Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>N1C=CC=CC=1>[S:24]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc(N2CCC(CO)CC2)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Reaction time: 4 h

Procedure:
The 4-hydroxymethyl-N-(4-nitrophenyl)piperidine (47.3 g, 200 mmol) obtained in Example 4(1) was dissolved in pyridine (300 ml), and p-toluenesulfonyl chloride (45.8 g, 240 mmol) was added thereto under ice-cooling, followed by stirring for 4 hours. Water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained solid was dried under reduced pressure, thereby obtaining 4-tosyloxymethyl-N-(4-nitrophenyl)piperidine (72.7 g, 93%) as a yellow solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)=[O:20].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:9]([C:8]1[CH:7]=[C:6]([CH:13]=[CH:12][CH:11]=1)[O:5][CH2:4][CH2:3][NH:2][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([C:19](=[O:20])[C:18]2[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:16]([O:15][CH3:14])[CH:17]=2)=[CH:22][CH:23]=1)#[N:10]
Reactant: COc1ccc(C(=O)c2ccc(C(=O)O)cc2)cc1OC
Reactant: N#Cc1cccc(OCCN)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)c2ccc(C(=O)NCCOc3cccc(C#N)c3)cc2)cc1OC
Reaction time: 8 h

Procedure:
0.68 g (3.45 mmol) of 3-(2-aminoethoxy)benzonitrile monohydrochloride was dissolved in 20 ml of N,N-dimethylformamide (dehydrated). 0.9 g (3.14 mmol) of 4-(3,4-dimethoxybenzoyl)benzoic acid, 0.47 g (3.45 mmol) of 1-hydroxybenzotriazole, 0.48 ml (3.45 mmol) of triethylamine and 0.66 g (3.45 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the residue was treated with ethyl acetate as the extraction solvent in an ordinary manner to obtain the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]2[O:30][N:29]=[C:28]([C:31]3[CH:36]=[CH:35][C:34]([CH2:37][OH:38])=[CH:33][CH:32]=3)[N:27]=2)[CH:19]=[N:18]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[C:21]([C:22]([F:23])([F:24])[F:25])=[C:20]([C:26]2[O:30][N:29]=[C:28]([C:31]3[CH:32]=[CH:33][C:34]([CH:37]=[O:38])=[CH:35][CH:36]=3)[N:27]=2)[CH:19]=[N:18]1
Reactant: OCc1ccc(-c2noc(-c3cnn(-c4ccccn4)c3C(F)(F)F)n2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=Cc1ccc(-c2noc(-c3cnn(-c4ccccn4)c3C(F)(F)F)n2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 67.4 %

Procedure:
300 mL of DCM was cooled to −78° C., then oxalyl chloride (0.475 mL, 5.42 mmol) was added and the mixture was stirred at −78° C. for 10 min. DMSO (0.586 mL, 8.26 mmol) was added and the mixture was stirred at −78° C. for 15 min. A solution of (4-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)methanol (1 g, 2.58 mmol) in 60 mL of DCM was added dropwise over 10 minutes into the reaction mixture, with the SM flask being rinsed with another 10 mL of DCM which was also added into the reaction dropwise. The reaction was kept at −78° C. for 40 min, then Hunig's Base (3.61 mL, 20.66 mmol) was added over 10 minutes. Stirring at −78° C. continued for 10 min, then the dry ice bath was removed and the reaction flask gradually warmed to room temperature. A 0.5 N KHSO4 solution (70 mL) was added and the mixture was extracted twice with DCM (50 mL). The organics were combined, dried with Na2SO4, and concentrated. Diethyl ether (100 mL) was added to the product, with the mixture being stirred overnight, then filtered and the solids washed with diethyl ether to afford 4-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (700 mg, 1.74 mmol). The compound had an HPLC retention time=3.69 min.−Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.2% H3PO4; Solvent B=90% MeOH, 10% H2O, 0.2% H3PO4. LC/MS M+1=386.01. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.69 (ddd, J=0.8 Hz, 5.0 Hz, 7.4 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 8.15 (d, J=8.3 Hz, 2H), 8.20 (dt, J=1.9 Hz, 7.7 Hz, 1H), 8.32 (d, J=8.3 Hz, 2H), 8.67 (dd, J=1.9 Hz, 4.7 Hz, 1H), 8.76 (s, 1H), 10.13 (s, 1H)
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:8]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[O:10])[S:6][CH:7]=1.[O:31]1[CH2:35][CH2:34][NH:33][C:32]1=[O:36].[H-].[Na+].CCOC(C)=O>CN(C=O)C>[CH3:30][O:29][C:22]1[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=1[CH2:20][N:8]([C:5]1[S:6][CH:7]=[C:3]([CH2:2][N:33]2[CH2:34][CH2:35][O:31][C:32]2=[O:36])[N:4]=1)[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=[O:10]
Reactant: O=C1NCCO1
Reactant: COc1ccc(CN(C(=O)NCc2cccc(F)c2)c2nc(CCl)cs2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(C(=O)NCc2cccc(F)c2)c2nc(CN3CCOC3=O)cs2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(4-Chloromethyl-thiazol-2-yl)-1-(2,4-dimethoxy-benzyl)-3-(3-fluoro-benzyl)-urea (Intermediate 21, 0.3 mmol) was taken up in DMF (2 ml). A solution of the oxazolidin-2-one (or sultam) (1 eq.) with NaH (1 eq.) in DMF (2 ml) was added. The reaction was allowed to stir at room temperature for 2 hours. An aqueous workup with EtOAc was performed. Purified by column chromatography using a gradient of 0-100% EtOAc/hexanes to give 1-(2,4-dimethoxybenzyl)-3-(3-fluorobenzyl)-1-(4-((2-oxooxazolidin-3-yl)methyl)thiazol-2-yl)urea.
Reaction SMILES: CCN(C(C)C)C(C)C.NC(N)=O.[B:14]1(B2OC(C)(C)C(C)(C)O2)[O:18]C(C)(C)C(C)(C)[O:15]1.[CH:32]1[CH:37]=[CH:36][C:35]([P:38]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C-:39]2[CH:43]=[CH:42][CH:41]=[CH:40]2)=[CH:34][CH:33]=1.[CH:50]1[CH:55]=[CH:54][C:53]([P:56]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C-:57]2[CH:61]=[CH:60][CH:59]=[CH:58]2)=[CH:52][CH:51]=1.[Cl:68][Pd:69][Cl:70].[Fe+2:71]>C(Cl)Cl.C1(C)C=CC=CC=1.O1CCOCC1>[CH:47]1[CH:46]=[CH:45][C:44]([P:38]([C:35]2[CH:36]=[CH:37][CH:32]=[CH:33][CH:34]=2)[C-:39]2[CH:43]=[CH:42][CH:41]=[CH:40]2)=[CH:49][CH:48]=1.[CH:65]1[CH:64]=[CH:63][C:62]([P:56]([C:53]2[CH:54]=[CH:55][CH:50]=[CH:51][CH:52]=2)[C-:57]2[CH:61]=[CH:60][CH:59]=[CH:58]2)=[CH:67][CH:66]=1.[Cl:68][Pd:69][Cl:70].[Fe+2:71].[BH:14]([OH:18])[OH:15]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: NC(N)=O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: OBO
Reaction time: 10 h

Procedure:
The fourth route to intermediate [1] is outlined in Scheme 4. Intermediate compound [C] is prepared as described in Scheme 2. 4-Amino benzamide [C] is then reacted with 2,2,2-trichloroethyl chloroformate or trichloromethyl chloroformate to form the corresponding carbamate [P]. Typically, this reaction is performed in the presence of a base such as TEA or DIPEA, solvent such as DCM, THF, or CHCl3, at reduced temperatures, i.e., about 0° C. to about rt, for about 2 to about 12 h, such as about 4 h. Reaction of compound [P] with an appropriately substituted aniline affords urea intermediate [O]. Typically, this reaction is performed in the presence of a base such as TEA or DIPEA, a solvent such as 1,4-dioxane, toluene, or mixtures thereof, at elevated temperatures such as about 90 to about 120° C., i.e., about 95° C., and over a period of about 10 to about 15 h, such as about 10 h. The urea intermediate [O] is then reacted with bis(pinacolato)diboron in the presence of a catalyst such as Pd(dppf)Cl2.DCM or Pd(dppf)Cl2 to form intermediate [1]. Typically, this reaction is performed in the presence of a base such as KOAc, solvent such as 1,4-dioxane or DMF, at elevated temperatures such as about 80 to about 120° C., such as about 110° C., and over a period of about 3 to about 15 h, such as about 10 h.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[S:19]([NH:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)([C:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[C:27]([N:28]([CH3:30])[CH3:29])[C:26]=2[CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.CO>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([NH:35][S:19]([C:22]5[C:34]6[C:26](=[C:27]([N:28]([CH3:30])[CH3:29])[CH:31]=[CH:32][CH:33]=6)[CH:25]=[CH:24][CH:23]=5)(=[O:21])=[O:20])[CH:37]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Nc3cccc(B(O)O)c3)cccc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CN(C)c1cccc2c(S(=O)(=O)Nc3cccc(-c4ccc5c(c4)CC[C@H]4N(C)C(=O)CC[C@]54C)c3)cccc12
Yield: 62.9 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (83 mg, 0.27 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 3-dansylaminophenylboronic acid (99 mg, 0.27 mmol), 0.3 mL of 2M sodium carbonate solution, 0.5 mL of toluene, and 0.1 mL of methanol, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 94 mg (63%) of the title compound as a yellow solid. mp 130°-140° (decomp.) FDMS: m/e=553. α[D]589 =+3.01 (c=1.03 methanol).
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7](Cl)[N:6]=1.C([O-])([O-])=[O:14].[K+].[K+]>O1CCOCC1.O>[Cl:11][C:9]1[CH:10]=[C:5]2[NH:4][CH2:3][CH2:2][N:6]2[C:7](=[O:14])[N:8]=1
Reactant: Clc1cc(NCCBr)nc(Cl)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=c1nc(Cl)cc2n1CCN2
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a mixture of N-(2-bromoethyl)-2,6-dichloropyrimidin-4-amine (10 g, 18 mmol) in 1,4-dioxane (30 mL) and water (30.0 mL) was added K2CO3 (4.85 g, 35.1 mmol). The reaction mixture was stirred at 70° C. for 4 h, then directly used into next step without workup and purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.C([O-])([O-])=O.[K+].[K+].C1COCC1.O.[C:24](Cl)(=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCOCC>[N:1]1([C:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:33])[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To ethyl piperidine-3-carboxylate (5.0 g, 30.2 mmol) and K2CO3 (4.2 g, 30.2 mmol) in 1:1 THF-water (100 mL) was added benzyl carbonochloridate (4.5 mL, 31.7 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hours, and then ether (50 mL) was added. The organic layer was separated, washed with brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by chromatography on silica gel (hexane:ethyl acetate 5:1) to give 1-benzyl 3-ethyl piperidine-1,3-dicarboxylate (7.60 g, 86% yield) as an oil.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7]2=[O:14])([O-])=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[NH:8][C:7]3=[O:14])=[CH:18][CH:17]=1
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2cc(Oc3ccc(F)cc3)ccc21
Reaction time: 3 h
Yield: 18.6 %

Procedure:
A mixture of 5-Nitro-isoindole-1,3-dione (177 g, 0.904 mol), 4-fluoro-phenol (128 g, 1.13 mol), K2CO3 (419 g, 3 mol) and DMF (2 l) was refluxed with stirring for 3 h before the mixture was poured into water (12 l) with stirring. The precipitate formed was isolated by vacuum filtration, washed with water (8 l) and dried in vacuo at 70° C. to give the title compound as a tan powder (43.2 g); 1H NMR (CDCl3) δ=7.79 (d, 1H), 7.57 (br s, 1H), 7.01 to 7.29 (m, 6 H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CN[C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]1NC.IC1C=CC=CC=1>[Cu]I.C1(C)C=CC=CC=1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: CN[C@@H]1CCCC[C@H]1NC
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Ic1ccccc1
Solvent: Cc1ccccc1
Product: O=C1OC[C@@H](Cc2ccccc2)N1c1ccccc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 921.2 %

Procedure:
A 15 mL resealable Schlenk tube was charged with CuI (9.6 mg, 0.0504 mmol, 5.0 mmol %), (R)-4-benzyl-2-oxazolidinone (215 mg, 1.21 mmol), K2CO3 (280 mg, 2.03 mmol), evacuated and backfilled with argon. Racemic trans-N,N′-dimethyl-1,2-cyclohexanediamine (16 μL, 0.102 mmol, 10 mol %), iodobenzene (106 μL, 0.947 mmol) and toluene (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 80° C. for 24 h. The resulting pale blue suspension was allowed to reach room temperature and then filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×15 cm, hexane-ethyl acetate 2:1, 15 mL fractions). Fractions 11–19 provided 238 mg (99% yield) of the desired product as a pale tan solid. HPLC analysis on a Daicel OD column (hexane-isopropanol 85:15, 0.7 mL/min, tr(R)=23.3 min, tr(S)=26.7 min) indicated >99.5% ee.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[CH:6]=1)([F:4])[CH3:3].O.O.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+].C(=O)([O-])O.[Na+]>O.C(O)C>[F:1][C:2]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[NH2:11])([F:4])[CH3:3]
Reactant: CC(F)(F)c1cccc([N+](=O)[O-])c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(F)(F)c1cccc(N)c1
Yield: 67.6 %

Procedure:
A mixture of 3.0 g (16 mmol) of 1-(1,1-difluoroethyl)-3-nitrobenzene, 18.0 g (80 mmol) of tin chloride dihydrate and 50 mL of ethanol is refluxed for one hour. The mixture is slowly poured on cooled water. The pH is adjusted to 7 by addition of an aqueous 10N solution of sodium hydroxide, then adjusted to 9 by addition of an aqueous saturated solution of sodium hydrogen carbonate. The product is extracted 4 times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The oily residue (2.2 g) is purified over 100 g of silica gel (eluant heptane/ethyl acetate 2/1) to give 1.7 g (68%) of 3-(1,1-difluoroethyl)aniline as an oil.
Reaction SMILES: N#N.[F:3][C:4]1([F:18])[CH:9]([OH:10])[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[F:18][C:4]1([F:3])[C:9](=[O:10])[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(F)(F)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: N#N
Agent: O=C([O-])O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(=O)C(F)(F)C1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to an ice-cold solution of tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate (2.40 g, 10.00 mmol) in dry CH2Cl2 (50 mL) was added a solution of Dess-Martin periodinane (50 mL of a 15% solution in CH2Cl2, 24.00 mmol). The reaction mixture was stirred at rt until completion of the reaction. Sat. aq. NaHCO3 (50 mL) was then added followed by 10% aq. Na2SO3 (50 mL). The mixture was stirred at rt for 1 h, the layers separated and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was redissolved in CH2Cl2 (30 mL) and stirred in the presence of molecular sieves for 24 h, filtered and concentrated under reduced pressure to give tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12](F)[CH:11]=[C:10]([F:18])[CH:9]=1)[CH3:2].C(N(CC)CC)C.[CH2:28]([NH2:32])[CH2:29][CH2:30][CH3:31]>CN(C=O)C>[CH2:28]([NH:32][C:12]1[CH:11]=[C:10]([F:18])[CH:9]=[C:8]([O:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:19][CH3:20])[CH2:1][CH3:2])[C:13]=1[N+:14]([O-:16])=[O:15])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCN
Reactant: CCN(CC)CCCOc1cc(F)cc(F)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCNc1cc(F)cc(OCCCN(CC)CC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a stirred solution of 6-(3-diethylaminopropoxy)-2,4-difluoronitrobenzene (11 mmol) and triethylamine (22 mmol) in DMF (20 mL), a solution of n-butylamine (11 mmol) in DMF (8 mL) was added dropwise at rt, and the mixture was stirred at rt for 10 h. The reaction was quenched by cold H2O (50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with brine (3×50 mL) and dried (anhydrous Na2SO4). The solvent was removed in vacuo to afford the desired 2-n-butylamino-6-(3-diethylaminopropoxy)-4-fluoronitrobenzene which was used for further transformation.
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[C:12]([NH2:14])[N:11]=[C:10]([C:15]3[N:19]=[C:18](C(Cl)(Cl)Cl)[O:17][N:16]=3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.Cl.[F:34][C:35]([F:46])([F:45])[CH2:36][O:37][CH2:38][CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>CN(C=O)C>[C:1]1([NH:7][C:8]2[N:13]=[C:12]([NH2:14])[N:11]=[C:10]([C:15]3[N:19]=[C:18]([N:42]4[CH2:41][CH2:40][CH:39]([CH2:38][O:37][CH2:36][C:35]([F:34])([F:45])[F:46])[CH2:44][CH2:43]4)[O:17][N:16]=3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1nc(Nc2ccccc2)nc(-c2noc(C(Cl)(Cl)Cl)n2)n1
Reactant: FC(F)(F)COCC1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc(Nc2ccccc2)nc(-c2noc(N3CCC(COCC(F)(F)F)CC3)n2)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 8.9 %

Procedure:
To 2-N-phenyl-6-[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]-1,3,5-triazine-2,4-diamine (Intermediate 134, 0.100 g, 0.268 mmol) in DMF (2 mL) was added DIPEA (93.6 μL, 0.537 mmol) at the mixture was stirred at room temperature for 5 min. 4-[(2,2,2-trifluoroethoxy)methyl]piperidine hydrochloride (Intermediate 179, 0.063 g, 0.268 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was then heated to 50 C for 18 h and to 70 C for 36 h. The reaction mixture was concentrated under reduced pressure, dissolved in EtOAc and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by preparative HPLC, Method C, to afford the title compound (10.8 mg, 8.9%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Br[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:12][CH2:11]1
Reactant: CCOC(=O)CCBr
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: CCOC(=O)CCN1CCN(c2ccccc2OC)CC1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
A mixture of 1-(2-methoxyphenyl)piperazine hydrochloride (9.10 g, 39.78 mmol), ethyl 3-bromopropionate (7.29 g, 5.14 mL, 40.29 mmol), potassium carbonate (20.00 g, 144.70 mmol) and a catalytic amount of potassium iodide in acetonitrile (80 mL) was heated at reflux for 18 hrs. After cooling at room temperature the solvent was evaporated under reduced pressure and the residue was taken up in dichloromethane. The organic phase was washed with water, dried over MgSO4 and evaporated to dryness. The resulting orange oil was purified by flash chromatography (Silica gel 60 Å, 45 μm, 50% ethyl acetate in hexane) and afforded 8.30 g (71%) ethyl 3-[4-(2-methoxyphenyl)piperazino]propanoate D1 as an oil.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH:6]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:7]([NH:9][CH:10]1[C:23](=[O:24])[N:12]2[CH:13]([C:18]3[NH:22][N:21]=[N:20][N:19]=3)[C:14]([CH3:17])([CH3:16])[S:15][C@H:11]12)=[O:8])=[O:4].CN(C)C=O.[SH:36][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:40]1[CH:41]=[CH:42][C:37]([S:36][CH2:2][C:3]([NH:5][CH:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]([NH:9][CH:10]2[C:23](=[O:24])[N:12]3[CH:13]([C:18]4[NH:22][N:21]=[N:20][N:19]=4)[C:14]([CH3:17])([CH3:16])[S:15][C@H:11]23)=[O:8])=[O:4])=[CH:38][CH:39]=1
Reactant: CC1(C)S[C@@H]2C(NC(=O)C(NC(=O)CBr)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Reactant: Sc1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)S[C@@H]2C(NC(=O)C(NC(=O)CSc3ccncc3)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Reaction time: 3 h
Yield: 33 %

Procedure:
To a stirred solution of 644 mg. of 6-(2-[2-bromoacetamido]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 15 ml. of N,N-dimethylformamide is added 45 mg. of 4-mercaptopyridine followed by 0.19 ml. of triethylamine. Stirring is continued for 3 hours at 25° C., and then the reaction solution is added dropwise into 200 ml. of vigorously stirred chloroform. The precipitate is removed by filtration, and the filtrate is added dropwise with stirring to 400 ml. of hexane. This causes the product to precipitate. After being slurried with methylene chloride, it weighs 228 mg. (33% yield), m.p. 182°-198° C. (dec.). IR (KBr disc): 1780 cm-1 (β-lactam) and 1667 cm-1 (amide I). NMR (DMSO-d6 /D2O): 8.33 ppm (d,4H), 7.33 (s,5H), 5.60 ppm (m, 3H), 5.15 ppm (s,1H), 3.68 ppm (s,2H), 1.47 ppm (s,3H), 1.00 ppm (s,3H).