Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])[CH:4]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CCOCC.CC(C)=O.CCOCC>[N:17]1([CH2:2][C:3]2[O:7][N:6]=[C:5]([C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[O:9])[CH:4]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: O=C(c1ccc(F)cc1)c1cc(CBr)on1
Reactant: C1COCCN1
Solvent: CCOCC
Solvent: CC(C)=O
Product: O=C(c1ccc(F)cc1)c1cc(CN2CCOCC2)on1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 4.5 g of (5-bromomethylisoxazol-3-yl-4-fluorophenylmethanone in 100 ml of Et2O was added dropwise to a solution of 7 ml of morpholine in 300 ml of 50% acetone/Et2O. The resulting mixture was stirred at room temperature for 20 hours. This mixture was filtered and the volatiles evaporated to give a residue which was dissolved in 600 ml of Et2O. The organic solution was washed with water until it became neutral and then with saturated NaCl, and dried over Na2SO4 and concentrated in vacuo to give 4.3 g of a crystalline solid. A 3.6 g sample of the amine was recrystallized from 65 ml of 8% toluene/hexane to yield 2.4 g (64%) of crystals, m.p. 72°-74°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:6]=1[CH:18](Br)Br)[CH3:2].[O:22]1CCCC1>O.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:6]=1[CH:18]=[O:22])[CH3:2]
Reactant: CCOC(=O)c1ccc(Oc2ccccc2)cc1C(Br)Br
Reactant: C1CCOC1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: CCOC(=O)c1ccc(Oc2ccccc2)cc1C=O

Procedure:
2-Dibromomethyl-4-phenoxy-benzoic acid ethyl ester (2.07 g) was dissolved in tetrahydrofuran (40 mL) and water (15 mL). Silver nitrate (2.56 g) was added. The resulting mixture was heated to reflux for 5 h. The precipitate was filtered off and the reaction was diluted with ethyl acetate. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The combined ethyl acetate layer was washed with saturated sodium bicarbonate solution, brine, and dried with magnesium sulfate. After concentration, the crude oil was diluted with 20% ethyl acetate in hexanes (100 mL) and filtered through a pad of silica gel. Further rinse was continued twice. The filtrate solution was concentrated to give the title compound 1.13 g as an oil. 1H NMR (200 MHz, CDCl3) δ 10.62 (s, 1H), 7.98 (d, J=8.6 Hz, 1H), 7.42-7.35 (m, 3H), 7.20-7.14 (m, 2H), 7.04 (d, J=8.2, 2H), 4.41 (q, J=7.0 Hz, 2H), 1.41 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:17](=[O:18])[O:16][C:14](=[O:15])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(O)(O)(=O)=O.[CH3:24][O:25][C:26](=[O:36])[C@H:27]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH2:28].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH3:24][O:25][C:26](=[O:36])[C@H:27]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH:28][C:17](=[O:18])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C1C[C@H](NC(=O)OCc2ccccc2)C(=O)O1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Reaction time: 4 h
Yield: 73.1 %

Procedure:
In 100.4 g of acetic acid, 25.1 g (0.1 mole) of N-benzyloxycarbonyl-L-aspartic anhydride was suspended and 22.7 g (0.1 mole) of L-phenylalanine methyl ester sulfate was added with stirring at 5°-10° C. Successively 17.6 g (0.21 mole) of sodium acetate was added at the same temperature. The reaction was carried out for 4 hours with stirring at the same temperature. Thereafter 87.1 g of water was added to the reaction mixture to adjust the concentration of organic carboxylic acid to 53.5% by weight. After cooling to 0°-5° C., precipitated crystals were filtered, washed and dried. Crystals of N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester were obtained. The yield was 31.2 g (73.1% yield on L-phenylalanine methyl ester sulfate).
Reaction SMILES: CCCCC.[H-].[Na+].O.[SH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[NH:12][CH:13]=[N:14]2.Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([CH:29]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1>CN(C=O)C.CO.C(Cl)Cl>[F:43][C:40]1[CH:41]=[CH:42][C:37]([CH:29]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[N:26]2[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][CH2:20][S:9][C:10]3[N:18]=[CH:17][N:16]=[C:15]4[C:11]=3[NH:12][CH:13]=[N:14]4)[CH2:28][CH2:27]2)=[CH:38][CH:39]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCN(CCCCl)CC2)cc1
Reactant: Sc1ncnc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: O
Solvent: CO
Product: Fc1ccc(C(c2ccc(F)cc2)N2CCN(CCCSc3ncnc4nc[nH]c34)CC2)cc1
Temperature: 0 °C
Yield: 44.6 %

Procedure:
Pentane (10mL) was added to sodium hydride (0.3 g, 6.3 mmol, 50% suspension in mineral oil), and the mixture was stirred under nitrogen. The pentane was decanted, anhydrous DMF (12 mL) was added and the suspension was cooled to 0° C. 6-Mercaptopurine monohydrate (0.93 g, 5.5 mmol) was added in small portions over a 15 min period. To the light beige, slightly hazy mixture was added, after an additional 10 min at 0° C., 1-(1-chloro-3-propanyl)-4-[bis(4-fluorophenyl)methyl]piperazine (2.0 g, 5.5 mmol) dissolved in anhydrous DMF (4 mL) within 5 min. After addition was complete, the mixture was allowed to warm to room temperature and it was stirred under nitrogen for 4 days. The DMF was evaporated in vacuo (1 mm Hg) at 50° C. The residue was triturated in methylene chloride and the mixture was filtered through celite. The filtrate was washed with water (2×50 mL), dried (sodium sulfate), filtered, and evaporated in vacuo to give the crude product (2.79 g). Silica gel flash chromatography using 10% methanol/methylene chloride gave the desired product (1.18 g, 45%) mp 90°-93° C. 300 MHz 1H NMR (CDCl3)δ: 8.60 (s, 1H), 8.14 (s, 1H), 7.31 (m, 4H), 6.95 (m, 4H), 4.17 (s, 1H), 3.38 (m, 2H), 2.35-2.6 (m, 10H), 2.02 (m, 2H). DCI/MS (M+1) 481.
Reaction SMILES: O1CCCC1.[CH3:6][C:7]1[C:11]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:13]=2[CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[C:10]([CH3:26])[O:9][N:8]=1.CCO.[OH-].[Na+]>O>[CH3:6][C:7]1[C:11]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:13]=2[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[C:10]([CH3:26])[O:9][N:8]=1
Reactant: CCOC(=O)CCc1ccc(O)cc1-c1c(C)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1noc(C)c1-c1cc(O)ccc1CCC(=O)O
Reaction time: 16 h
Yield: 43.7 %

Procedure:
To a 10 mL RB flask fitted with magnetic stirrer was charged with 3 mL of tetrahydrofuran. To the stirred solvent were added ethyl 3-[2-(3,5-dimethyl-1,2-oxazol-4-yl)-4-hydroxy phenyl]propanoate (0.10 g, 0.35 mmol), ethanol (3 mL) and sodium hydroxide (0.015 g, 0.0.35 mmol) in water (0.5 mL). The reaction mixture was stirred at room 16 h. After completion of the reaction, the solvent was removed, the sodium salt was washed with diethyl ether (5 mL); the aqueous layer was acidified with 1N HCl to pH 2.0 and extracted with ethyl acetate (5 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to obtain the product (0.04 g, yield: 44.4%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.[H-].[Na+].[CH3:9][Si:10]([CH3:17])([CH3:16])[CH2:11][CH2:12][O:13][CH2:14]Cl.[Cl-].[NH4+]>CN(C)C=O>[CH3:9][Si:10]([CH3:17])([CH3:16])[CH2:11][CH2:12][O:13][CH2:14][N:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1
Reactant: Nc1cc[nH]n1
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc(N)n1
Reaction time: 0.5 h

Procedure:
To a solution of 10 g of 1H-pyrazol-3-amine in 100 ml of N,N-dimethylformamide was added 9.6 g of sodium hydride (60%, in oil) under cooling with ice. The reaction mixture was stirred for 30 minutes, and then 21.3 ml of 2-(trimethylsilyl)ethoxymethyl chloride was added thereto. After stirring the resulting mixture at room temperature for 1 hour, aqueous ammonium chloride was added thereto, and the mixture was extracted with chloroform. The resulting organic layer was washed with water and brine, and then dried over magnesium sulfate. The organic layer was filtered and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=4/1 to 1/2) to give the title compound.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[C:27]([NH:30][CH2:31][C:32](O)=O)(=[O:29])[CH3:28]>>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17]2[N:18]=[C:32]([CH2:31][NH:30][C:27](=[O:29])[CH3:28])[O:20][N:19]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: CC(=O)NCC(=O)O
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1C[C@@H](c2noc(CNC(C)=O)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and (acetylamino)acetic acid, the title compound was obtained in 72% purity by HPLC. MS(ESI+): m/z=434.2.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]1[C:20]2[C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17][C:16]=2[CH:15]=[C:14]([CH:25]([N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[CH3:26])[CH:13]=1.C(=O)(O)[O-].[Na+].[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41]>C(Cl)(Cl)Cl.CC(C)=O>[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].[N:27]1([CH:25]([C:14]2[CH:13]=[CH:12][C:20]3[C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[S:17](=[O:9])[C:16]=3[CH:15]=2)[CH3:26])[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(c1ccc2c(c1)sc1ccccc12)n1ccnc1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC(c1ccc2c(c1)S(=O)c1ccccc1-2)n1ccnc1
Reaction time: 2 h
Yield: 63.6 %

Procedure:
Under ice-cooling, m-chloroperbenzoic acid (0.18 g) was gradually added in small portions to a solution of 1-[1-(dibenzothiophen-3-yl) ethyl]-1H-imidazole (0.2 g) obtained in Example 8 in chloroform (5 ml), and the mixture was stirred at the same temperature for 2 hours. A saturated sodium bicarbonate aqueous solution was added and the chloroform layer was separated and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the resulting residue was purified by silica gel column chromatography to obtain an oily material from a chloroform-methanol (100:1) eluate. This oily material was dissolved in acetone and mixed with 40 mg of fumaric acid which was dissolved by heating. After cooling, the thus precipitated crystals were washed with acetone to obtain 90 mg of 3-[1-(1H-imidazo1-1-yl)ethyl]dibenzothiophene-5-oxide monofumarate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@@H:4]([NH:14]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[CH:7]=1.C(OC(N[C@@H](CC1C=C(F)C=C(F)C=1)C(OC)=O)=O)C1C=CC=CC=1.Cl.C(=O)(O)[O-].[Na+]>CO>[NH2:14][C@@H:4]([CH2:5][C:6]1[CH:7]=[C:8]([F:13])[CH:9]=[C:10]([F:12])[CH:11]=1)[C:3]([O:2][CH3:1])=[O:22]
Reactant: COC(=O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Agent: COC(=O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1cc(F)cc(F)c1

Procedure:
(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid methyl ester (II, EXAMPLE 1, 0.60 g (0.002 moles, 1 equivalent), methanol (20 mL) and hydrochloric acid (3N, 20 mL) are mixed. The mixture is then heated to 500 and stirred until complete as measured by HPLC. When the reaction is complete, the contents are cooled to 20-25° and the pH of the mixture is adjusted to 8 with saturated sodium bicarbonate and then concentrated under reduced pressure. This mixture is extracted with ethyl acetate (2×20 mL) and the combined organic phases are dried over sodium sulfate, filtered and concentrated, HPLC (Retention time=2.89 min; Zorbax RX-C8 acetonitrile/0.05M potassium dihydrogen phosphate, 60/40; 1.0 mL/min, λ=210 nm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9](Br)[CH:10]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:50]([C:52]([C:71]1[CH:76]=[CH:75][C:74]([C:77]#[C:78][C:79]2([O:85][Si:86]([CH3:89])([CH3:88])[CH3:87])[CH2:84][CH2:83][O:82][CH2:81][CH2:80]2)=[C:73]([CH3:90])[CH:72]=1)([C:55]1[CH:60]=[CH:59][C:58](B2OC(C)(C)C(C)(C)O2)=[C:57]([CH3:70])[CH:56]=1)[CH2:53][CH3:54])[CH3:51].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:58]2[CH:59]=[CH:60][C:55]([C:52]([CH2:53][CH3:54])([C:71]3[CH:76]=[CH:75][C:74]([C:77]#[C:78][C:79]4([O:85][Si:86]([CH3:87])([CH3:89])[CH3:88])[CH2:84][CH2:83][O:82][CH2:81][CH2:80]4)=[C:73]([CH3:90])[CH:72]=3)[CH2:50][CH3:51])=[CH:56][C:57]=2[CH3:70])[CH:10]=1
Reactant: COC(=O)Cc1cncc(Br)c1
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCOCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCOCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 90.7 %

Procedure:
(5-Bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 40 mg, 0.173 mmol), palladium acetate (2.7 mg, 0.012 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (9.9 mg, 0.024 mmol), potassium phosphate (74 mg, 0.348 mmol) and water (0.2 mL) were added to a solution of 4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenylethynyl)-4-trimethylsilanyloxy-tetrahydro-pyran (Example 130-(4); 66.4 mg, 0.116 mmol) in toluene (3 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for 3.5 hours. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the target compound as a colorless oil (62.9 mg, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][OH:15]>>[NH2:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][C:4]=1[O:15][CH2:14][CH2:13][N:12]([CH3:16])[CH3:11]
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: CN(C)CCO
Product: CN(C)CCOc1cc(Cl)ccc1CN

Procedure:
The title compound is synthesized by coupling followed by reduction of 4-chloro-2-fluoro-benzonitrile and 2-dimethylamino-ethanol analogously to the preparation of Intermediate 113.1. colorless oil; ES-MS: M+=229.2; HPLC: AtRet=1.18 min.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][C:18](=O)[NH:17][CH2:16][CH:15]2[CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)=[CH:10][CH:9]=1>O1CCCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH:15]2[CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)=[CH:10][CH:9]=1
Reactant: O=C1CC(c2ccc(F)cc2)C(COc2ccc3c(c2)OCO3)CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc(C2CCNCC2COc2ccc3c(c2)OCO3)cc1
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of lithium aluminium hydride in tetrahydrofuran (1.0M solution, 2 ml, 2.0 mmol) was added over ten minutes to a well stirred solution of 4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine-6-one (0.41 g, (0.96 mmol) in tetrahydrofuran (7 ml), maintaining the temperature below 25° C. The reaction solution was stirred for 2 hours and then quenched first of all with water (0.16 ml), then with 15% aqueous sodium hydroxide solution (0.1 ml), and finally with water again (0.4 ml). The reaction mixture was stirred for 0.5 hours to complete the precipitation, diluted with dichloromethane (30 ml) and filtered. The filtrate was evaporated in vacuo to give the title product with a trans/cis ratio=72:28. Yield 90%.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:38])[C:22]([C:24]4[N:25]=[C:26]([NH:29][C:30]([O:32][C:33]([CH2:36][CH3:37])([CH3:35])[CH3:34])=[O:31])[S:27][CH:28]=4)=[O:23])[C:18](=[O:39])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:4][N:3]=1.[OH-].[Na+].[BH4-].[Na+]>CO.O>[CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:38])[CH:22]([OH:23])[C:24]4[N:25]=[C:26]([NH:29][C:30]([O:32][C:33]([CH2:36][CH3:37])([CH3:34])[CH3:35])=[O:31])[S:27][CH:28]=4)[C:18](=[O:39])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:4][N:3]=1
Reactant: CCC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnc(C)s4)CS[C@H]23)cs1
Agent: CCC(C)(C)OC(=O)N=c1[nH]c(C(=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnc(C)s4)CS[C@H]23)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(C)(C)OC(=O)Nc1nc(C(O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnc(C)s4)CS[C@H]23)cs1
Reaction time: 0.17 h

Procedure:
To a solution of 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, (3.36 g.) in methanol (35 ml.) was added 1 N sodium hydroxide aqueous solution (5.5 ml.) under ice-cooling, and to the mixture was dropwise added an aqueous solution of sodium borohydride (91 mg.) in water (2.5 ml.) over 2 minutes at 10° to 15° C. The mixture was stirred for 10 minutes at the same temperature, and then methanol was distilled off from the mixture below 40° C. under reduced pressure. The remaining aqueous solution was washed with a small amount of ethyl acetate, adjusted to pH 5 to 6, with 10% hydrochloric acid, further washed with a small amount of ethyl acetate. The solution was adjusted to pH 2 with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate and then treated with an activated charcoal. The solvent was distilled off from the extract till the volume of the extract became a small amount. The precipitates were collected by filtration, washed with a small amount of ethyl acetate, and then dried to give 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (1.69 g.). On the other hand, the mother liquor and the ethyl acetate washing were combined together and concentrated under reduced pressure, and then the precipitates were similarly treated as aforementioned to give the same object compound (0.80 g.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[CH:11]1(B(O)O)[CH2:13][CH2:12]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH:11]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]#[N:10])[CH2:13][CH2:12]1
Reactant: OB(O)C1CC1
Reactant: N#CCc1ccccc1Br
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CCc1ccccc1C1CC1
Temperature: 100 °C
Reaction time: 48 h
Yield: 63.6 %

Procedure:
To a solution of 0.784 g (4 mmol) 2-bromophenyl-acetonitrile in 16 ml toluene were added 0.8 ml water, 0.412 g (4.8 mmol) cyclopropylboronic acid, 2.97 g (14 mmol) tribasic potassium phosphate, 0.1 12 g (0.4 mmol) tricyclohexylphosphine and 0.045 g (0.2 mmol) palladium(II) acetate. The reaction mixture was stirred at 100° C. for 2 days. The solvent was evaporated and the residue taken up in water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified using column chromatography (SiO2, heptane/ethyl acetate 98:2) to yield 0.40 g of (2-cyclopropyl-phenyl)-acetonitrile as a light-yellow oil that was used directly for the next step.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH:17]=[C:16]4[CH2:19][CH2:20][CH2:21][C@@H:22]5[CH2:27][C@@:26]([OH:32])([C:28]([F:31])([F:30])[F:29])[CH2:25][CH2:24][C@@:23]5([C:33]#[N:34])[C:15]4=[CH:14][C:13]=3[CH:12]=[N:11]2)=[CH:6][CH:5]=1.Br[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[CH2:36]([O:32][C@@:26]1([C:28]([F:31])([F:30])[F:29])[CH2:27][C@H:22]2[CH2:21][CH2:20][CH2:19][C:16]3[C:15](=[CH:14][C:13]4[CH:12]=[N:11][N:10]([C:7]5[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=5)[C:18]=4[CH:17]=3)[C@:23]2([C:33]#[N:34])[CH2:24][CH2:25]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: N#C[C@@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#C[C@@]12CC[C@](OCc3ccccc3)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
To a suspension of sodium hydride (60 wt % in oil, 103 mg, 2.57 mmol) in DMF (5 mL) was added a solution of (3R,4aR,12bS)-9-(4-fluorophenyl)-3-hydroxy-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carbonitrile (32, R1=4-Fluorophenyl, R3=Trifluoromethyl) (760 mg, 1.71 mmol) in DMF (15 mL) at a dropwise rate. The reaction was stirred for about 10 min at rt, then (bromomethyl)benzene (0.26 mL, 2.14 mmol) was added. The mixture was stirred for about 1 h. Solvents were removed under reduced pressure. The residue was dissolved in DCM (50 mL) and washed with water (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated onto silica gel (10 g). The crude product was purified on silica gel (40 g) using a gradient of 20-40% EtOAc in heptane. Product fractions were combined and concentrated under reduced pressure to yield (3R,4aR,12bS)-3-(benzyloxy)-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carbonitrile (33, R1=4-Fluorophenyl, R3=Trifluoromethyl, Rx=Benzyl) (890 mg, 97%) as a white solid; LC/MS, method 3, Rt=3.08 min, MS m/z 534 (M+H)+, 1H NMR (400 MHz, DMSO) δ 8.35 (d, J=0.8 Hz, 1H), 8.12 (s, 1H), 7.86-7.78 (m, 2H), 7.71 (s, 1H), 7.48-7.29 (m, 7H), 4.80-4.66 (m, 2H), 3.41-3.31 (m, 1H), 3.13-3.01 (m, 1H), 2.74-2.62 (m, 1H), 2.61-2.51 (m, 1H), 2.29-2.22 (m, 1H), 2.18-1.93 (m, 4H), 1.89-1.70 (m, 3H), 1.42-1.27 (m, 1H).