Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)(O)[CH2:6][CH2:5]2)[O:3]C1.O>C(O)(C(F)(F)F)=O>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:7]2[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH:6]=2)=[CH:16][CH:15]=1
Reactant: OC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC=C(c2ccc(F)cc2)CC1
Yield: 103.9 %

Procedure:
Compound 4-(4-Fluoro-phenyl)-4-hydroxy-cyclohexanone ethylene ketal (8.23 g, 32.6 mmol) from Step 1 was stirred in TFA (25 mL) for 15 minutes. The reaction mixture was poured into H2O (100 mL) and then extracted with CHCl3 (2×75 mL). The organic solution was washed with saturated bicarbonate, dried (Na2SO4), filtered and concentrated under reduced pressure to afford crude 1-(4-fluorophenyl)-cyclohexen-4-one (6.44 g): 1H NMR (300 MHz, CDCl3) δ 7.35 (dd, J=8, 8 Hz, 2H), 7.04 (dd, J=8, 8 Hz, 2H), 6.05 (m, 1H), 3.05 (m, 2H), 2.87 (m, 2H), 2.65 (dd, J=7, 7 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:21][O:20]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:7]=3[N:8]([CH2:18][C:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)([OH:20])[CH3:21])[C:9]=2[CH:10]=1
Reactant: CC1(c2ccncc2)CO1
Reactant: CN1CCc2[nH]c3cc(Cl)ccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3ccc(Cl)cc3n2CC(C)(O)c2ccncc2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A flask was charged with 7-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.2 g, 5.0 mmol) in DMF (10 mL) and stirred for 5 min. NaH (60% in hexane) (654 mg, 16 mmol) was added and the mixture stirred at RT for 10 min. Then 4-(2-methyloxiran-2-yl)pyridine (1.35 g, 10 mmol) was added and the mixture stirred at RT for 16 h. The progress of reaction was monitored by TLC. The reaction mixture was poured into ice water and filtered. The filtrate was washed with water and concentrated. The residue was recrystallized from ether to get pure product. 1HNMR (DMSO, HCl salt) d (ppm): 8.70 (d, 2H), 7.95 (d, 2H), 7.50 (m, 1H), 7.40 (m, 1H), 7.0 (t, 1H), 6.10 (m, 1H), 4.60 (m, 1H), 4.42-4.20 (m, 3H), 3.30 (m, 3H), 2.90 (s, 3H), 1.60 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[C:20]1([CH2:26][NH:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([N:33]3[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][NH:27][CH2:26][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:31][CH2:32]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: c1ccc(CNCCN2CCNCC2)cc1
Product: O=C(N1CCN(CCNCc2ccccc2)CC1)N1Cc2ccccc2Oc2ccc(Cl)cc21
Yield: 44.5 %

Procedure:
The title compound of Example 2 (0.72 g, 2.45 mmol) was combined with N-(phenylmethyl)-1-piperazineethanamine (0.75 g, 3.40 mmol) and the reaction was carried out by the method of Example 4. Following chromatographic separation, 0.52 g of the white solid title product was obtained.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18]C(O)=[C:16]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[O:22])[CH:15]=1.Cl>O1CCCC1.N1C=CC=CC=1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][C:5]2[O:4][C:2](=[O:3])[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=3)[C:21](=[O:22])[C:16]=2[CH:15]=1
Reactant: COC(=O)Cl
Reactant: COc1cccc(NC(=O)c2cc(-c3ccc(F)cc3F)ccc2O)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cccc(-n2c(=O)oc3ccc(-c4ccc(F)cc4F)cc3c2=O)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 12 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 12 (1.42 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0□. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 24.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>[Pd].CO>[F:15][C:12]([F:13])([F:14])[C:8]1[CH:7]=[C:6]2[C:11]([CH:2]=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: FC(F)(F)c1ccc2cccnc2c1
Reaction time: 3.5 h

Procedure:
4-Chloro-7-(trifluoromethyl)quinoline (9.35 g, 0.0404 mol) was hydrogenated in the presence of 5% palladium on carbon (4 g) in methanol (180 mL) in the presence of triethylamine (6 mL). The solution was stirred for 3.5 hours, and then filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was treated with ethyl acetate and water. The organic layer was separated, washed with water (2×75 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=O)[CH2:9][C:10](=[O:21])[CH2:11][C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=2)=O)[CH:3]=1.[NH3:23]>CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[NH:23][C:12]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=3)=[CH:11][C:10](=[O:21])[CH:9]=2)[CH:3]=1
Reactant: N
Reactant: O=C(CC(=O)c1cc(Cl)ccn1)CC(=O)c1cc(Cl)ccn1
Solvent: CC(C)O
Product: O=c1cc(-c2cc(Cl)ccn2)[nH]c(-c2cc(Cl)ccn2)c1
Temperature: 4 °C

Procedure:
38.5 g (0.114 mol) of 1,5-bis(4-chloropyridin-2-yl)pentane-1,3,5-trione are suspended in 1.25 l of 2-propanol. A total of 230 ml of 25% (w/w) ammonia solution is added at 60° C.-70° C. over the course of five and a half hours. The mixture is cooled to 4° C. and the whitish 4,4″-dichloro-1′H-[2,2′;6′,2″]terpyridin-4′-one formed is filtered off. 1H-NMR (360 MHz, DMSO-d6): 8.65 (d, 2H, J=5.4 Hz); 8.57 (d, 2H, J=2.2 Hz); 7.82 (s, 2H); 7.59 (dd, 2H, J=5.4,2.2 Hz).
Reaction SMILES: [CH3:1][C:2](=[O:5])[CH:3]=[CH2:4].[C:6]1([CH:13]=CC(O)=[CH:9][CH:8]=1)[OH:7]>C1(C)C=CC=CC=1>[C:2]([CH:3]1[CH2:4][CH2:9][CH:8]=[C:6]([CH3:13])[O:7]1)(=[O:5])[CH3:1]
Reactant: C=CC(C)=O
Reactant: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C1CCC=C(C)O1
Temperature: 200 °C
Reaction time: 4 h

Procedure:
A solution of 100 g of 3-buten-2-one in 100 ml of toluene stabilized with 1 g of hydroquinone was heated to 200° C. in a steel pressure vessel and held at that temperature for 4 hours. The resulting mixture was distilled under reduced pressure to give 2-acetyl-3,4-dihydro-6-methyl-2H-pyran (16A), as a liquid, b.p.: 38°-42° C., 0.02 Torr.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16](B1OC(C)(C)C(C)(C)O1)[NH:17]2>O1CCOCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[Cl:11][C:4]1[N:3]=[C:2]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[C:13]([F:12])[CH:21]=[CH:20][CH:19]=3)[C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1
Reactant: CC1(C)OB(c2cc3c(F)cccc3[nH]2)OC1(C)C
Reactant: OCCc1ccc(Cl)nc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: OCCc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Temperature: 90 °C
Reaction time: 8 h
Yield: 19.8 %

Procedure:
To a degassed solution of 2-(2,6-dichloropyridin-3-yl)ethanol (200 mg, 1.04 mmol) and 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (272 mg, 1.04 mmol) in 1,4-dioxane (8 mL) and water (200 μl) was added CS2CO3 (679 mg, 2.08 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium chloride (68 mg, 0.10 mmol) under N2 protection. The resulting mixture was heated to 90° C. and stirred at this temperature overnight. The reaction was cooled, filtered through a pad of the celite and washed with ethyl acetate. The combined filtrate was evaporated in vacuo. Preparative TLC (eluted with 20% EtOAc/DCM) to provide 2-(6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-yl)ethanol (60 mg, yield: 19%) MS (M+H)+: 291.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[CH:14]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15]1.CC(C)([O-])C.[K+].Cl>O1CCCC1>[Cl:13][C:10]1[CH:11]=[CH:12][C:3]([CH2:2][O:19][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:4]([CH:9]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)ccc1CBr
Reactant: OC1CCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)ccc1COC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.1 %

Procedure:
A mixture of methyl 2-(bromomethyl)-5-chlorobenzoate (200 mg, 0.80 mmol), cyclopentanol (379 mg 4.4 mmol), and potassium tert-butoxide (448 mg, 4.0 mmol) in tetrahydrofuran (8 mL) was stirred at room temperature for 3 hours. The mixture was acidified with 2 N hydrochloric acid and the acidic aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1/1) to afford 100 mg (49%) of the title compound:
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][C@H:15]([CH2:28][CH:29]=C)[C:14]3=[O:31])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].C(Cl)Cl.C[OH:40]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=4)[CH2:16][C@H:15]([CH2:28][CH2:29][OH:40])[C:14]3=[O:31])=[CH:11][CH:12]=2)=[CH:32][CH:33]=1
Reactant: CO
Reactant: C=CC[C@H]1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1[C@@H](CCO)C[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
(3S,5R)-1-[4-(4-chlorophenoxy)phenyl]-3-allyl-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one (56 mg, 0.119 mmol) is dissolved in 3 mL of a 2:1 mixture of CH2Cl2-MeOH and is cooled to −78° C. Ozone is bubbled through the solution until a blue color persisted and then nitrogen is bubbled through until it is clear. NaBH4 (2.5 eq) is added and the reaction mixture is allowed to warm to room temperature. The mixture is stirred for 2 h, and then most of the solvent is removed by evaporation in vacuo. Water is added (10 mL) and the aqueous layer is extracted with ethyl acetate (5×10 mL). The combined extracts are washed with brine (10 mL), dried over Na2SO4, filtered and evaporated. The residue is purified on silica gel (0-55% ethyl acetate in hexane) to give (3R,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-3-(2-hydroxyethyl)pyrrolidin-2-one (51 mg, 89%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.51-7.46 (m, 1H), 7.44-7.37 (m, 2H), 7.36-7.30 (m, 3H), 7.21-7.16 (m, 2H), 6.87-6.78 (m, 4H), 5.21 (dd, J=10.5, 2.0 Hz, 1H), 3.85-3.68 (m, 2H), 2.97-2.85 (m, 1H), 2.45-2.32 (m, 1H), 2.26-2.15 (m, 2H), 2.10-1.98 (m, 1H), 1.80-1.69 (m, 1H). HPLC-MS calculated for C25H21ClF3NO3 (M+H+) 476.12, found 476.10.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)/[CH:10]=[N:11]/O)=[CH:4][CH:3]=1.N>C(O)C.[Ni]>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH2:10][NH2:11])[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: O/N=C/c1cccc(Oc2ccc(F)cc2)c1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCc1cccc(Oc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.2 %

Procedure:
To a mixture of (E)-3-(4-fluorophenoxy)benzaldehyde oxime (3.0 g, 12.9 mmol, 1.0 eq) in ethanol, was added Raney nickel (300 mg, 10% wt/wt) followed by aqueous ammonia (10% in volume). The reaction mixture was stirred at ambient temperature under hydrogen pressure for 4 h, before being filtered. The filtrate was concentrated under high vacuum to obtain the desired compound (1.8 g, 64%). 1H NMR (400 MHz, DMSO-d6) δ 7.30-7.17 (m, 3H), 7.07-6.80 (m, 4H), 6.79-6.76 (t, 1H), 3.67 (s, 1H). MS (ESI): 218.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:32][CH:33]([NH2:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([NH:13][C:14]([NH:38][CH:33]([CH3:32])[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:19])=[O:20])[C:16]#[N:17])[CH:4]=[C:3]([C:2]([F:31])([F:1])[F:30])[CH:8]=1
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(N)C(C)(C)C
Product: CC(NC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1)C(C)(C)C
Yield: 68 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chloro-phenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.300 g, 0.6 mmol) was stirred in 1,2,2-trimethylpropylamine (1 ml) for 19 h at 75° C. under nitrogen. The reaction mixture was concentrated and the residue dissolved in DCM, washed twice with 1N aqueous HCl and once with water. The organic phase was dried (sodium sulfate) and concentrated. The residue was crystallised from ethyl acetate/heptane 1:3 to give 225 mg (68%) of the title compound. Mp 155.5-158.5° C. 1H NMR (300 MHz, CDCl3): δ=0.9 (s, 9H), 1.0 (d, 3H), 3.0 (m, 1H), 7.40 (s, 2H), 7.50 (d, 2H), (s, 1H), 7.82 (d, 2H); MA calc for C23H22ClF6N3O2S: C, 49.87%; H, 4.00%; N, 7.59%. Found: C, 49.86%; H, 4.29%; N, 7.55%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][C@@H:11]([CH2:13][OH:14])[CH2:10][O:9][C:8]=2[CH:15]=1)([O-])=O.[N+](C1C=C(S(OC[C@@H]2CO2)(=O)=O)C=CC=1)([O-])=O>>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[NH:12][C@H:11]([CH2:13][OH:14])[CH2:10][O:9][C:8]=2[CH:15]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)OC[C@H](CO)N2
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Product: Nc1ccc2c(c1)OC[C@@H](CO)N2

Procedure:
(R)-(7-amino-3,4-dihydro-2h-benzo[b][1,4]oxazin-3-yl)methanol was prepared using the same procedure as for (s)-(3,4-dihydro-7-nitro-2h-benzo[b][1,4]oxazin-3-yl)methanol, except (s)-(oxiran-2-yl)methyl 3-nitrobenzenesulfonate was used as starting material.
Reaction SMILES: [Br:1][C:2]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:3]=1[O:4][C:5]1[C:6]([NH:20][C:21]2[S:22][CH:23]=[C:24]([CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[N:25]=2)=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1.C(O)(C(F)(F)F)=O.O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:3]=1[O:4][C:5]1[C:6]([NH:20][C:21]2[S:22][CH:23]=[C:24]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:25]=2)=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1
Reactant: COc1cccc(Sc2cnc(Nc3nc(C4CCN(C(=O)OC(C)(C)C)CC4)cs3)c(Oc3ccc(F)cc3Br)c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1cccc(Sc2cnc(Nc3nc(C4CCNCC4)cs3)c(Oc3ccc(F)cc3Br)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 103.3 %

Procedure:
A 20 mL vial was charged with tert-butyl 4-(2-(3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate (100 mg, 0.145 mmol) and CH2Cl2 (2 mL). TFA (2 mL) was added and stirred at room temperature for 5 minutes. The reaction was poured into water and diluted with CH2Cl2. Solid Na2CO3 added slowly to neutralize the TFA. The aqueous layer was extracted and dried to afford the title compound (88 mg, 103% yield). 1H NMR (d6-DMSO) δ 8.16 (d, 1H), 7.74 (m, 1H), 7.30 (m, 2H), 7.21 (t, 1H), 6.92 (d, 1H), 6.78 (m, 1H), 6.70 (m, 3H), 3.69 (s, 3H), 3.17 (m, 2H), 2.77 (m, 3H), 2.01 (m, 2H), 1.62 (m, 2H). Mass spectrum (apci) m/z=587.2, 589.2 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C@H:13]([NH2:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[N:11][C:10]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C@@H:28]1[C@H:32]([CH:33]=O)[CH2:31][N:30]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C[N+]1([O-])CCOCC1>C(Cl)Cl.O=[Os](=O)(=O)=O>[CH2:1]([N:8]1[C:12]([C@H:13]([NH:18][CH2:33][C@H:32]2[C@@H:28]([F:27])[CH2:29][N:30]([C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[CH2:31]2)[C:14]([CH3:17])([CH3:16])[CH3:15])=[N:11][C:10]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F
Reactant: CC(C)(C)[C@@H](N)c1nc(-c2cc(F)ccc2F)nn1Cc1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)(C)[C@@H](NC[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)c1nc(-c2cc(F)ccc2F)nn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropan-1-amine (2.55 g, 7.15 mmol) in CH2Cl2 (59 mL) was added the crude (3R,4S)-benzyl 3-fluoro-4-formylpyrrolidine-1-carboxylate (obtained from 1.4 equiv. of (3R,4R)-benzyl 3-fluoro-4-vinylpyrrolidine-1-carboxylate) in CH2Cl2 (10 mL) and NaBH(OAc)3 (2.3 g, 10.7 mmol). The reaction mixture was then stirred for 16 h at room temperature. After quenched with saturated NaHCO3 aqueous solution, the reaction mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude reductive amination product was contaminated by the HF eliminated alkene product, which was not separable on either silica column chromatography or preparative reverse phase HPLC. Therefore, the crude mixture (3.0 g) was dissolved in acetone and water (5:1, 120 mL). 4-Methylmorpholine N-oxide (715 mg, 6.1 mmol) and OsO4 (2.15 mL of a 4% w/v solution) were added to this reaction mixture, which was then stirred for over the weekend at room temperature. After removal of acetone in vacuo, the remaining aqueous layer was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The desired (3R,4R)-benzyl 3-(((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate was obtained on silica column chromatography (35% to 80% EtOAc in Hexanes, 1.5 g, 35%). LC/MS (uplc) MH+ 592.3, 0.97 min.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[O:9][N:8]=[C:7]([C:10]2[N:14]3[N:15]=[C:16]([OH:23])[C:17]4[C:22]([C:13]3=[N:12][N:11]=2)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=1.O>CN(C)C=O>[OH:23][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]2=[N:12][N:11]=[C:10]([C:7]3[CH:6]=[C:5]([O:2][CH3:1])[O:9][N:8]=3)[N:14]2[N:15]=1
Reactant: C[O-]
Reactant: Oc1nn2c(-c3cc(Cl)on3)nnc2c2ccccc12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-c2nnc3c4ccccc4c(O)nn23)no1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Sodium methoxide (165 mg, 0.3 mmol) was added to a stirred suspension of 3-(5-chloroisoxazol-3-yl)-6-hydroxy-1,2,4-triazolo[3,4-a]phthalazine (400 mg, 0. 14 mmol) (prepared from Intermediate 7 using the procedure described in Example 15 part b) in N,N-dimethylformamide (20 ml) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 3 h then water was added (5 ml) and the solvents evaporated in vacuo. The residue was taken up in water and acidified to pH 2 using 2M hydrochloric acid. The resulting precipitate was filtered off, washed with hexane and azeotroped with ethanol to give crude 6-hydroxy-3(5-methoxyisoxazol-3-yl)-1,2,4-triazolo[3,4-a]phthalazine, MS (ES30) 284 [MH]+. The title-compound was prepared from this material using the procedure described in Example 103 part a, 1H NMR (250 MHz, CDCl3) δ 2.49 (3H, s, CH3), 4.15 (3H, s, CH3), 6.10 (1H, s, Ar—H), 7.45 (2H, d, J=8.5 Hz, Ar—H), 7.92 (1H, m, Ar—H), 8.06 (1H, m, Ar—H), 8.26-8.32 (3H, m, 3 of Ar—H), 8.64 (1H, d, Ar—H); MS (ES30) 438 [MH]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].C(N(CC)CC)C.Cl[C:15]1[S:19][N:18]=[C:17]([O:20][CH3:21])[N:16]=1>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>[CH3:21][O:20][C:17]1[N:16]=[C:15]([NH:2][CH2:3][C:4]([NH2:6])=[O:5])[S:19][N:18]=1
Reactant: NCC(N)=O
Reactant: COc1nsc(Cl)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1nsc(NCC(N)=O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16 %

Procedure:
To a suspension of glycinamide hydrochloride (0.55 g, 5 mmol) in DMF (10 mL) was added triethylamine (1.7 mL, 12 mmol) and the resulting mixture was stirred for 15 min at room temperature. This was added to a solution of 5-chloro-3-methoxy-[1,2,4]thiadiazole (0.38 g, 2.5 mmol, prepared according to the procedure by Goerdeler, J. et al. in Chem. Ber. 1955, 88, 843) in DMF (15 mL). Then, tetra-butylammonium bromide (50 mg) was added and the resulting suspension was heated at 80-85° C. for 1.5 h. On cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate. The organic layer was collected, washed with brine, sat. Sodium bicarbonate solution, brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by column chromatography on silica gel using a solvent mixture of dichloromethane and methanol (95/5 and 9/1) afforded 2-(3-methoxy-[1,2,4]thiadiazol-5-ylamino)-acetamide (75 mg, 16%) as a white solid. 1H-NMR (MeOD) δ4.03 (s, 2H, NCH2), 3.94 (s, 3H, OMe); 13C-NMR (MeOD) δ182.0, 173.3, 170.0, 56.7 (MeO), 47.9; MS (m/z) 189 (M+ +1), 172, 144, 87.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[CH:5]=[C:6]([Cl:10])[CH:7]([Cl:9])[Cl:8]>>[CH2:1]([NH:3][CH2:5][C:6]([Cl:10])=[C:7]([Cl:9])[Cl:8])[CH3:2]
Reactant: CCN
Reactant: ClC=C(Cl)C(Cl)Cl
Product: CCNCC(Cl)=C(Cl)Cl

Procedure:
From ethylamine and 1,2,3,3-tetrachloropropene, proceeding as in Example 1, there was obtained N-ethyl-N-(2,3,3-trichloroallyl)-amine with b.p.35 mm =91° C.-92° C.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25]C(=O)CC4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][CH:18]2OC(=O)C)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>ClCCl.C(O)C(C)C>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:35])[CH:24]([NH2:25])[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(C)CO
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Temperature: 0 °C
Reaction time: 4 h
Yield: 60.8 %

Procedure:
To a solution of the above starting material (3a) in dichloromethane (13 parts) under nitrogen are added at -5° to 0° C. pyridine (2 equivalents) and at -30° to -25° C. phosphorus pentachloride (1.7 equivalents). The mixture is stirred at -15° to -10° C. for 4 hours, cooled to -25° to -30° C., mixed with isobutanol (10 parts) cooled at -30° to -20° C., and let stand at 0° to 5° C. overnight. The reaction mixture is cooled to -20° to -25° C., mixed dropwise with triethylamine (10.9 equivalents), and kept at 0° to 5° C. overnight. The reaction mixture is diluted with dichloromethane (20 parts) and ice water (20 parts) and stirred for 20 minutes. The formed organic layer is taken, washed with hydrochloric acid, water, aqueous sodium hydrogen carbonate, and water, dried, and concentrated. The residue is crystallized from ethyl acetate to give 7beta-amino-3-cephem-4-carboxylic acid diphenylmethyl ester (5). Yield: 60.8%.