Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH3:12])[CH:6]=[CH:5][N:4]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:24]=[CH:23][C:18]2[N:19]=[C:20]([SH:22])[NH:21][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:10][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][S:22][C:20]2[NH:21][C:17]3[CH:16]=[C:15]([C:14]([F:26])([F:25])[F:13])[CH:24]=[CH:23][C:18]=3[N:19]=2)[C:8]=1[CH3:9])[CH3:12]
Reactant: CCOc1ccnc(CCl)c1C
Reactant: FC(F)(F)c1ccc2nc(S)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccnc(CSc2nc3ccc(C(F)(F)F)cc3[nH]2)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5 g of 2-(chloromethyl) 4-ethoxy-3-methylpyridine and 5 g of 5-(trifluoromethyl) 2 benzimidazolethiol in 130 ml of abs. acetone was treated with 5 g of finely ground potassium carbonate and stirred at room temperature under argon for 2 hours. 100 ml of acetone were distilled off in a vacuum, whereupon the remaining portion of the reaction mixture was poured onto ice The crystallized-out product was filtered off and dissolved in methylene chloride. The solution obtained was washed with water, dried and concentrated. The residue was chromatographed on silica gel while eluting using methylene chloride and methylene chloride/ethyl acetate (1:1), with the medium pressure flash chromatography method. 2-[[(4 ethoxy-3-methyl-2-pyridyl) methyl]thio]-5-(trifluoromethyl)benzimidazole which melts at 173°-177° was obtained after recrystallization from ethyl acetate/ether.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11](=[O:30])[N:10]2[CH2:31][C:32]([OH:34])=[O:33])=[CH:5][CH:4]=1)#[N:2].C(C1C=CC([C@H]2C3C(=O)CCCC=3N(C3C=CC=C(C(F)(F)F)C=3)C(=O)N2CC(OC)=O)=CC=1)#N>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=3)[C:11](=[O:30])[N:10]2[CH2:31][C:32]([OH:34])=[O:33])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(=O)O)cc1
Agent: COC(=O)CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)[C@@H]1c1ccc(C#N)cc1
Product: N#Cc1ccc([C@H]2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(=O)O)cc1

Procedure:
The title compound is prepared in analogy to 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(tri-fluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazolin-3(4H)-yl)acetic acid (example 32), using (S)-methyl 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazolin-3(4H)-yl)acetate (example 31B, 30 mg, 62 μmol) as starting material. Yield: 23 mg; ESI mass spectrum [M+H]+=470; Retention time: 1.09 min (V001—006).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[C:24]([O:28][C:29]([NH:31][C:32]([CH3:39])([CH3:38])[CH:33]=[CH:34][C:35]([OH:37])=O)=[O:30])([CH3:27])([CH3:26])[CH3:25].[NH2:40][C@H:41]([CH2:64][C:65]1[CH:74]=[CH:73][C:72]2[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=2)[CH:66]=1)[C:42]([N:44]([CH3:63])[C@@H:45]([C:57]1[O:61][N:60]=[C:59]([CH3:62])[N:58]=1)[CH2:46][C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=1)=[O:43].FC(F)(F)C(O)=O.C(N(CC)CC)C>CN(C)C=O>[C:24]([O:28][C:29](=[O:30])[NH:31][C:32]([CH3:39])([CH3:38])[CH:33]=[CH:34][C:35](=[O:37])[NH:40][C@@H:41]([C:42](=[O:43])[N:44]([CH3:63])[C@@H:45]([C:57]1[O:61][N:60]=[C:59]([CH3:62])[N:58]=1)[CH2:46][C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=1)[CH2:64][C:65]1[CH:74]=[CH:73][C:72]2[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=2)[CH:66]=1)([CH3:25])([CH3:26])[CH3:27]
Reactant: Cc1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@H](N)Cc2ccc3ccccc3c2)n1
Reactant: CC(C)(C=CC(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)NC(=O)C=CC(C)(C)NC(=O)OC(C)(C)C)n1

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.26 g, 1.38 mmol) and 1-hydroxybenzotriazole monohydrate (0.21 g, 1.38 mmol) were added to a solution of N-tertbutoxycarbonyl-4-amino-4-methylpent-2-enoic acid (0.32 g, 1.38 mmol) in N,N-dimethylformamide (5 ml). After 30 min at 20° C. a mixture of (2R)-2-amino-N-methyl-N-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-3-(2-naphthyl)propionamide, trifluoroacetic acid (0.57 g, 0.99 mmol) and triethylamine (0.10 g, 0.99 mmol) in N,N-dimethylformamide (6 ml) were added. After 18 h at 20° C. the reaction mixture was poured on water (75 ml) and extracted several times with ethyl acetate (total 30 ml). The organic phases were collected and washed with aqueous citric acid (10%, 15 ml), a saturated solution of sodium hydrogencarbonate (3×15 ml) and water (3×15 ml). After drying (magnesium sulfate) the solution was concentrated in vacuo to give 0.68 g of crude (1,1-dimethyl-3-[(1R)-1-{N-methyl-N-{(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl}carbamoyl}-2-(2-naphthyl)ethylcarbamoyl]allyl}carbamic acid tertbutyl ester which was used for the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]3[CH:18]=[N:17][CH:16]=[CH:15][C:12]=3[CH:13]=O)[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:19].[F:20][C:21]([F:27])([F:26])[S:22]([NH2:25])(=[O:24])=[O:23].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:20][C:21]([F:27])([F:26])[S:22]([NH:25][CH2:13][C:12]1[CH:15]=[CH:16][N:17]=[CH:18][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]2[O:4][C:3](=[O:19])[N:2]([CH3:1])[C:6]=2[CH:7]=1)(=[O:24])=[O:23]
Reactant: Cn1c(=O)oc2ccc(-c3cnccc3C=O)cc21
Reactant: NS(=O)(=O)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cn1c(=O)oc2ccc(-c3cnccc3CNS(=O)(=O)C(F)(F)F)cc21
Temperature: 70 °C
Reaction time: 15 h
Yield: 22.2 %

Procedure:
A mixture of 3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)isonicotinaldehyde (128 mg, 0.5 mmol), trifluoromethanesulfonamide (94 mg, 0.63 mmol), acetic acid (60.5 mg, 1 mmol) and 4° A molecular sieves in 1,2-dichloroentane (2 mL) heated at 70° C. under nitrogen for 6 h. The suspension was cooled to room temperature and sodium triacetoxyborohydride (excess amount) was added. The reaction mixture was further stirred at room temperature for an additional 15 h. The mixture was diluted with dichloromethane (20 mL) and filtered through a pad of celite. The filter cake was thoroughly washed with an additional 30 mL of dichloromethane. The combined filtrates were washed with NaHCO3 (saturated solution). The aqueous phase was extracted with dichloromethane (2×50 mL). The organic phases were combined, dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by flash column (0-100% ethyl acetate in heptane, v/v) and yielded 43 mg of 1,1,1-trifluoro-N-((3-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)pyridin-4-yl)methyl)methane-sulfonamide as colorless solid ESI-MS m/z; 388.0 [M+1]+, Retention time 1.19 min; 1HNMR (MeOD, 400.342 MHz): δ 3.43 (s, 3H), 4.41 (5, 2H), 7.12 (dd, J=8.2, 1.8 Hz, 1H), 7.15 (s, 1H), 7.21 (d, J=1.6 Hz, 1H), 760 (d, J=5.2 Hz, 1H), 8.46 (s, 1H), 8.60 (d, J=8.2 Hz, 1H); and 5-(4-(hydroxymethyl)pyridin-3-yl)-3-methylbenzo[d]oxazol-2(3H)-one 37 mg as pinkish solid ESI-MS m/z: 257.0 [M+1]+, Retention time 0.84 min; 1HNMR (MeOD, 400.342 MHz): δ 3.3 (s, 3H), 4.41 (s, 2H), 7.12 (dd, J=1.76, 8.2 Hz, 1H), 7.21 (d, J=1.56 Hz, 1H), 7.37 (d, J=8.2 Hz, 1H), 7.60 (d, J=5.2 Hz, 1H), 8.46 (s, 1H), 8.60 (d. J=5.2 Hz, 1H).
Reaction SMILES: [CH:1]([CH:3]1[CH2:9][CH:8]2[CH:6]([CH2:7]2)[CH2:5][N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:2].CC(=CC)C.[O-:22]Cl=O.[Na+]>CC(C)=O.O>[C:13]([O:12][C:10]([N:4]1[CH:3]([C:1]([OH:22])=[O:2])[CH2:9][CH:8]2[CH:6]([CH2:7]2)[CH2:5]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: [O-][Cl+][O-]
Reactant: CC(C)(C)OC(=O)N1CC2CC2CC1C=O
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CC2CC2CC1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
To a mixture of tert-butyl 4-formyl-3-azabicyclo[4.1.0]heptane-3-carboxylate (D16) (615 mg, 2.73 mmol) in acetone/water (30/20 ml) NaH2PO4.2H2O (426 mg, 2.73 mmol), 2-methyl-2-butene (1.3 ml, 12.28 mmol) and NaClO2 (864 mg, 9.55 mmol) were added and the reaction mixture was stirred at RT overnight. Solvents were evaporated in vacuo and the remaining residue was taken up into EtOAc (10 ml) and water (10 ml). Phases were separated and the aqueous layer was extracted with EtOAc (2×10 ml). The combined organic extracts after solvent evaporation afforded the title compound (D17) (0.5 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:12]=3[O:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CCN(CC)CC.[CH3:28][C:29]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:32]([O:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:12]=3[O:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])([C:29]([CH3:31])([CH3:30])[CH3:28])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc2c(-c3ccc(OC)c(O)c3)coc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(-c3ccc(OC)c(O[Si](C)(C)C(C)(C)C)c3)coc2c1
Reaction time: 12 h
Yield: 92.2 %

Procedure:
To a solution of 14 (3.51 g, 12.9 mmol) in CH2Cl2 (30 mL), under nitrogen, was added Et3N (1.98 mL, 14.2 mmol) followed by DMAP (0.162 g, 14.2 mmol) and TBSCl (2.4 g, 14.2 mmol) at 0° C. The reaction mixture was stirred for 12 h allowing too reach room temperature. The reaction was quenched with water, the phases separated, and the aqueous phase was extracted with CH2Cl2 (3×30 mL). The combined organic solutions were dried over MgSO4 and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, elution with hexanes) afforded 4.57 g (11.9 mmol, 92%) of the protected benzo[b]furan 15 as a colorless oil.
Reaction SMILES: COC(=O)C[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[Cl:16].C([Li])(CC)C.C1CCCCC1.CN(CN1C2C(=CC(OC)=CC=2)C=C1)C.C1(S(Cl)(=O)=O)C=CC=CC=1>C1COCC1>[Cl:16][C:6]1[NH:7][C:8]2[C:13]([CH:5]=1)=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2
Reactant: COC(=O)Cc1c(Cl)[nH]c2ccc(OC)cc12
Agent: COc1ccc2c(ccn2CN(C)C)c1
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(Cl)cc2c1
Reaction time: 0.3 h
Yield: 29 %

Procedure:
2-Chloro-5-methoxy-1H-indole-3-acetic acid methyl ester. Cooling with a dry ice-ethanol bath, 20 mL (0.026 mol) of 1.3M sec-butyl lithium/cyclohexane was added to 5.1 g (0.025 mol) of 1-dimethylaminomethyl-5-methoxy-1H-indole in 100 mL of THF keeping the temperature below -50° C. The cooling bath was removed and the temperature allowed to reach 0° C. and the bath then replaced. At -60° C., 3.32 mL (0.026 mol) of benzenesulfonyl chloride in 10 mL of THF was added, stirred 0.3 hours, the bath removed, and the temperature allowed to reach 20° C. over 1 hour. To this mixture was added 100 mL of 1N HCl and 50 mL of EtOAc and the mixture stirred for 20 hours. After making basic with 5N NaOH, the EtOAc layer was separated, washed with water, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica eluting with toluene to give 1.37 g (29% yield) of crude 2-chloro-5-methoxy-1H-indole. To this material (7.55 mmol) in 30 mL of THF was added 4.7 mL (7.55 mmol) of 1.6M n-butyl lithium/hexane keeping the temperature below 10° C. with an ethanol-ice bath. After 0.25 h, 7.55 mL (7.55 mmol) of 1M ZnCl2 /ether was added, stirred 2 hours, concentrated at reduced pressure, and 40 mL of toluene added followed by 0.72 mL (7.55 mmol) of methyl 2-bromoacetate. The mixture was stirred for 16 hours, warmed at 76° C. for 4 h, cooled, and 50 mL of 1N HCl and 40 mL of EtOAc added. After 0.5 hour, the organic layer was separated, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica and eluted with a solvent gradient (toluene→20% EtOAc/toluene) to give 0.79 g (41% yield) of 2-chloro-5-methoxy-1H-indole-3-acetic acid methyl ester, as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][C:5](=[O:7])[CH:4]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][CH:9]=2)[CH2:3]1.[BH4-].[Na+].O>CO>[CH3:1][C:2]1([CH3:14])[CH2:6][C@H:5]([OH:7])[C@@H:4]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][CH:9]=2)[CH2:3]1
Reactant: Cn1nccc1C1CC(C)(C)CC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cn1nccc1[C@H]1CC(C)(C)C[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
To a solution of the 4,4-dimethyl-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanone (750 mg, 3.90 mmol) prepared in Example 93d in methanol (8.0 mL), sodium borohydride (150 mg, 3.97 mmol) was added with cooling on ice, and the reaction solution was stirred at room temperature for 1 hour. To the reaction solution, water (50 mL) was added, followed by extraction with ethyl acetate (100 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (dichloromethane/methanol=97:3) to yield the title compound (390 mg, 52%) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1B(O)O>>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cc(-c2ccc(F)cc2F)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, white solid (53 mg, 53%), MS (ISP) m/z=338.4 [(M+H)+], mp 216.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (90 mg, 0.296 mmol) and commercially available 2,4-difluoro-phenylboronic acid (60.7 mg, 0.385 mmol).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.C([Li])CCC.[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15]>C(OCC)C.C(=O)([O-])O.[Na+]>[CH2:21]([Sn:16]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:17][CH2:18][CH2:19][CH3:20])[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1ccoc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccoc1
Temperature: -76 °C
Reaction time: 0.25 h

Procedure:
3-Bromofuran (1.23 ml) was dissolved in diethyl ether (15 ml) and cooled to -76° C. Butyllithium (8.5 ml, 1.6M in hexane) was added dropwise ensuring the temperature remained below -60° C. After stirring for 15 minutes, tributyltin chloride (3.69 ml) was added. The reaction was stirred at -76° C. for 1 hour. The reaction was diluted with aqueous sodium hydrogencarbonate (20 ml) and the product extracted with diethyl ether (3×20 ml). The combined organic fractions were dried (brine, MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica eluting with hexane to yield the title compound as a colourless oil. 1H NMR (CDCl3, 360 MHz), δ 0.91 (9H, t, J 8.9 Hz), 1.03 (6H, t, J 10.4 Hz), 1.34 (6H, sx, J 7.3 Hz), 1.58 (6H, m), 6.35 (1H, d, J 1.5 Hz), 7.23 (1H, s), 7.56 (1H, t, J 1.4 Hz).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[CH:9]=1)[CH:2]([CH3:4])[CH3:3].[F:21][C:22]([F:26])([F:25])[CH2:23]I.N1C(=O)N=CC=1>>[CH2:1]([C:5]1[NH:6][C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:17])[F:18])[C:9]=1[CH2:23][C:22]([F:26])([F:25])[F:21])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1cn(-c2ccccc2C(F)(F)F)c(=O)[nH]1
Reactant: FC(F)(F)CI
Agent: O=C1N=CC=N1
Product: CC(C)Cc1[nH]c(=O)n(-c2ccccc2C(F)(F)F)c1CC(F)(F)F
Yield: 14 %

Procedure:
This material was obtained in analogy to the procedure outlined in example 23 from 4-isobutyl-1-(2-trifluoromethyl-phenyl)-1,3-dihydro-imidazol-2-one (obtained in example 18, 200 mg) by alkylation with 2,2,2-trifluoroethyl iodide (162 mg). In contrast to the other, similar reactions, alkylation occurred predominantly at C-5 instead of N-3 of the imidazolone core. Thus, this reaction yielded 4-isobutyl-5-(2,2,2-trifluoro-ethyl)-1-(2-trifluoromethyl-phenyl)-1,3-dihydro-imidazol-2-one as a light yellow solid (36 mg). MS (ESI): 367.0 (MH+).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=[CH:12]3)[CH:5]=[CH:4][N:3]=1.[CH3:22][NH2:23]>C1COCC1>[CH3:22][NH:23][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=[CH:12]3)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1cccc2cc(Oc3ccnc(F)n3)ccc12
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nccc(Oc2ccc3c(C(=O)O)cccc3c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(2-Fluoropyrimidin-4-yloxy)-1-naphthoic acid (step a, 1 g, 3.53 mmol) was suspended in THF (10 mL) and warmed to partially dissolve. The mixture was cooled to RT and N-methylamine (2 M in THF, 8.9 mL, 17.7 mmol) was added. After 2 h, the solvent was concentrated in-vacuo. The residue was diluted with H2O and made pH 7 using 1 N HCl. The solid was filtered and rinsed with water and Et2O to yield the title compound as a pink solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[NH2:11].[Cl:13]N1C(=O)CCC1=O>C(O)(C)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[C:6]([Cl:13])[C:5]=1[NH2:11]
Reactant: COC(=O)c1cc(I)ccc1N
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(C)O
Product: COC(=O)c1cc(I)cc(Cl)c1N
Temperature: 80 °C
Yield: 72 %

Procedure:
To a round bottom flask was combined 1.00 g (3.61 mmol) of 2-amino-5-iodo-benzoic acid methyl ester and 18.0 mL isopropyl alcohol. To the solution was added 541 mg (4.05 mmol) of N-chlorosuccinimide and the solution was heated at 80° C. in an oil bath for 2.25 hours. The solution was cooled to room temperature and concentrated. The resulting residue was dissolved in ethyl acetate and an aqueous solution of sodium bisulfite was added. The organic layer was washed three times with water and brine, then dried over sodium sulfate. The organic layer was concentrated to dryness and recrystallized from hexanes to afford 809 mg (2.60 mmol, 72% yield) of 2-amino-3-chloro-5-iodo-benzoic acid methyl ester as tan-orange crystals. 1H NMR (500 MHz, DMSO-d6) δ 7.96 (d, 1H), 7.74 (d, 1H), 6.86 (s, br., 2H), 3.82 (s, 3H).
Reaction SMILES: [C:1]([OH:6])(=O)[CH2:2][CH2:3][CH3:4].[NH2:7][C:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH:9]=1.CN(C1C=CC=CN=1)C.C(N(C(C)C)CC)(C)C.C(N=C=NCCCN(C)C)C>ClCCl>[O:14]=[C:10]1[CH2:11][CH2:12][CH2:13][C:8]([NH:7][C:1](=[O:6])[CH2:2][CH2:3][CH3:4])=[CH:9]1
Reactant: NC1=CC(=O)CCC1
Reactant: CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)NC1=CC(=O)CCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 10 %

Procedure:
Butyric acid (465 mg, 5.28 mmol) and 3-amino-2-cyclohexene-1-one (645 mg, 5.81 mmol) were dissolved in dichloromethane (50 mL). Dimethylaminopyridine (750 mg, 5.81 mmol), diisopropylethylamine (774 mg, 6.34 mmol) and 1-ethyl-3-dimethylaminopropyl carbodiimide (1.13 g, 5.81 mmol) were added to the resulting mixture, followed by stirring at room temperature for about 14 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified using silica gel chromatography (developing solvent: n-hexane/ethyl acetate=6/4) to obtain the N-(3-oxo-cyclohexen-1-yl)butyramide (1a-1) shown by the formula below.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.[NH2:13][N:14]1[C:18](=[O:19])[CH2:17][S:16][C:15]1=[S:20]>O1CCOCC1>[O:19]=[C:18]1[CH2:17][S:16][C:15](=[S:20])[N:14]1[NH:13][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: NN1C(=O)CSC1=S
Solvent: C1COCCO1
Product: O=C1CSC(=S)N1NC1=NS(=O)(=O)c2ccccc21
Temperature: 110 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To a solution of o-sulfobenzimide (5.00 g) in dioxane (20 ml) were added thionyl chloride (7.5 ml) and dimethylformamide (0.25 ml), and the mixture was stirred overnight at 110° C. The reaction mixture was concentrated under reduced pressure, and to the residue was added toluene (20 ml) to give 3-chloro-1,2-benzisothiazole 1,1-dioxide (3.77 g) as crystals. The obtained 3-chloro-1,2-benzisothiazole 1,1-dioxide (3.77 g) was dissolved in dioxane (20 ml), 3-aminorhodanine (2.77 g) was added thereto, and the mixture was stirred at 110° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and to the residue was added chloroform (20 ml) to give 3-[(4-oxo-2-thioxothiazolidin-3-yl)amino]-1,2-benzisothiazole 1,1-dioxide (3.56 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]2[C:20]([CH3:22])([CH3:21])[CH:19](O)[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:24]([O:26][CH3:27])=[O:25])[CH:17]=3)[NH:12]2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]2[C:20]([CH3:21])([CH3:22])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:24]([O:26][CH3:27])=[O:25])[CH:17]=3)[NH:12]2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(Cl)cc([N+](=O)[O-])c1)N2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(Cl)cc([N+](=O)[O-])c1)N2
Yield: 52.1 %

Procedure:
To a solution of methyl 2-(3-chloro-5-nitrophenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (250 mg, 0.64 mmol) in dichloromethane (5 mL) was added a solution of trifluoroacetic acid (300 mg, 0.8 mmol) in dichloromethane (5 mL) under a nitrogen atmosphere with an ice bath slowly (1.5-2 h). The resultant mixture was stirred at room temperature for 3 h. The mixture was treated with 1 g of Sodium bicarbonate and filtered. The filtrate was concentrated, and purified on preparative Thin layer chromatography to afford 125 mg of methyl 2-(3-chloro-5-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid. Yield=52%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:2]1[CH:3]=[CH:4][CH:8]=[CH:9][CH:10]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccccc1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1Nc2ccc(Cl)cc2C1(c1ccccc1)c1ccccc1

Procedure:
This compound is prepared by the method described in Helv. Chim. Acta, 1946, 29, 415-431, by the reaction of benzene with 5-chloroisatin in the presence of aluminum chloride. M.p.=281° C.
Reaction SMILES: [Cl:1][P:2]1(Cl)[N:7]=[P:6](Cl)([Cl:8])[N:5]=[P:4]([Cl:11])(Cl)[N:3]=1.[O-:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+]>>[Cl:1][P:2]1([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:7]=[P:6]([Cl:8])([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=[P:4]([Cl:11])([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: [O-]c1ccccc1
Reactant: ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1
Agent: [Na+]
Product: ClP1(Oc2ccccc2)=NP(Cl)(Oc2ccccc2)=NP(Cl)(Oc2ccccc2)=N1

Procedure:
Examples 8 to 12 below illustrate embodiments of the invention in which hexachlorocyclotriphosphazene (compound 1) is reacted first with sodium phenoxide to produce an intermediate (trischlorotrisphenoxycyclotriphosphazene), 19 which is then reacted without separation with sodium 4-nitrophenoxide to afford tris(4-nitrophenoxy)tris(phenoxy)cyclotriphosphazene 20. The nitro groups of 20 are reduced to afford the corresponding tris amino compound 21 which is then used according to Scheme I or Scheme II shown in FIG. 2 and FIG. 3, respectively.