent recrystallization from ethyl acetate/n-hexane there is obtained 7-chloro-4,5-dihydro-3-(methoxymethyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 143°-144°.
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=[O:2].[K+].[K+].[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[O:27][C:20]3([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:19][C:18]=2[CH:28]=1>C(#N)C.O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[O:27][C:20]3([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:19](=[O:2])[C:18]=2[CH:28]=1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: Brc1ccc2c(c1)CC1(CCCCCC1)O2
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C1c2cc(Br)ccc2OC12CCCCCC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred mixture of 17.57 g of potassium persulfate, 5.19 g of cupric sulfate and 100 ml of distilled water was added a solution of 9.13 g of 5-bromo-spiro[benzofuran-2(3H),1'-cycloheptane] in 100 ml of acetonitrile. The mixture was stirred and heated to reflux; after 1.5 hours, GC showed only 6% unreacted starting material. Another 3.51 g of potassium persulfate was added and the mixture was refluxed for another hour and thereafter cooled to room temperature. The mixture was diluted with water (1.0 liter) and extracted with ether (1×500 ml, 2×250 ml). The combined ether extracts were washed with water (250 ml) and saturated sodium chloride solution (250 ml), dried overnight over anhydrous sodium sulfate, filtered and concentrated in vacuo to a gum weighing 7.63 g. This material was taken up in 100 ml of hexane and gravity-filtered to remove insoluble material, and the flask, filter paper and insoluble material were rinsed with another 100 ml of hexane. The hexane filtrate was concentrated in vacuo to an oil weighing 5.84 g. Vacuum distillation of this material afforded 2.76 g of viscous distillate, b.p. 135°-140° C. @ 0.15 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[CH:6]=[CH:7][C:8]=1[O:9][Si](C)(C)C.C(NC(C)C)(C)C.[Li].[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH:43]=[O:44])=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:41][CH2:42][CH:43]([OH:44])[CH2:17][C:16](=[O:18])[CH2:15][CH2:14][C:5]2[CH:6]=[CH:7][C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:39][CH:40]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc(CCC(C)=O)ccc1O[Si](C)(C)C
Reactant: O=CCCc1ccc(OCc2ccccc2)cc1
Agent: [Li]
Solvent: CC(C)NC(C)C
Product: COc1cc(CCC(=O)CC(O)CCc2ccc(OCc3ccccc3)cc2)ccc1O
Yield: 11.5 %

Procedure:
In a manner similar to Example 3, 2.2 g (10 mmol) of 4-(3-methoxy-4-trimethylsilyloxyphenyl)butan-2-one was treated with 10 mmol of lithium diisopropylamine, followed by 3 g (12 mmol) of 3-(4-benzyloxyphenyl)propan-1-al. Purification of reaction mixture by dry column chromatography (silica gel, hexane: ethyl acetate, 2:1) gave 0.5 g of the desired product as a pale yellow oil. MS(EI):434.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CS(C)=O>[CH2:14]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCCCOc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of 4′-hydroxyacetophenone (25.0 g; 183.6 mmol) in DMSO (300. mL) was added KOH (11.3 g; 201.9 mmol.) and the reaction mixture was stirred for 1 hour at RT. After 1 hour the reaction mixture was cooled (0° C.) and 1-bromooctane (34.9 mL; 201.9 mmol) was added. The ice bath was removed and the reaction mixture was stirred overnight at RT. The reaction mixture was extracted with EtOAc/5% aqueous NaHCO3 solution. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O:hexanes 1:3) to afford 1-(4-octyloxy-phenyl)-ethanone (43.08 g)