Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]1[C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3]1.[CH3:19][C:20](OC(C)=O)=[O:21].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:2]1[C:6]2([CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)[CH2:5][CH2:4][N:3]1[C:20](=[O:21])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCC2(CCNCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
A stirred solution of tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate hydrochloride (400 mg, 1.445 mmol) in DCM (5 mL) was treated with TEA (0.604 mL, 4.34 mmol), followed by Ac2O (0.164 mL, 1.734 mmol), stirred at room temperature for 2 h. To this reaction mixture was added TFA (2.115 mL, 27.5 mmol) and stirred at room temperature for h. Concentrated under reduced pressure to obtain crude material which purified by SCX cartridge, loading with MeOH, washed with additional MeOH. Product was recovered eluting with 2M NH3 in MeOH. Solvent evaporation gave 1-(2,8-diazaspiro[4.5]decan-2-yl)ethanone (165 mg)
Reaction SMILES: [C:1]([C:4]1[C:21]([OH:22])=[CH:20][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=[O:16])=[C:6]([CH2:23][CH3:24])[CH:5]=1)(=O)[CH3:2].Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>CO>[OH:27][N:26]=[C:1]([C:4]1[C:21]([OH:22])=[CH:20][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=[O:16])=[C:6]([CH2:23][CH3:24])[CH:5]=1)[CH3:2]
Reactant: CCc1cc(C(C)=O)c(O)cc1OCCCCCC(C)(C)C(=O)O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCc1cc(C(C)=NO)c(O)cc1OCCCCCC(C)(C)C(=O)O
Temperature: 25 °C
Yield: 42.5 %

Procedure:
A mixture of 7.1 g of 7-(4-acetyl-2-ethyl-5-hydroxyphenoxy)-2,2-dimethylheptanoic acid, 0.149 g of hydroxylamine hydrochloride, 0.176 g of sodium acetate, and 50 ml of methanol were heated at reflux for 48 hours. The reaction mixture was allowed to cool to room temperature and the resulting solid collected by filtration. The solid was crystallized from methylene chloride/ hexane to provide 0.32 g of the desired titled product.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].CC(C)([O-])C.[K+].Cl[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:18]([O:17][CH2:16][N:4]1[C:3](=[O:8])[CH:2]([CH3:1])[NH:6][C:5]1=[O:7])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCOCc1ccccc1
Reactant: CC1NC(=O)NC1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1NC(=O)N(COCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5-Methylimidazolidine-2,4-dione (1.00 g) was dissolved in N,N-dimethylformamide (20 mL), potassium tert-butoxide (1.08 g) and benzyl chloromethyl ether (1.32 mL) were added under ice-cooling, and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give the title compound (0.98 g).
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[NH:10][C:9]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:9]1[CH3:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1[nH]c2ccc(Br)cc2c1Cc1ccccc1
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(Cc2ccccc2)c2cc(Br)ccc2n1Cc1ccccc1

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 3. Thus, 3-benzyl-5-bromo-2-methyl-1H-indole (1.651 g, 5.5 mmol) was reacted with k-t-butoxide (0.648 g, 5.775 mmol) and benzyl bromide (0.991 g, 5.775 mmol) in DMF (20 ml) to give the product (1.842 g, 4.719 mmol, 86%) as a viscous brown oil. 1H NMR (DMSO-d6) δ 2.33 (s, 3H), 4.03 (s, 2H), 5.42 (s, 2H), 6.95 (d, J=7.3 Hz, 2H), 7.10-7.14 (m, 2H), 7.18-7.29 (m, 7H), 7.34 (d, J=8.7 Hz, 1H), 7.53 (d, J=1.8 Hz, 1H); [ESI(+)], m/z 390/392 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:19])[CH2:9][O:10][C:11]2[C:12](=[O:18])[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=2)[CH2:4][CH2:3]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23](O)[CH:22]=1>>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([F:20])=[CH:22][C:23]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8](=[O:19])[CH2:9][O:10][C:11]2[C:12](=[O:18])[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=2)[CH2:6][CH2:7]1)(=[O:29])[CH3:28]
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: Cn1nccc(OCC(=O)N2CCC(O)CC2)c1=O
Product: CC(=O)c1ccc(F)cc1OC1CCN(C(=O)COc2ccnn(C)c2=O)CC1
Yield: 17 %

Procedure:
Compound 23 is prepared from intermediate 5c and from 1-(4-fluoro-2-hydroxy-phenyl)-ethanone following synthesis method 3 (yield: 17%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[O:17])=[CH:11][CH:10]=1)(=[O:7])[CH3:6]>O.C(OCC)C>[CH2:1]([NH:4][C:16](=[O:17])[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:5](=[O:7])[CH3:6])=[CH:14][CH:13]=1)[CH2:2][CH3:3]
Reactant: CCCN
Reactant: CC(=O)Oc1ccc(CC(=O)Cl)cc1
Solvent: O
Solvent: CCOCC
Product: CCCNC(=O)Cc1ccc(OC(C)=O)cc1
Temperature: 0 °C

Procedure:
To an ice-cold solution of 1-propylamine (9 g) in water (50 ml) was added solution of 4-acetoxyphenylacetyl chloride (10.6 g) in diethyl ether (100 ml), keeping the temperature of the mixture between 15° and 250° C. with external cooling. The ether layer was separated, washed with brine and evaporated to give N-(1-propyl)-4-acetoxyphenylacetamide as a pale yellow oil, essentially pure by TLC, which was used without further purification or characterisation.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([S:25]([NH:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=3)[N:14]=2)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(COCc2ccc(F)cc2)n1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: O=S(=O)(Nc1cccc(COCc2ccc(F)cc2)n1)c1cccc(Cl)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.07 g) and 3-chloro-benzenesulfonyl chloride (0.07 g) as a light yellow gum (0.059 g). MS (ESI−): 405.2 ([M−H]−).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](I)=[CH:24][N:23]=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:34][C:35]1[C:40]([CH:41]([CH3:43])[CH3:42])=[CH:39][C:38](B(O)O)=[C:37]([O:47][CH3:48])[CH:36]=1.O>C(=O)([O-])[O-].[K+].[K+].C1COCC1>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:38]4[CH:39]=[C:40]([CH:41]([CH3:43])[CH3:42])[C:35]([F:34])=[CH:36][C:37]=4[O:47][CH3:48])=[CH:24][N:23]=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ncc1I
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)c(C(C)C)cc1-c1cnc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 85 °C

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-iodo-2-(trifluoromethyl)pyridin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (9.7 mg, 0.0162 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (5.2 mg, 0.0243 mmol), and 1,1′-bis(di-t-butylphosphinoferrocene)palladium dichloride (1.0 mg, 0.00162 mmol) in 1N aqueous potassium carbonate (0.7 mL) and THF (0.7 mL) was heated at 85° C. in a sealed tube for 2 h. The reaction mixture was cooled to room temperature and water (10 mL) was added. The mixture was extracted with EtOAc (3×20 mL) and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-40% EtOAc in hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-(4-fluoro-5-isopropyl-2-methoxyphenyl)-2-(trifluoromethyl)pyridin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.40 (20% EtOAc/hexanes). LCMS calc. 639.2; found 639.2 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers): δ 8.55 (s, 1H); 7.87 (s, 1H); 7.74-7.68 (m, 3H); 7.02 (dd, J=4.5, 8.1 Hz, 1H); 6.72 (d, J=11.7 Hz, 1H); 5.64 (d, J=8.0 Hz, 0.5H); 5.48 (d, J=7.9 Hz, 0.5H); 4.84 (d, J=16.4 Hz, 0.5H); 4.77 (d, J=16.5 Hz, 0.5H); 4.21 (d, J=16.5 Hz, 0.5H); 3.96 (d, J=16.3 Hz, 0.5H); 3.92-3.85 (m, 0.5H); 3.8-3.73 (m, 3.5H); 3.25-3.17 (m, 1H); 1.30-1.18 (m, 6H); 0.56 (d, J=6.4 Hz, 1.5H); 0.42 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: C(N(C(=O)C1C=CC(O)=CC=1)C1C=C(OC)[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Cl[CH2:39][C:40]([N:42]([CH2:44][CH2:45][CH2:46][O:47][CH3:48])[CH3:43])=O>>[CH2:40]([N:42]([CH2:43][C:14]1[CH:19]=[CH:18][C:17]([O:22][CH2:39][CH2:40][N:42]([CH2:44][CH2:45][CH2:46][O:47][CH3:48])[CH3:43])=[CH:16][CH:15]=1)[C:44]1[CH:45]=[C:46]([O:47][CH3:48])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:39]
Reactant: COCCCN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)CCCOC)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 110.5 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-(3-methoxypropyl)-N-methylacetamide (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.8 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6](Br)=[C:5]([N+:8]([O-:10])=[O:9])[N:4]=[C:3]1[CH2:11][O:12][C:13](=[O:15])[CH3:14].[CH3:16][N:17](C)C=O>>[CH3:1][N:2]1[C:6]([C:16]#[N:17])=[C:5]([N+:8]([O-:10])=[O:9])[N:4]=[C:3]1[CH2:11][O:12][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)OCc1nc([N+](=O)[O-])c(Br)n1C
Reactant: CN(C)C=O
Product: CC(=O)OCc1nc([N+](=O)[O-])c(C#N)n1C

Procedure:
2.78 G. (0.01 moles) of 1-methyl-2-acetoxymethyl-4-nitro-5-bromoimidazole and 0.0115 moles of cupric cyanide are combined in 20 ml. of dimethylformamide and heated on a steam bath for 12 hours. The reaction mixture is cooled and poured into 200 ml. of 3% aqueous ammonia and extracted with chloroform. The extracts are washed with water, dried and evaporated under a high vacuum. The residue is recrystallized from isopropanol affording 1.0 g. 1-methyl-2-acetoxymethyl-4-nitro-5-cyanoimidazole, m.p. 92° to 93°C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]2[N:10]=[C:11]([N:13]([CH3:15])[CH3:14])[NH:12][C:4]=2[CH:3]=1.[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:14][N:13]([CH3:15])[C:11]1[NH:12][C:4]2[CH:3]=[C:2]([C:22]3[CH:23]=[CH:24][C:19]([O:18][CH2:16][CH3:17])=[C:20]([C:28]([F:29])([F:31])[F:30])[CH:21]=3)[N:7]=[C:6]([C:8]#[N:9])[C:5]=2[N:10]=1
Reactant: CN(C)c1nc2c(C#N)nc(Cl)cc2[nH]1
Reactant: CCOc1ccc(B(O)O)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1ccc(-c2cc3[nH]c(N(C)C)nc3c(C#N)n2)cc1C(F)(F)F
Temperature: 130 °C
Yield: 3 %

Procedure:
A suspension of 6-chloro-2-dimethylamino-1H-imidazo[4,5-c]pyridine-4-carbonitrile (100 mg, 0.45 mmol), 4-ethoxy-3-trifluoromethyl-phenyl boronic acid (198 mg, 0.88 mmol) tetrakis(triphenylphosphine)palladium(0) (50 mg, ˜10 mol %) and potassium carbonate (193.0 mg, 1.39 mmol) in THF (3 ml) was heated to 130° C. for 6 minutes in the “Smith” microwave. The crude mixture was concentrated under reduced pressure to remove THF before partitioning between ethyl acetate and water. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The material was then dissolved in DMSO and purified in aliquots by preparative HPLC. The desired fractions were collected and concentrated to give a white solid which was washed with ether to afford 2-dimethylamino-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (5.0 mg)
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:16])([F:15])[S:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1.I[CH:18]([CH3:20])[CH3:19]>C1C=CC=CC=1>[CH:18]([CH:12]([C:9]1[CH:8]=[CH:7][C:6]([S:5][C:4]([F:15])([F:3])[F:16])=[CH:11][CH:10]=1)[C:13]#[N:14])([CH3:20])[CH3:19]
Reactant: N#CCc1ccc(SC(F)(F)F)cc1
Reactant: CC(C)I
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CC(C)C(C#N)c1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 87.4 %

Procedure:
Fifty percent sodium hydroxide (13.5 ml) is added over a 30-minute period dropwise to a suspension of 4-trifluoromethylthiophenylacetonitrile (9.7 g, 0.045 mol), 2-iodopropane (9.5 g, 0.056 mol), and 18 crown-6 (0.61 g, 0.0023 mol) in 13.5 ml of benzene and the exotherm reaches 43° C. After stirring 2.5 hours at ambient temperature, an aliquot placed on glc shows none of the starting nitrile remaining. The reaction is worked up by adding ice water and extracting with ether, which is washed with 10% HCl, water, and dried over sodium sulfate. Evaporation in vacuo gave 10.2 g (86.8%) of a red-brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[Br-].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[Br:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:6]/[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=1
Reactant: BrCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [Br-]
Product: COc1cc(/C=C/CCCBr)cc(OC)c1OC

Procedure:
3,4,5-Trimethoxybenzaldehyde (9.81 g) and 4-bromobutyltriphenylphosphonium bromide (23.93 g) were treated in the same manner as in Preparation Example 83 to obtain the title compound.
Reaction SMILES: Cl.[C:2]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[NH:4])[NH2:3].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:37])[C:23](=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=1)[C:24](=O)[CH3:25].C[O-].[Na+]>C(O)C>[NH2:4][C:2]1[NH:3][C:24]([CH3:25])=[C:23]([C:22](=[O:37])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=2)[C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)CCCCCCCCCCBr
Reactant: CCOC(=O)CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(C)=C(C(=O)CCCCCCCCCCBr)C1c1cccc([N+](=O)[O-])c1

Procedure:
12.7 g of ethyl amidinoacetate hydrochloride and 33.4 g of 14-bromo-3-(3-nitrobenzylidene)tetradecane-2,4-dione are dissolved in 300 ml of ethanol and the solution is treated with 14.5 ml of a 5.25M of sodium methoxide solution. The mixture is heated to boiling under reflux for 7 h and then concentrated in vacuo. The residue is dissolved in ethyl acetate and the solution is washed with water, dried over sodium sulfate, filtered and concentrated again. The oily residue is dried in vacuo and reacted in the next stage without further purification.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[F:19][C:20]1([F:28])[CH2:24][NH:23][C@H:22]([C:25]([NH2:27])=[O:26])[CH2:21]1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([N:23]3[CH2:24][C:20]([F:28])([F:19])[CH2:21][C@H:22]3[C:25]([NH2:27])=[O:26])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H]1CC(F)(F)CN1
Agent: Cl
Product: NC(=O)[C@@H]1CC(F)(F)CN1C(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 47 b, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3 c, 50 mg, 214 μmol) and (2S)-4,4-difluoro-2-pyrrolidinecarboxamide hydrochloride (CAN 426844-51-1; 44 mg, 236 μmol) as starting materials and isolated (63 mg, 80%) as off-white solid; LC-MS (UV peak area, ESI) 100%, 366.1629 [MH+].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[NH2:18][C:19]1[O:20][C:21]([C:24](O)=[O:25])=[CH:22][N:23]=1>>[NH2:18][C:19]1[O:20][C:21]([C:24]([NH:17][CH:15]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[C:3]([Cl:2])[CH:4]=2)[CH3:16])=[O:25])=[CH:22][N:23]=1
Reactant: CC(N)c1cnc(OCC(F)(F)F)c(Cl)c1
Reactant: Nc1ncc(C(=O)O)o1
Agent: Cl
Product: CC(NC(=O)c1cnc(N)o1)c1cnc(OCC(F)(F)F)c(Cl)c1
Yield: 47 %

Procedure:
The title compound is prepared in 47% yield (106 mg, clear colorless oil) from (+)-1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (182 mg, 0.63 mmol, Amine-5, single enantiomer) and 2-aminooxazole-5-carboxylic acid (80 mg, 0.63 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][C:24]([NH2:26])=[O:25].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[NH2:26][C:24](=[O:25])[CH2:23][O:22][NH:21][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20]
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NOCC(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: NC(=O)CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.200 g, 0.723 mmol, US 2005/20572 A1) in DCM (6.0 mL) were added 2-(aminooxy) acetamide 53 (0.098 g, 1.086 mmol), 1-hydroxybenzotriazole (0.147 g, 1.086 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.208 g, 1.086 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 54 (0.203 g, 81%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35]>C1COCC1>[F:32][C:33]([F:37])([F:36])[CH2:34][NH:35][C:16]1[N:17]=[C:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[CH3:26])[C:13]2[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: NCC(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NCC(F)(F)F)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The product of Example 48 (300 mg, 0.67 mmol) and trifluoroethylamine (300 mg, 3 mmol) were dissolved in THF (10 ml) and sealed in a vial under Ar. The mixture was heated in an oil bath to 600 for 4 days. The solvents were removed in vacuo, and the residue was flash chromatographed with 60-90% CH2Cl2/hexane. Recrystallization from CH2Cl2/hexane gave the title compound as a white crystalline solid. mp 195-196°, LC MS m/z=465 (MH+). Retention time=2.38 min.
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:19]1[N:24]=[C:23]([NH:25][C@@H:26]2[C@@H:31]3[CH2:32][C@@H:28]([CH:29]=[CH:30]3)[C@@H:27]2[C:33]([NH2:35])=[O:34])[C:22]([Cl:36])=[CH:21][N:20]=1>>[Cl:36][C:22]1[C:23]([NH:25][C@@H:26]2[C@@H:31]3[CH2:32][C@@H:28]([CH:29]=[CH:30]3)[C@@H:27]2[C:33]([NH2:35])=[O:34])=[N:24][C:19]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][CH:2]([F:17])[F:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:20][CH:21]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: Nc1ccc2c(c1)CCC(NCC(F)F)CC2
Product: NC(=O)[C@@H]1[C@H](Nc2nc(Nc3ccc4c(c3)CCC(NCC(F)F)CC4)ncc2Cl)[C@H]2C=C[C@@H]1C2
Yield: 51.7 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2-Difluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide to yield (1S,2S,3R,4R)-3-{5-Chloro-2-[7-(2,2-difluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (54.09 mg, 51.7% yield) as a white powder. 1H-NMR (CDCl3) δ 7.86 (s, 1H), 7.40 (d, J=8.2 Hz, 1H), 7.28 (m, 1H), 7.01 (d, J=8.1 Hz, 1H), 6.88 (s, 1H), 6.82 (t, J=8.9 Hz, 1H), 6.31 (m, 2H), 5.83 (m, 1H), 5.56 (br s, 1H), 5.40 (br s, 1H), 4.36 (m, 1H), 3.05 (m, 3H), 2.89 (s, 1H), 2.78 (m, 3H), 2.47 (d, J=8.1 Hz, 1H), 2.24 (d, J=9.3 Hz, 1H), 2.07 (m, 2H), 1.63 (d, J=9.4 Hz, 1H), 1.31 (m, 2H). LC/MS (ESI+)=503 (M+H). MP=166° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([Br:14])[CH:5]=1)(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:18][C:19]([CH3:21])=[CH2:20]>CN(C=O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:20][C:19]([CH3:21])=[CH2:18])[C:11](=[O:13])[CH3:12])=[C:6]([Br:14])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: C=C(C)CBr
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)CN(C(C)=O)c1ccc(C(C)=O)cc1Br
Reaction time: 1 h
Yield: 105.7 %

Procedure:
N-(4-Acetyl-2-bromophenyl)acetamide (25 g, 0.1 mole) in dry DMF (250 ml) was treated with sodium hydride (60%, 4.5 g, 0.11 mole) at 25° C. under argon with stirring for 1 h. 3-Bromo-2-methylpropene (1.1 ml, 0.11 mole) was added and the mixture stirred for a further 16 h. The mixture was concentrated in vacuo and partitioned between water and Et2O. The organic phase was dried and concentrated in vacuo to give the title compound (32.8 g, 100%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7](Cl)[CH:6]=[C:5]([NH:10][CH2:11][CH2:12][O:13][CH3:14])[C:4]=1[N+:15]([O-:17])=[O:16].[CH3:18][O-:19].[Na+]>CO>[CH3:1][NH:2][C:3]1[CH:8]=[C:7]([O:19][CH3:18])[CH:6]=[C:5]([NH:10][CH2:11][CH2:12][O:13][CH3:14])[C:4]=1[N+:15]([O-:17])=[O:16]
Reactant: C[O-]
Reactant: CNc1cc(Cl)cc(NCCOC)c1[N+](=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CNc1cc(OC)cc(NCCOC)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
0.019 mole (5 g) of 2-methylamino-6-(β-methoxyethyl)amino-4-chloronitrobenzene was refluxed with 35 ml of 26% sodium methylate in methanol for 45 minutes then diluted with 100 ml of ice water to precipitate the desired product. Following filtering, water washing and drying under vacuum in the presence of P2O5, the product obtained was recrystallized from isopropanol. It melted at 84° C.