Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH:7]=O.[BH4-].[Na+].[CH3:16][NH2:17]>CO>[Cl:1][C:2]1[C:3]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH2:7][NH:17][CH3:16]
Reactant: O=Cc1sc2cccc(F)c2c1Cl
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1sc2cccc(F)c2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
A solution of 3-chloro-4-fluoro-benzo[b]thiophene-2-carbaldehyde (880 mg, 4.04 mmol) in CH3NH2 (20 mL of a 2.0 M solution in MeOH, 40 mmol) was stirred at room temperature overnight. The mixture was concentrated. The residue was dissolved in EtOH (30 mL), and after cooling in an ice bath, NaBH4 (153 mg, 4.04 mmol) was added. The mixture was slowly warmed to room temperature and then stirred overnight. The mixture was concentrated. The residue was taken up in NaOH (30 mL) and the mixture was extracted with Et2O (3×). The combined organics were washed with satd NaCl, dried (Na2SO4) and concentrated. Purification by column chromatography (silica gel, 95:5 CH2Cl2/MeOH) gave the title compound (443 mg, 48%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.54 (dd, J=8.0, 0.6 Hz, 1H), 7.27 (ddd, J=8.0, 8.0, 4.6 Hz, 1H), 7.03 (ddd, J=11.4, 8.0, 0.6 Hz, 1H), 4.05 (s, 2H), 2.53 (s, 3H), 1.55 (s, 1H).
Reaction SMILES: [Na].[CH2:2]([SH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:12][C:13](=[O:33])[C:14]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)(COS(C)(=O)=O)[C:15](OCC)=O)[CH3:11]>C(O)C>[CH2:10]([O:12][C:13](=[O:33])[CH:14]([CH2:15][S:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH3:11]
Reactant: SCc1ccccc1
Reactant: CCOC(=O)C(COS(C)(=O)=O)(CC1CCCCC1)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CSCc1ccccc1)CC1CCCCC1
Temperature: 0 °C
Reaction time: 24 h
Yield: 18.4 %

Procedure:
Sodium (0.097 g, 4.2 mmol) was dissolved in ethanol (10 mL) and the resulting solution was cooled to 0° C. and treated with a mixture comprising benzyl mercaptan (0.493 mL, 4.2 mmol) and 2-cyclohexylmethyl-2-methylsulfonyloxymethyl-malonic acid diethyl ester (1.466 g, 4.02 mmol). The reaction was stirred at room temperature for 17 hours, 53° C. for 20 hours and 73° C. for 24 hours. The ethanol was removed by rotary evaporation, the reaction mixture was poured into water and the product was extracted with ethyl acetate. The extracts were washed with saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed by rotary evaporation at reduced pressure and the residue was chromatographed on silica gel eluting with ethyl acetate/hexane to give 2-benzylsulfanylmethyl-3-cyclohexyl-propionic acid ethyl ester (0.237 g).
Reaction SMILES: [N:1]1[N:2]2[CH2:10][CH2:9][CH2:8][C:3]2=[CH:4][C:5]=1[CH2:6][OH:7]>O=[Mn]=O.C(Cl)(Cl)Cl>[N:1]1[N:2]2[CH2:10][CH2:9][CH2:8][C:3]2=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: OCc1cc2n(n1)CCC2
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: O=Cc1cc2n(n1)CCC2

Procedure:
MnO2 (activated) (24.4 g) was added to the CHCl3 (350 mL) solution of (5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methanol (4.87 g) and refluxed for 1 h under a nitrogen atmosphere. The reaction mixture was filtered through a pad of Celite. The filtrate was reduced under reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with n-hexane-AcOEt (1/1-1/2). The title compound was obtained as yellow oil (4.35 g, 91%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O.C(OCC)(=O)C>[F:16][C:15]([F:17])([F:18])[CH2:14][CH2:13][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][OH:11]
Reactant: CC(C)(C)OC(=O)NC(CCC(F)(F)F)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NC(CO)CCC(F)(F)F
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a stirred solution of 2-((tert-butoxycarbonyl)amino)-5,5,5-trifluoropentanoic acid (500 mg, 1.843 mmol) in THF (15 mL) cooled to −10° C. under nitrogen atmosphere was added N-methylmorphline (0.223 mL, 2.028 mmol) followed by isobutyl chloroformate (0.266 mL, 2.028 mmol) dropwise. The solution was then stirred for 30 min then filtered. The filtrate was added to sodium borohydride (147 mg, 3.87 mmol) in water (10 mL), stirred for 5 min and diluted with ethyl acetate (10 mL). The organic layer was separated and washed with brine (2×10 mL), dried (Na2SO4) and evaporated under reduced pressure to afford tert-butyl (5,5,5-trifluoro-1-hydroxypentan-2-yl)carbamate (400 mg, 1.555 mmol, 84% yield) as a white solid which was taken to the next step without further purification. 1H NMR (400 MHz, MeOD) δ 3.44-3.56 (m, 3H), 2.16-2.26 (m, 2H), 1.83-1.92 (m, 1H), 1.57-1.67 (m, 1H), 1.47 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].[C:13]1([Mg]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.CO.C(O)(C(F)(F)F)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([OH:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1Nc2c(F)cccc2C1=O
Reactant: Br[Mg]c1ccccc1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C1Nc2c(F)cccc2C1(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirring solution of 7-fluoroindoline-2,3-dione (12.22 g, 74 mmol) in THF (40 mL) at 0° C. was added phenylmagnesium bromide (148 mL, 148 mmol) dropwise. The reaction mixture was allowed to stir at room temperature after addition was completed. The reaction mixture was judged complete by HPLC after 15 min. The reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel chromatography (EtOAc/hexane) to afford Intermediate A11A (18.84 g, 88%) as yellow solid: HPLC: RT=1.810 min (H2O/MeOH with TFA, CHROMOLITH® SpeedROD, 4.6×50 mm, gradient=4 min, wavelength=220 nm); MS(ES): m/z=226 [M+H+—H2O]; 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.37-7.25 (m, 5H), 7.19 (ddd, J=10.4, 8.1, 1.3 Hz, 1H), 7.04-6.92 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].[NH4+].[Cl-]>ClCCl.CN(C)C1C=CN=CC=1>[Si:20]([O:1][CH2:2][CH:3]1[CH2:4][CH2:5][CH:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C1CCC(CO)CC1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CCC(CO[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 391A (43.6 g) and triethylamine (42.3 mL) in dichloromethane (633 mL) was added tert-butyldimethylsilyl chloride (38.1 g) and 4-dimethylaminopyridine (3.09 g) and the reaction was stirred overnight at room temperature. A saturated solution of aqueous NH4Cl was added and the layers were separated. The organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated by rotary evaporation. The residue was purified by regular phase flash column chromatography (Analogix, 0-40% hexanes/ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[C:29]#[N:30])[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[CH3:25])=[O:6].C=O.[C:33](O)(=O)C.[BH4-].[Na+]>C(#N)C>[C:29]([C:28]1[CH:27]=[CH:26][C:4]([C:5]([NH:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:24])([C:20]([F:21])([F:22])[F:23])[C:16]([F:17])([F:18])[F:19])=[CH:10][C:9]=2[CH3:25])=[O:6])=[CH:3][C:2]=1[NH:1][CH3:33])#[N:30]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C#N)c(N)c1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: CNc1cc(C(=O)Nc2c(C)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2C)ccc1C#N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 58 %

Procedure:
3-Amino-4-cyano-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide (3.01 g, 6.95 mmol) (Example I2) was dissolved in acetonitrile (50 ml) and aqueous formaldehyde (36.5% w/v) (0.64 ml, 6.95 mmol) and acetic acid (30 ml) were added successively. The reaction mixture was stirred at ambient temperature for 45 minutes. Then sodium borohydride (0.44 g, 6.95 mmol) and more acetic acid (5 ml) were added. The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and the solution washed with aqueous sodium hydroxide (1N). The aqueous phase was extracted three times with ethyl acetate (200 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:5) to give 4-cyano-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-3-methylamino-benzamide (1.80 g, 58% yield). M.p. 204-206° C. 1H-NMR (400 MHz, CDCl3): 7.53 (d, 1H), 7.37 (s, 3H), 7.23 (s, 1H), 7.10 (q, 1H), 5.88 (d, 1H), 3.02 (d, 3H), 2.35 (s, 6H) ppm.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]1[CH2:18][CH:17]([F:19])[CH2:16][CH:15]1[CH2:20]O)=[O:13])([CH3:10])([CH3:9])[CH3:8].[NH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.ClCCCl.CC(O)=O.O.C(N(CC)CC)C.CS(C)=O>[C:7]([O:11][C:12]([N:14]1[CH2:18][CH:17]([F:19])[CH2:16][CH:15]1[CH2:20][NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=1)=[O:13])([CH3:8])([CH3:9])[CH3:10]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CC(F)CC1CO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccc(NCC2CC(F)CN2C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 76.8 %

Procedure:
To a stirred solution of oxalyl chloride (0.28 ml, 2.3 mmol) in CH2Cl2 (20.0 ml) was added DMSO (0.39 ml) at −78° C. After 5 minutes, to the mixture was added 1-tert-butoxycarbonyl-4-fluoro-2-pyrrolidinylmethanol (500 mg, 2.28 mmol) in CH2Cl2 (5.0 ml). The mixture was stirred for 30 minutes at −78° C., and triethylamine (1.6 ml) was added The mixture was stirred for 30 minutes at −78° C., and stirred for 30 minutes at room temperature. Water was added to the mixture, and extracted with CH2Cl2. The organic layer was dried over Na2SO4, and concentrated in vacuo. The crude product was used to the subsequent reaction without further purification. To a stirred solution of the crude product, methyl 4-aminobenzoate(302 mg, 2.0 mmol), and AcOH (0.13 ml) in DCE (10 ml) was added NaBH(OAc)3 (656 mg, 3.09 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 hr. The mixture was concentrated in vacuo. Sat. NaHCO3 was added to the residue, and extracted with CH2Cl2. The extract was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with EtOAc-n-hexane (1:3, v/v) as eluent to give methyl 4-(1-tert-butoxycarbonyl-4-fluoro-2-pyrrolidinyl)methylaminobenzoate (541 mg, 77%) as a pale yellow oil. 1H-NMR (CDCl3) δ1.55-1.59 (m, 1H), 2.16-2.27 (m, 1H), 2.89-3.03 (m, 2H), 3.19-3.28 (m, 2H), 3.69-3.73 (m, 1H), 3.84 (s, 3H), 5.15 and 5.29 (each s, total 1H), 6.55-6.58 (m, 2H), 7.84-7.86 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][C@@H]2CCC[C@H]2O)=[CH:4][C:3]=1F.[Br:16][C:17]1[N:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C12OC1CCCC2>>[Br:16][C:17]1[N:22]=[CH:21][C:20]([O:23][C@@H:4]2[CH2:3][CH2:2][CH2:14][CH2:13][C@H:5]2[OH:6])=[CH:19][CH:18]=1
Reactant: O[C@@H]1CCC[C@H]1Oc1ccc(Br)c(F)c1
Reactant: Oc1ccc(Br)nc1
Agent: C1CCC2OC2C1
Product: O[C@@H]1CCCC[C@H]1Oc1ccc(Br)nc1

Procedure:
The title compound of Step 1 was prepared according to the general procedure for the synthesis of trans-2-(4-bromo-3-fluorophenoxy)cyclopentanol in Preparation 3, except that 6-bromopyridin-3-ol was used instead of 4-bromo-3-fluorophenol, and 7-oxabicyclo[4.1.0]heptane in place of 6-oxabicyclo[3.1.0]hexane. The crude product (preparation run in four batches) was recrystallized from heptane to provide trans-2-[(6-bromopyridin-3-yl)oxy]cyclohexanol as an off-white solid. Yield: 11.09 g, 40.75 mmol, 46%. 1H NMR (500 MHz, CDCl3) δ 1.27-1.46 (m, 4H), 1.76-1.80 (m, 2H), 2.09-2.13 (m, 2H), 2.41 (d, J=2.6 Hz, 1H), 3.74 (m, 1H), 4.00 (m, 1H), 7.17 (dd, J=8.7, 3.1 Hz, 1H), 7.37 (d, J=8.5 Hz, 1H), 8.10 (d, J=3.0 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH:14]=1)([O-])=O.O.NN.N.C(Cl)Cl>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc2[nH]cc(C3=CCN(CCO)CC3)c2c1
Agent: [Ni]
Agent: N
Agent: NN
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Nc1ccc2[nH]cc(C3=CCN(CCO)CC3)c2c1
Yield: 86.9 %

Procedure:
A solution of 2-(4-(5-nitro-1H-indol-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanol (0.225 g, 0.783 mmol) in dry methanol (5 mL) was treated with hydrazine hydrate (0.244 mL, 7.83 mmol), followed by Raney-nickel (0.1 g, 0.783 mmol) at room temperature. The resulting mixture was placed in a pre-heated oil bath and refluxed for 5 minutes (TLC basis, 2 M NH3 in MeOH:CH2Cl2, 1:9). The reaction was brought to room temperature, filtered through a Celite bed, and washed with methanol (3×10 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 1:9) to obtain 2-(4-(5-amino-1H-indol-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanol (0.175 g, 87%) as a solid. 1H NMR (DMSO-d6) δ 10.59 (s, 1H), 7.15 (d, 1H, J=2.4 Hz), 7.05 (d, 1H, J=8.4 Hz), 6.99 (s, 1H), 6.48 (dd, 1H, J=1.8, 8.4 Hz), 5.96 (s, 1H), 4.48 (brs, 2H), 4.40 (t, 1H, J=5.4 Hz), 3.55 (q, 2H), 3.16-3.10 (m, 2H), 2.65 (t, 2H, J=5.7 Hz), 2.50-2.45 (m, 4H); ESI-MS (m/z, %): 258 (MH+, 30), 185 (100).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][Cl:22].C(Cl)Cl>CN(C=O)C>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:6]1[CH:7]=[C:2]([CH3:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: ClCCCCCBr
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cn(CCCCCCl)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
5-methyl-2,4(1H,3H)-pyrimidinedione (commercially available, 0.55 g, 3.97 mmol) was dissolved in dry DMF (15 mL). K2CO3 (0.548 g, 3.97 mmol) was added and the mixture stirred at room temperature for 1 hour. 1-bromo-5-chloropentane (0.526 ml, 3.97 mmol) was then added and the suspension was stirred at room temperature for 4 h. The volume of solvent was reduced, then DCM was added and the organic layer was washed with water, the organic phase was evaporated and the crude purified by FC (DCM/MeOH 98/2-95/5) to afford 0.1 g of the title compound (y=11%).
Reaction SMILES: [C:1]1(OP(OC2C=CC=CC=2)OC2C=CC=CC=2)C=CC=C[CH:2]=1.BrC1C=CC(CCBr)=CC=1.BrC1C=CC(CCO)=CC=1.CC(C)([O-])C.[K+].[CH2:49]([CH:52]1[CH2:57][CH2:56][CH:55]([CH:58]2[CH2:63][CH2:62][CH:61]([CH2:64][CH:65]=O)[CH2:60][CH2:59]2)[CH2:54][CH2:53]1)[CH2:50][CH3:51]>CCOCC.C1COCC1.C1(C)C(C)=CC=CC=1>[CH2:49]([CH:52]1[CH2:57][CH2:56][CH:55]([CH:58]2[CH2:63][CH2:62][CH:61](/[CH:64]=[CH:65]\[CH2:1][CH3:2])[CH2:60][CH2:59]2)[CH2:54][CH2:53]1)[CH2:50][CH3:51]
Reactant: CCCC1CCC(C2CCC(CC=O)CC2)CC1
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Agent: BrCCc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: OCCc1ccc(Br)cc1
Solvent: Cc1ccccc1C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC/C=C\C1CCC(C2CCC(CCC)CC2)CC1

Procedure:
Into a flask, were placed triphenylphosphite (2.6 g, 10 mmol) and 4-bromophenethylbromide (2.6 g, 10 mmol) prepared from 4-bromophenethylalcohol, followed by adding and dissolving xylene (10 ml), heating under reflex for 10 hours after the completion of reaction, filtering off the deposited white crystals of 4-bromo-phenethyltriphenylphosphoniumbromide, and drying the white crystals (5.1 g, 9.5 mmol). The obtained white crystals were dissolved into THF (30 ml), followed by stirring under ice cooling, adding potassium-t-butoxid (1 g, 9 mmol) slowly into the reaction solution, stirring the solution at room temperature for 2 hours after the completion of dropping, adding THF (20 ml) solution of 4-(4-propylcyclohexyl)cyclohexylacetaldehyde (2.2 g, 9 mmol), further stirring for 5 hours, adding ether after the completion of reaction, filtrating off white solid deposited, concentrating the filtrate under reduced pressure, purifying the obtained brown oil by means of silica gel chromatography, to obtain a mixture (2.2 g, 5.3 mmol) of 1-(4-bromophenyl)-4-(4-(4-propylcyclohexyl)cyclohexyl-2Z-butene with its E-isomer.
Reaction SMILES: CO.C(O)(=O)C.O.[CH3:8][O:9][N:10]=[C:11]([C:37]1[N:41]=[C:40]([NH2:42])[S:39][N:38]=1)[C:12]([NH:14][CH:15]1[C:35](=[O:36])[N:17]2[C:18]([C:22]([O:24]CC3C=CC([N+]([O-])=O)=CC=3)=[O:23])=[CH:19][CH2:20][S:21][C@H:16]12)=[O:13]>O1CCCC1.[C].[Pd]>[CH3:8][O:9][N:10]=[C:11]([C:37]1[N:41]=[C:40]([NH2:42])[S:39][N:38]=1)[C:12]([NH:14][CH:15]1[C:35](=[O:36])[N:17]2[C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH2:20][S:21][C@H:16]12)=[O:13]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1nsc(N)n1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.4 %

Procedure:
In a mixture of tetrahydrofuran (20 ml), methanol (10 ml), acetic acid (0.25 ml) and water (2.5 ml) was dissolved 4-nitrobenzyl 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate (syn isomer) (0.87 g) and thereto was added 5% palladium-carbon (0.87 g). The resulting mixture was shaken under a hydrogen atmosphere at atmospheric pressure and ambient temperature for 6 hours. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was dissolved in an aqueous solution of sodium bicarbonate and the solution was washed with ethyl acetate. The aqueous layer was adjusted to pH 2 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated to dryness. The residue was triturated with diethyl ether to give the title compound (350 mg), mp. 190° to 195° C. (dec.).
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[C:4](=[CH2:13])[CH2:3]1.[C:14](Cl)(=[O:17])[CH2:15][CH3:16]>N1C=CC=CC=1.C(Cl)Cl>[CH3:12][C:8]1[CH2:7][CH2:6][CH:5]2[C:9]=1[CH2:10][CH2:11][CH:2]([O:1][C:14](=[O:17])[CH2:15][CH3:16])[CH2:3][C:4]2=[CH2:13]
Reactant: C=C1CC(O)CCC2=C(C)CCC12
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C1CC(OC(=O)CC)CCC2=C(C)CCC12
Reaction time: 3 h
Yield: 96 %

Procedure:
A solution of 2.5 g of 6-hydroxy-1-methyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene in 5 ml of pyridine and 50 ml of methylene chloride was treated at -10° with 1.73 ml of propionyl chloride. After 3 hours stirring, the solution was poured on to ice and worked up in a conventional manner. After distillation of the crude product under high vacuum, there were obtained 3.15 g (96%) of pure 1-methyl-4-methylene-6-propionyloxy-2,3,3a,4,5,6,7,8-octahydroazulene; b.p.0.05 65-70°; IR(film): νmax = 1380, 1730, 1640, 1460, 1440, 1375, 1340, 1270, 1190, 1158, 1080, 1018, 895 cm-1. The compound has a woody, spicy, balsamic, slightly earthy odour.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[Br:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([C:31]2[CH:35]=[CH:34][N:33]([Si](C(C)C)(C(C)C)C(C)C)[CH:32]=2)[CH:30]=1>O>[Br:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([C:31]2[CH:35]=[CH:34][NH:33][CH:32]=2)[CH:30]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2cncc(Br)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Brc1cncc(-c2cc[nH]c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
Tetrabutylammonium fluoride (1M tetrahydrofuran solution: 1 ml) was added to a tetrahydrofuran (2 ml) solution containing 3-bromo-5-(1-(triisopropylsilyl)-1H-pyrrol-3-yl)pyridine (71 mg), followed by stirring at room temperature for 2 hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Then the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=5:1 to 2:1), and a white solid of 3-bromo-5-(1H-pyrrol-3-yl)pyridine (28 mg) was thus obtained.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:43]I>C(OCC)(=O)C>[I:43][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1
Reactant: CCCCCCCC(=O)c1ccc(CCO)cc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCCCCCCC(=O)c1ccc(CCI)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4′-(2-Hydroxy ethyl)octanophenone prepared in the step B (137 g), imidazole (53 g) and triphenyl phosphine (174 g) were dissolved in ethyl acetate (550 ml) to obtain a solution. Iodine (197 g) was added to the solution with cooling, and the solution was stirred at room temperature for 1 hour. Then the reaction solution was diluted with ethyl acetate, the solution was washed with saturated sodium sulfite solution, and saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated. The concentrated residue was extracted with hexane-ethyl acetate (20:1), and extracted solution was passed through a silica gel layer. The filtrate was concentrated to obtain 4′-(2-iodoethyl)octanophenone (175 g) in the form of white crystal.
Reaction SMILES: [CH3:1][C:2]1[N:3](C(OCC(C)C)=O)[C:4]2[C:5]([N:21]=1)=[N:6][CH:7]=[C:8]([C:10]1[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[CH:20]=1)[CH:9]=2.Cl[C:30]1[C:39]2[CH2:38][C:37]([CH3:41])([CH3:40])[CH2:36][CH2:35][C:34]=2[N:33]=[C:32]([CH2:42][N:43]([CH2:54][CH2:55][F:56])C(=O)OCC2C=CC=CC=2)[N:31]=1>>[CH3:40][C:37]1([CH3:41])[CH2:36][CH2:35][C:34]2[N:33]=[C:32]([CH2:42][NH:43][CH2:54][CH2:55][F:56])[N:31]=[C:30]([N:16]3[CH2:15][C:14]4[CH:20]=[C:10]([C:8]5[CH:9]=[C:4]6[NH:3][C:2]([CH3:1])=[N:21][C:5]6=[N:6][CH:7]=5)[CH:11]=[CH:12][C:13]=4[O:19][CH2:18][CH2:17]3)[C:39]=2[CH2:38]1
Reactant: CC1(C)CCc2nc(CN(CCF)C(=O)OCc3ccccc3)nc(Cl)c2C1
Reactant: Cc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2n1C(=O)OCC(C)C
Product: Cc1nc2ncc(-c3ccc4c(c3)CN(c3nc(CNCCF)nc5c3CC(C)(C)CC5)CCO4)cc2[nH]1

Procedure:
Prepared by the method of example 6 using 2-methylpropyl 2-methyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate and benzyl (4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)methyl(2-fluoroethyl)carbamate (reagent preparation 17) in step 3 followed by Cbz deprotection. 1H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 0.5H), 12.55 (s, 0.5H), 8.57 (d, 0.5H), 8.49 (d, 0.5H), 8.09 (d, 0.5H), 7.97 (d, 0.5H), 7.73 (d, 1H), 7.54 (dd, 1H), 7.03 (dd, 1H), 4.68 (s, 2H), 4.45 (t, 1H), 4.38-4.25 (m, 3H), 3.93-3.82 (m, 2H), 3.66 (s, 2H), 2.85-2.65 (m, 4H), 2.57-2.52 (m, 3H), 2.46 (s, 2H), 1.59 (t, 2H), 0.86 (s, 6H); MS (EI) for C29H34FN7O: 516 (MH+).