Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([C:26]([O:28][CH3:29])=[O:27])[C@H:8]1[C:17]2[C:12](=[C:13]([Br:22])[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=2)[NH:11][C@@H:10]([CH:23]2[CH2:25][CH2:24]2)[CH2:9]1.[C:39](Cl)([Cl:41])=[O:40].C(Cl)(Cl)=O.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1)[CH2:6][N:7]([C:26]([O:28][CH3:29])=[O:27])[C@H:8]1[C:17]2[C:12](=[C:13]([Br:22])[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=2)[N:11]([C:39]([Cl:41])=[O:40])[C@@H:10]([CH:23]2[CH2:24][CH2:25]2)[CH2:9]1
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)Nc2c(Br)cc(C(F)(F)F)cc21
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)N(C(=O)Cl)c2c(Br)cc(C(F)(F)F)cc21
Reaction time: 24 h

Procedure:
A solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-8-bromo-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (Example 100C) (1.0 g) in 50 mL of a 20% phosgene in toluene solution was heated to reflux for 24 h. Additional phosgene/toluene (50 ml) was added and heating was continued for an additional 24 h. Excess phosgene was removed by purging with nitrogen. The resulting solution was concentrated to afford the crude title product which was used without further purification. MS m/z 681.5 (M+).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:18]([OH:23])(=O)[CH2:19][CH2:20][CH3:21].Cl.C[N:26](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([CH:19]([CH2:20][CH3:21])[C:18]([NH2:26])=[O:23])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=12
Reactant: CCCC(=O)O
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Product: CCC(C(N)=O)c1ccc(-n2ncc3c(N)ncnc32)cc1
Reaction time: 0.17 h
Yield: 19.3 %

Procedure:
Title compound 11A, 1-(4-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (38 mg, 1.1 eq, 0.17 mmol) was added to a solution of butyric acid (13 mg, 1.0 eq, 0.15 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 1.1 eq, 0.17 mmol), 1-hydroxybenzotriazole (21 mg, 1.0 eq, 0.15 mmol) in DMF (1 ml) which had been stirred for 10 minutes under an inert atmosphere. The reaction was stirred at room temperature for 18 hours, after which methanol (1 ml) was added and the solvents were removed in vacuo. The resultant solid purified by semi-preparative HPLC to yield the title compound as a white solid (8.5 mg, 0.029 mmol, 19%). LCMS: [M+H]+=297, Rt=1.45 min, 100% purity.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][N:4]1[C:9]2([CH2:11][CH2:10]2)[CH2:8][CH2:7][N:6]2[C:12](=[O:22])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[N:15]=[C:5]12.C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[O:1]=[C:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][N:4]1[C:9]2([CH2:11][CH2:10]2)[CH2:8][CH2:7][N:6]2[C:12](=[O:22])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[N:15]=[C:5]12
Reactant: O=c1cc(-c2ccncc2)nc2n1CCC1(CC1)N2C[C@@H](O)c1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=C(CN1c2nc(-c3ccncc3)cc(=O)n2CCC12CC2)c1ccccc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 25.2 %

Procedure:
0.31 g (0.83 mmol) of 1′-[(2S)-2-hydroxy-2-phenylethyl]-8′-pyridin-4-yl-3′,4′-dihydrospiro[cyclopropane-1,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one was dissolved in 8 ml of anhydrous dichloromethane and mixed with 0.145 g (1.24 mmol) of N-methylmorpholine N-oxide, 0.003 g (0.0083 mmol) of tetra-n-propylammonium perruthenate and 1 g of powdered molecular sieves (4A). The mixture was stirred at 20° C. under nitrogen atmosphere for 12 h. The mixture was filtered. The filtrate was washed with a saturated aqueous solution of ammonium chloride, dried and evaporated to give crude product. Purification by chromatography on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 100/0 to 95/5 gave the compound in the form of free base which was transformed into its hydrochloride salt to give 0.078 g of pure product.
Reaction SMILES: C[Si]([CH2:5][OH:6])(C)C.[H-].[Na+].[N+]([C:12]1[CH:19]=[CH:18][CH:17]=[C:14]([C:15]#[N:16])[C:13]=1[C:20]#[N:21])([O-])=O>CN(C)C=O>[CH3:5][O:6][C:12]1[CH:19]=[CH:18][CH:17]=[C:14]([C:15]#[N:16])[C:13]=1[C:20]#[N:21]
Reactant: C[Si](C)(C)CO
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(C#N)c1C#N
Temperature: 5 °C
Reaction time: 1 h
Yield: 1 %

Procedure:
In 60 ml of N,N-dimethylformamide were dissolved 20 g of trimethylsilylmethanol. This was maintained at 5° C. in a water bath and 4.6 g of sodium hydride were added thereto in the atmosphere of argon. The resulting mixture was stirred at 5° C. for 1 hour. Thereafter, 33.3 g of 3-nitrophthalonitrile dissolved in 160 ml of N,N-dimethylformamide were added dropwise to the mixture. After completion of the addition, the ice bath was removed and the mixture was stirred at room temperature for 24 hours. The reaction product was then added with 200 ml of dilute hydrochloric acid and extracted with 1 liter of toluene. The organic layer was washed well with water, followed by the removal of water with magnesium sulfate and the purification with a toluene/silica gel column. However, the desired compound shown by the above formula (XV) was hardly obtained. The yield was about 1% and 3-methoxyphthalonitrile as a by-product was yielded in an amount of several times that of the compound (XV).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][C:10](=[O:12])[CH:9]=[CH:8][O:7]1)=[O:5])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][C:10](=[O:12])[CH2:9][CH2:8][O:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC(=O)C=CO1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC(=O)CCO1
Reaction time: 4 h
Yield: 33.1 %

Procedure:
A mixture of 4-oxo-3,4-dihydro-2H-pyran-2-carboxylic acid ethyl ester (8.0 g, 46 mmol) and Pd/C (10%, 0.20 g) in ethyl acetate (70 mL) was stirred under hydrogen (1 atm) for 4 hours. The mixture was filtered through a pad of Celite®. The filtrate was concentrated, and the residue was purified by silica gel column using 30% EtOAc in petroleum ether to give 4-oxo-tetrahydro-pyran-2-carboxylic acid ethyl ester (2.62 g, 33% yield) as an oil. 1H NMR (500 MHz, CDCl3) δ 4.40 (m, 1H), 4.23-4.31 (m, 3H), 3.79 (m, 1H), 2.61-2.74 (m, 3H), 2.40 (d, J=15.0 Hz, 1H), 1.31 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6](=[O:7])[C:5]2=[CH:15][CH:16]=1.O>CO.[BH4-].[K+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:15][CH:16]=1)[C:6](=[O:7])[N:8]([CH2:11][CH:12]([CH3:13])[CH3:14])[CH:9]2[OH:10]
Reactant: CC(C)CN1C(=O)c2ccc(Br)cc2C1=O
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)CN1C(=O)c2ccc(Br)cc2C1O
Temperature: 20 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
5-Bromo-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-bromo-3-hydroxy-2-isobutyl-2,3-dihydroinsoindol-1-one are prepared as described in Example 1, starting with 23.6 g of 4-bromo-N-isobutylphthalimide in 200 cm3 of methanol and 4.5 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 16 hours and is then cooled to a temperature in the region of 0° C. and 175 cm3 of distilled water are added dropwise. The methanol is then partially evaporated off under reduced pressure (2 kPa) at a temperature in the region of 40° C. The aqueous phase is extracted 3 times with 200 cm3 of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 23.7 g of 5-bromo-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-bromo-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a white powder (Rf=0.79, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)).
Reaction SMILES: COC(=O)[NH:4][C@H:5]1[C@@H:10]([CH3:11])[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1.[OH-].[K+]>CO.O>[CH2:12]([N:7]1[CH2:8][CH2:9][C@H:10]([CH3:11])[C@H:5]([NH2:4])[CH2:6]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)N[C@@H]1CN(Cc2ccccc2)CC[C@@H]1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H]1CCN(Cc2ccccc2)C[C@H]1N
Yield: 37.8 %

Procedure:
A mixture of racemic cis (1-benzyl-4-methyl-piperidin-3-yl)-carbamic acid methyl ester (1.56 g, 5.95 mmol) and potassium hydroxide (9.90 mL, 59.5 mmol, 6M solution) in methanol (50 mL) was heated at reflux for 48 hours. The cooled reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine then dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel (gradient: 0 to 7% 2M NH3 in methanol solution in DCM) to afford 460 mg (38%) of racemic cis 1-benzyl-4-methyl-piperidin-3-ylamine. LCMS (Method H, ESI): RT=0.35 min, m+H=204.9; 1H NMR (400 MHz, CDCl3) δ: 7.29-7.28 (m, 5H), 3.45 (s, 2H), 2.76-2.72 (m, 3H), 2.20-2.11 (m, 1H), 1.97 (td, 1H), 1.42 (m, 5H), 0.91 (d, 3H).
Reaction SMILES: [CH2:1]([N:13]([CH2:15][CH2:16][O:17][C:18]1[CH:28]=[CH:27][C:21]2[CH2:22][CH2:23][C:24](=[O:26])[O:25][C:20]=2[CH:19]=1)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:29][OH:30]>>[CH2:1]([N:13]([CH2:15][CH2:16][O:17][C:18]1[CH:28]=[CH:27][C:21]([CH2:22][CH2:23][C:24]([O:30][CH3:29])=[O:26])=[C:20]([OH:25])[CH:19]=1)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN(C)CCOc1ccc2c(c1)OC(=O)CC2
Reactant: CO
Product: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)OC)c(O)c1
Yield: 100 %

Procedure:
A solution of 7-[2-(N-Dodecyl-N-methylamino)ethoxy]-3,4-dihydro-2H-1-benzopyran-2-one (2.0 g, 5.13 mmol) in methanol (30 ml) was stirred at 22° C. for 0.5 h. The solvent was then removed in vacuo at 40° C. to afford the title compound (2.14 g, 100%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:11])[CH2:9][CH3:10])=[C:4]([F:12])[CH:3]=1.C(O)C.N[C@H](C(O)=O)CC(O)=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:11])[CH2:9][CH3:10])=[C:4]([F:12])[CH:3]=1
Reactant: CCC(N)c1ccc(Cl)cc1F
Agent: N[C@@H](CC(=O)O)C(=O)O
Solvent: O
Solvent: CCO
Product: CC[C@@H](N)c1ccc(Cl)cc1F
Temperature: 72 °C
Reaction time: 8 h

Procedure:
Step 4—Three runs were carried out in parallel and combined in the work-up. A mixture of 1-(4-chloro-2-fluoro-phenyl)-propylamine (497.6 g, 2.65 mol, 1.0 eq) from Step 3, ethanol and water (3.1 L ethanol/1.3 L water) and L-aspartic acid (353 g, 2.65 mol, 1.0 eq) was heated to 72° C. (oil bath) for 1 hour and then allowed to cool to room temperature. The resulting precipitate was filtered off, washed with ethanol (2 L) and air dried to give a white solid (4381.6 g-contains solvent, dry weight estimated by 1H NMR at 2674.2 g), which was split into four. To each of the four portions was added a mixture of ethanol and water (11.9 L EtOH, 4.9 L H2O) and the resulting mixture was then stirred at room temperature overnight before isolating the solid by filtration, washing with ethanol, and drying the solid in a vacuum oven overnight at 40° C., to give (R)-1-(4-chloro-2-fluoro-phenyl)-propylamine as the aspartate salt, a white solid (1409.2 g). 1H NMR (400 MHz, DMSO-d6): 7.56 (1H, t), 7.34 (1H, dd), 7.29 (1H, dd), 4.03 (1H, t), 3.68 (1H, dd), 2.67 (1H, dd), 2.38 (1H, dd), 1.69-1.49 (2H, m), 0.80 (3H, t).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[NH:9][C:10]=2[N:11]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[N:9]([CH2:19][C:18]3[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)[C:10]=2[N:11]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1COc2ccc(Br)nc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)COc3ccc(Br)nc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A suspension of 6-bromo-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (2.0 g; prepared according to WO 01/30782) in DMF (40 mL) was treated with 4-methoxybenzyl chloride (1.18 mL) and Cs2CO3 (8.5 g) and stirred at rt for 2 h. The solvent was evaporated under reduced pressure and the residue was partitioned between EA and water. The org. layer was washed with brine, dried over MgSO4 and evaporated under reduced pressure. The residue was triturated with Hept, affording a beige solid (2.8 g; 92% yield).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:13])=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1.[H-].[Na+].[C:16]([O:20][C:21]([N:23]1C(C2C=CC(C#N)=CC=2)O1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21](=[O:22])[NH:23][N:3]1[C:4]([CH3:13])=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:6]=[C:2]1[CH3:1])([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1nc(-c2cccnc2)c(C)[nH]1
Reactant: CC(C)(C)OC(=O)N1OC1c1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Product: Cc1nc(-c2cccnc2)c(C)n1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-(2,5-Dimethyl-1H-imidazol-4-yl)-pyridine (0.035 g, 0.220 mmol) was weighed into an oven dried, nitrogen swept 10 mL round bottomed flask. Tetrahydrofuran (THF, 1 mL) was added via syringe and the resulting slurry cooled on an ice bath under nitrogen and treated with sodium hydride (0.0097 g, 0.242 mmol 60% dispersion in oil) with stirring. After 10 minutes, 3-(4-cyano-phenyl)-oxaziridine-2-carboxylic acid tert-butyl ester (0.052 g, 0.212 mmol) was added as a solid and the thick yellow slurry allowed to warm to room temperature and stir for 2 hours. The crude reaction mixture was loaded directly onto a flash silica gel column and eluted with CH2Cl2:MeOH/10:1 giving (2,5-dimethyl-4-pyridin-3-yl-imidazol-1-yl)-carbamic acid tert-butyl ester as a light yellow oil as a 5:1 mixture with its regioisomer (0.027 g, 46%): IR (film) 3389, 2978, 2930, 1730, 1478, 1275, 1252, 1156, 1017, 951, 711, 573 cm−1; 1H NMR (300 MHz, DMSO, Major isomer) δ 10.41 (s, 1H), 8.81 (s, 1H), 8.39 (s, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.44-7.28 (m, 1H), 2.21 (s, 3H), 2.18 (s, 3H), 1.46 (s, 9H); ESIMS m/z 289 [(M+H)]+ and 287 [(M−H)]−.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([O:33][CH3:34])=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[CH:19]=[C:18]2[NH:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[CH:27][C:26]=1[Cl:32]>>[N:1]1[N:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([O:33][CH3:34])=[CH:15][CH:16]=[C:17]3[C:22]=2[O:21][C:20](=[O:23])[CH:19]=[C:18]3[NH:24][C:25]2[C:30]([Cl:31])=[CH:29][N:28]=[CH:27][C:26]=2[Cl:32])[N:3]=[N:4][CH:5]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Reactant: c1nnn[nH]1
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCn1ncnn1

Procedure:
The title compound was prepared from tetrazole and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 98. 1H NMR (400 MHz, DMSO-d6): δ 9.52 (s, 1H), 8.94 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.19 (d, 1H), 4.72 (t, 2H), 4.63 (s, 1H), 3.96 (t, 2H), 3.90 (s, 3H), 1.98 (m, 2H), 1.70 (m, 2H), 1.46 (m, 2H); MS (ESI): 490.9.
Reaction SMILES: [CH2:1]([CH:8]([C:14](OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].IC[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28]>>[F:31][C:26]([F:32])([C:27]([F:28])([F:29])[F:30])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:14][CH:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: C=CCCCCCC(C(=O)OCC)C(=O)OCC
Reactant: FC(F)(F)C(F)(F)CCCCCCI
Product: C=CCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)OCC

Procedure:
Starting with the diethyl 2-(6-heptenyl)malonate prepared in Example 9 and the 1-iodo-7,7,8,8,8-pentafluoro-octane prepared in Example 4, the same procedure as shown in Example 5 was repeated to give ethyl 2-(7,7,8,8,8-pentafluorooctyl)-8-nonenoate.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[F:25][C:26]1[N:37]=[CH:36][CH:35]=[CH:34][C:27]=1[C:28](N(OC)C)=[O:29]>O1CCCC1>[F:25][C:26]1[N:37]=[CH:36][CH:35]=[CH:34][C:27]=1[C:28]([C:22]1[S:21][C:20]([N:16]2[CH2:17][CH2:18][CH2:19][N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:12])[CH2:14][CH2:15]2)=[N:24][CH:23]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nccs2)CC1
Reactant: CON(C)C(=O)c1cccnc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCN(c2ncc(C(=O)c3cccnc3F)s2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 36.9 %

Procedure:
A 2.5M n-butyl lithium in tetrahydrofuran solution (0.9 ml, 2.25 mmol) was added dropwise to a solution of tert-butyl-4-(thiazol-2-yl)-1,4-diazepane-1-carboxylate (570 mg, 2 mmol) in tetrahydrofuran (7 ml), cooled to −78° C. Thirty minutes later, a solution of 2-fluoro-N-methoxy-N-methylnicotinamide (370 mg, 2 mmol) in tetrahydrofuran (2 ml) added dropwise. The reaction mixture was stirred at −78° C. for one hour, then at 0° C. for an extra hour. It was quenched with a saturated sodium bicarbonate aqueous solution. The reaction mixture was diluted with ethyl acetate, then washed with brine. The organic was dried over magnesium sulfate, then concentrated in vacuo. The residue was purified by flash chromatography (40 g silica gel, pentane/ethyl acetate) to afford the title compound (300 mg, 38%). 1H NMR (CD3OD): 1.42 (9H, s), 1.90-2.00 (2H, M0, 3.45-3.50 (2H, m), 3.65-6.75 (2H, m), 3.80-3.90 (2H, m), 7.46-7.49 (1H, t), 7.67-7.69 (1H, d), 8.10-8.15 (1H, t), 8.39-8.40 (1H, d). MS (ES+): 407.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]>CO.[Pd]>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(C)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1c(C)cccc1N

Procedure:
2-Methyl-6-nitrobenzoic acid is reacted with trimethylsilyldiazomethane to yield methyl 2-methyl-6-nitrobenzoate with m.p. 44-45° (Chem. Pharm. Bull., Vol. 29, 1475 (1981)). Methyl 2-methyl-6-nitrobenzoate is hydrogenated in methanol in the presence of palladium, 10% on carbon powder, at room temperature and atmospheric pressure to give methyl 2-methyl-6-aminobenzoate.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][NH:10][C:11]([C:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[N:18][C:19]=2[C:20]([O:35]C(C2C=CC=CC=2)C2C=CC=CC=2)=[C:21]2[C:25](=[O:26])[N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:23][C:22]=12)=[O:12])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:6]([O:5][P:4]([CH2:9][NH:10][C:11]([C:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[N:18][C:19]=2[C:20]([OH:35])=[C:21]2[C:25](=[O:26])[N:24]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:23][C:22]=12)=[O:12])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(CNC(=O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOP(=O)(CNC(=O)c1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2)OCC
Yield: 66.5 %

Procedure:
A solution of 216 (20 mg, 0.030 mmol) in 0.30 mL of CH2Cl2 was stirred with TFA (231 μL, 3.00 mmol) and TES (479 μL, 3.00 mmol) for 30 minutes when the starting materials were completely consumed as judged by TLC and LCMS. The reaction was worked up by removal of the solvent in vacuo and crystallizing the product from EtOAc-Hex to provide 10 mg (66%) of ({[7-(4-Fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-amino}-methyl)-phosphonic acid diethyl ester 217 as a yellow solid. 1H NMR (300 MHz, CD3OD) δ 1.32 (t, 6H, J=7 Hz), 3.96 (d, 2H, J=12 Hz), 4.16 (septet, 4H, J=7 Hz), 4.56 (s, 2H), 4.79 (s, 2H), 7.10 (t, 2H, J=9 Hz), 7.39 (dd, 2H, J=9 Hz), 7.76 (br s, 1H), 8.66 (d, 1H, J=8 Hz), 8.95 (br s, 1H); 31P (121.4 MHz, CD3OD) δ 23.2; 19F NMR (282.6 MHz, CD3OD) δ −76.2, 59.9; MS (m/z) 502.5 [M+H]+, 1003.0 [2M]+, 1025.1 [2M+Na]+.
Reaction SMILES: [F:1][C:2]1[C:12]([F:13])=[C:11](F)[C:10]([F:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:16]([O:18][C:19]([N:21]([CH2:23][CH:24]1[O:29][CH2:28][CH2:27][NH:26][CH2:25]1)[CH3:22])=[O:20])[CH3:17].C(=O)([O-])O.[Na+]>C(#N)C>[CH2:16]([O:18][C:19]([N:21]([CH2:23][CH:24]1[CH2:25][N:26]([C:11]2[C:10]([F:15])=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([F:1])[C:12]=2[F:13])[CH2:27][CH2:28][O:29]1)[CH3:22])=[O:20])[CH3:17]
Reactant: CCOC(=O)c1cc(F)c(F)c(F)c1F
Reactant: CCOC(=O)N(C)CC1CNCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cc(F)c(N2CCOC(CN(C)C(=O)OCC)C2)c(F)c1F
Yield: 71.8 %

Procedure:
A suspension of 22.2 g of ethyl 2,3,4,5-tetrafluorobenzoate, 22.2 g of 2-(N-ethoxycarbonyl-N-methylaminomethyl)morpholine and 8.4 g of sodium hydrogen carbonate in 130 ml of acetonitrile is refluxed for 7 hours. The reaction mixture is concentrated under reduced pressure, to the obtained residue is added 100 ml of chloroform and the solution is washed with water. After drying over anhydrous magnesium sulfate, the chloroform is distilled off under reduced pressure and the residue is puiified by chromatography on silica gel to give 29.0 g of ethyl 4-[2-(N-ethoxycarbonyl-N-methylaminomethyl)morpholino]-2,3,5-trifluorobenzoate in 72% yield, as an oily substance.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[SH:14])([O-:3])=[O:2].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][Cl:22]>>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][S:14][C:5]1[CH:6]=[CH:7][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S
Reactant: ClCCCCCCBr
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1SCCCCCCCl

Procedure:
Following the procedures of Preparation 1, the title compound is prepared from 2-nitro-4-trifluoromethylthiophenol and 1-bromo-6-chlorohexane.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[S:12][C:11]([NH:14][C:15]([NH:17][CH2:18][CH3:19])=[O:16])=[N:10][C:9]=2[CH:8]=[C:7]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=1)=O.[CH2:26]([NH2:28])[CH3:27]>>[CH2:26]([NH:28][C:3]([C:5]1[C:13]2[S:12][C:11]([NH:14][C:15]([NH:17][CH2:18][CH3:19])=[O:16])=[N:10][C:9]=2[CH:8]=[C:7]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=1)=[O:2])[CH3:27]
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)OC)c2s1
Reactant: CCN
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)NCC)c2s1
Temperature: 100 °C
Yield: 5 %

Procedure:
A stirred mixture of 2-Amino-5-pyridin-3-yl-benzothiazole-7-carboxylic acid methyl ester (125 mg, 0.439 mmol), ethyl isocyanate (0.21 ml, 2.187 mmol) and dibutyltindiacetate (12 drops) in anhydrous 1,4-dioxane (10 ml) was heated in a sealed vessel at 100° C. for 16 h. After cooling to ambient temperature, the solvent was removed in vacuo to give 2-(3-Ethyl-ureido)-5-pyridin-3-yl-benzothiazole-7-carboxylic acid methyl ester which was used without further purification. A stirred mixture of 2-(3-Ethyl-ureido)-5-pyridin-3-yl-benzothiazole-7-carboxylic acid methyl ester (78 mg, 0.22 mmol) and aqueous ethylamine solution (70% w/v, 3 ml) was heated by microwave irradiation in a CEM Discover reactor at 100° C. for 1 h. The reaction mixture was purified by Preparative HPLC to provide the 2-(3-Ethyl-ureido)-5-pyridin-3-yl-benzothiazole-7-carboxylic acid ethylamide as a white solid (8.7 mg, 5%).