Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](O)=[N:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:24]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:24])=[N:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(O)nc2cc(C(F)(F)F)ccc2c1C
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(Cl)nc2cc(C(F)(F)F)ccc2c1C
Temperature: 25 °C
Yield: 98.6 %

Procedure:
4.3 g (14.4 mmol) 2-hydroxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester (precursor VVV05) were heated together with 13.3 ml (144.1 mmol) POCl3 for 2 h at 100° C. After cooling to RT the mixture was concentrated to small volume under vacuum. 4.5 g (14.2 mmol, 98%) 2-chloro-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester were obtained as residue.
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)C.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1>C1COCC1>[O:19]1[CH2:8][CH:12]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1cccnc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: c1cncc(C2CO2)c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
The title compound was prepared by following general procedure 3. Sodium hydride 50% dispersion in oil (1.64 g, 34.2 mmol, 1.8 equiv.) was taken into DMSO (12 mL) and heated at 65° C. for 1 h. THF (36 mL) was added at the same temperature and heated for 10 min. The reaction mixture was cooled to 0° C. and trimethylsulfonium iodide (3.81 g, 18.6 mmol, 1 equiv.) was added, followed by nicotinaldehyde (2 g, 18.6 mmol, 1 equiv.) and stirred at RT for 1 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was poured in ice and extracted with diethyl ether, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford 3-(oxiran-2-yl)pyridine (1 g).
Reaction SMILES: [OH:1][C@@H:2]([CH2:15][S:16][C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3][C@@H:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:5]([OH:7])=[O:6].N1C=CN=C1.[Si:41](Cl)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42].O>CN(C=O)C>[Si:41]([O:1][C@@H:2]([CH2:15][S:16][C:17]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:3][C@@H:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:5]([OH:7])=[O:6])([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: CCCCCCC[C@H](C[C@@H](O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCC[C@H](C[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)O[Si](C)(C)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of 3.72 g (7.88 mmol) of the crude product of Example 21 dissolved in 10 mL of DMF was added 2.68 g (0.039 mol) of imidazole followed by 2.85 g (0.019 mol) of t-butyldimethylsilyl chloride. The reaction mixture was stirred at room temperature for 2 h and then poured into 200 mL of H2O. The resulting solution was extracted with ether and the combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in 10 mL of methanol/THF (1:1) and 5.0 mL of 1N NaOH solution was added. After stirring for 0.75 h at room temperature the reaction mixture was acidified with 5% HCl solution to pH 5 and then extracted with ether. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 4.76 g (100%) of the desired product as a colorless oil. Electrospray Mass Spec: 603.5 (M-H)-.
Reaction SMILES: C([N:4](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:34][C:35]([O:38][C:39]([C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[C:43]([N+:50]([O-:52])=[O:51])[CH:42]=1)=[O:40])([CH3:37])[CH3:36]>CN(C)C=O>[NH2:4][C:45]([C:44]1[CH:48]=[CH:49][C:41]([C:39]([O:38][C:35]([CH3:37])([CH3:36])[CH3:34])=[O:40])=[CH:42][C:43]=1[N+:50]([O-:52])=[O:51])=[O:46]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(C(N)=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
N,N-Diisopropylethylamine (0.41 mL, 2.30 mmol) was added to a mixture of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (321 mg, 0.84 mmol) and 4-{[(1,1-dimethylethyl)oxy]carbonyl}-2-nitrobenzoic acid (prepared according to Gao, Y. et. al WO2001070737) (205 mg, 0.77 mmol) in N,N-dimethylformamide (2 mL), and the reaction mixture was stirred at room temperature for 30 minutes. Ammonia was bubbled into the reaction mixture and stirring was continued for 45 minutes. The reaction mixture was quenched with 0.5M aqueous hydrochloric acid solution (20 mL) and extracted with ethyl acetate (3×20 mL), and the combined extract was washed with water (20 mL), then brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash chromatography (25 to 75% ethyl acetate in hexanes) to give the 1,1-dimethylethyl 4-(aminocarbonyl)-3-nitrobenzoate (160 mg, 78% yield). 1H NMR (400 MHz, CDCl3): 8.55 (s, 1H), 8.25 (d, 1H), 7.64 (d, 1H), 6.51 (br, 1H), 6.26 (br, 1H), 1.61 (s 9H); MS (EI) for C12H14N2O5: 267 (MH+).
Reaction SMILES: [CH2:1]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)=[CH:14][N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(O)(=O)C.Br>O>[CH2:1]([C:11]1[S:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)=[CH:14][N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1ncc(-c2ccc(OC)cc2)s1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCCCc1ncc(-c2ccc(O)cc2)s1
Reaction time: 16 h
Yield: 63 %

Procedure:
Then, in a 500 ml-three-necked flask, 11.6 g (35.0 mM) of 2-decyl-5-(4-methoxyphenyl)tiazole, 93 ml of acetic acid and 102 ml of 47%-hydrobromic acid were placed, followed by heat-stirring for 16 hours at 100°-110° C. After the reaction, the reaction mixture was poured into cool water, followed by extraction with benzene. The organic layer was successively washed with water, 5%-sodium hydrogenecarbonate aqueous solution and water, followed by distilling-off of the solvent under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform) and recrystallized from toluene to obtain 7.0 g of 2-decyl-5-(4-hydroxyphenyl )thiazole (Yield: 63.1%).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[F:21])[C:13]2=[O:22])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH3:29][O:30][CH2:31][CH2:32][N:33]1[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[F:21])[C:13]2=[O:22])[C:9]([NH:38][C:35]2[CH:36]=[CH:37][N:33]([CH2:32][CH2:31][O:30][CH3:29])[N:34]=2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COCCn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2c(F)cccc2C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCCC2)N2Cc3c(F)cccc3C2=O)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
A solution of (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (230 mg, 0.75 mmol) in methylene chloride (10 mL) was treated with N,N-dimethylformamide (1 drop) and cooled to 0° C. It was then treated with a solution of oxalyl chloride (2.0 M in methylene chloride, 452 μL, 0.91 mmol) and stirred for 15 min at 0° C. and then warmed to room temperature and stirred for 30 min. After this time, the reaction mixture was concentrated in vacuo to about 1 mL and then methylene chloride was added (5 mL). One third of the resulting volume (˜2 mL, ˜0.25 mmol of the in situ generated acid chloride) was added to a flask containing 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared as in US20080021032, Example 72, 53 mg, 0.38 mmol) and 2,6-lutidine (55 μL, 0.50 mmol) in methylene chloride (5 mL) at 0° C. The reaction mixture was then allowed to warm up to room temperature and stirred overnight for 16 h. After this time, the reaction mixture was quenched with an aqueous saturated sodium bicarbonate solution (10 mL) and extracted with methylene chloride (3×10 mL). The organic layers were then combined and washed with a 1N aqueous hydrochloric acid solution, dried over magnesium sulfate, filtered to remove the drying agent and the filtrate concentrated in vacuo. The crude material was purified using an Analogix Intelliflash 280 chromatography system (4 g silica gel column, 40-60% ethyl acetate/hexanes) to afford (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-propionamide (70 mg, 65%) as a white foam: [α]28D=−63.0° (c=0.10, methylene chloride); HR-ES(+) m/e calcd for C23H29N4O3F [M+H]+ 429.2297, observed 429.2297; 1H NMR (300 MHz, DMSO-d6) δ 10.88 (s, 1H), 7.41-7.62 (m, 4H), 6.39 (d, J=2.11 Hz, 1H), 5.11 (dd, J=4.68, 10.72 Hz, 1H), 4.91 (d, J=17.81 Hz, 1H), 4.61 (d, J=17.81 Hz, 1H), 4.14 (t, J=4.98 Hz, 2H), 3.63 (t, J=4.98 Hz, 2H), 3.20 (s, 3H), 1.46-2.02 (m, 7H), 0.83-1.24 (m, 6H).
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].N(OC(C)(C)C)=O>O1CCCC1>[C:19]([C:4]1[C:3]([S:21][C:22]([F:23])([F:25])[F:24])=[CH:2][N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:9][C:8]=2[Cl:18])[N:5]=1)#[N:20]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1SC(F)(F)F
Yield: 80.9 %

Procedure:
A solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole (4.0 g) in dry tetrahydrofuran (20 ml) was treated with tert-butyl nitrite (5.76 g) at room temperature. The mixture was then heated under reflux for 3 hours and evaporated in vacuo to give a yellow solid. Purification by chromatography eluting with petroleum ether/dichloromethane (2:1) gave 3 -cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)4-trifluoromethylthiopyrazole (3.12 g), m.p. 126.5°-128° C., in the form of a white solid. By proceeding in a similar manner but replacing the 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole by the following phenylpyrazoles, there was obtained:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([F:27])[CH:18]=1>CN(C=O)C>[F:27][C:19]1[CH:18]=[C:17]([CH2:16][NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[F:1])[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1ccc(CBr)cc1F
Reactant: Nc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNc2ccccc2F)cc1F
Temperature: 60 °C

Procedure:
To a mixture of 2-fluoroaniline (0.12 mL, 1.2 mmol) and potassium carbonate (207 mg, 1.5 mL) in DMF (5 mL) was added methyl 4-(bromomethyl)-2-fluoro-benzoate (247 mg, 1 mmol). The mixture was heated to 60° C. for 18 hours. The solvent was removed in vacuo. The mixture was partitioned between DCM (15 mL) and water (15 mL), the layers were separated and the organic phase was passed through a hydrophobic fit. The solvent was removed in vacuo and the residue was used directly in the next step without any further purification. LCMS (Method 2): [MH+]=278 at 3.60 min.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH3:8][C:9]([CH3:17])([C:11]([CH:13]1[CH2:16][CH2:15][CH2:14]1)=[O:12])[CH3:10].O>CS(C)=O.O1CCCC1>[C:9]([C:11]1([CH:13]2[CH2:16][CH2:15][CH2:14]2)[CH2:4][O:12]1)([CH3:17])([CH3:10])[CH3:8]
Reactant: C[S+](C)C
Reactant: CC(C)(C)C(=O)C1CCC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C1(C2CCC2)CO1
Temperature: 60 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
A suspension of sodium hydride (from 1.68 gms of petrol-washed 80% oil dispersion) in dimethylsulphoxide (40 mls) was stirred at 60° C. for 11/2 hours under a nitrogen atmosphere. The solution was cooled to 20° C., diluted with dry tetrahydrofuran (40 ml) and cooled to -5° C. A slurry of trimethylsulphonium iodide (11.42 gms) in dimethyl sulphoxide (30 mls) was added followed, after 10 minutes stirring, by a solution of the product of Stage 1 (4.9 g) in Tetrahydrofuran (30 mls). The mixture was stirred for 2 hours at -5° C., stood overnight at 20° C., and poured into water and extracted with petrol (30°-40° C.). The extracts were washed with brine, dried and evaporated to give 4.67 gms of yellow product. Gas chromatography showed 75% of a major component. The product was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:11]([NH2:22])=[N:12][CH:13]=[C:14]([C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=4)[N:15]=3)[NH:7][C:6]=2[CH:23]=1.C(N(CC)CC)C.[CH3:31][N:32]([CH3:37])[S:33](Cl)(=[O:35])=[O:34]>CS(C)=O>[NH2:22][C:11]1[N:12]=[CH:13][C:14]([C:16]2[CH2:17][CH2:18][N:19]([S:33]([N:32]([CH3:37])[CH3:31])(=[O:35])=[O:34])[CH2:20][CH:21]=2)=[N:15][C:10]=1[C:8]1[NH:7][C:6]2[CH:23]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N:9]=1
Reactant: Cc1ccc2nc(-c3nc(C4=CCNCC4)cnc3N)[nH]c2c1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1ccc2nc(-c3nc(C4=CCN(S(=O)(=O)N(C)C)CC4)cnc3N)[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
A solution of 3-(6-methyl-1H-benzimidazol-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-amine (58 mg, 0.1893 mmol) and triethylamine (38.31 mg, 52.77 μL, 0.3786 mmol) in DMSO (1.450 mL) was treated with N,N-dimethylsulfamoyl chloride (35.34 mg, 26.43 μL, 0.2461 mmol). The solution was stirred at RT for 16 hours and then partitioned between EtOAc and water. The aqueous layer was separated, organics dried over MgSO4 and concentrated in vacuo to give a yellow solid which was washed with MeOH and filtered to give the desired product (47 mg, 57% Yield). 1H NMR (400.0 MHz, DMSO) d 2.46 (s, 3H), 2.77 (s, 2H), 2.80 (s, 6H), 3.48 (s, 2H), 3.96 (d, J=3.0 Hz, 2H), 6.76 (s, 1H), 7.10 (s, 1H), 7.61-7.40 (m, 3H) and 8.34 (s, 1H) ppm; MS (ES+) 414
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:10][CH2:11][S:12][CH3:13])[C:14]([O:16][CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN1CCC(O)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CSCCC(NC(=O)OC(C)(C)C)C(=O)OC1CCN(C)CC1
Yield: 56 %

Procedure:
A solution of tert-butoxycarbonyl-L-methionine (5 g; 20 mmol), 4-hydroxy-1-methylpiperidine (3.3 g; 20 mmol); DMAP (2.44 g; 20 mmol) and EDC (4.6 g; 2.4 mmol) in dichloromethane (200 ml) was stirred at ambient temperature overnight. The mixture was extracted with dichloromethane. The organic phase was evaporated and purified by flash chromatography, eluting with dichloromethane/ethanol (97/3) to give 1-methylpiperidin-4-yl 2-tert-butoxycarbonylamino-4-methylsulfanylbutyrate. Yield 56%.
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:22])[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH3:13].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CCCCCC>CCOC(C)=O>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]2([CH3:13])[C:3](=[O:23])[C:4]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:10][C:11]2=[O:22])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccccc1NC(=O)C(C)c1ccc(OC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(C2(C)C(=O)Nc3ccccc3C2=O)cc1
Yield: 56.8 %

Procedure:
The objective compound was prepared by the same procedure for the example 1, using a 2-[2-(4-methoxy-phenyl)-propionyl amino]-benzoic acid methyl ester (1.00 g, 3.19 mmol) and LiHMDS (9.57 mmol, 1M solution in THF). After normal workup, the objective compound (0.51 g, 57%) was obtained as yellow solid by a flash column chromatography (n-hexane:EtOAc=5:1): 1H NMR (200 MHz, CDCl3) δ 1.83 (s, 3H, CH3), 3.73 (s, 3H, OCH3), 6.77 d, J=8.9 Hz, 2H, ArH), 6.89-7.07 (m, 2H, ArH), 7.21 (d, J=8.9 Hz, 2H, ArH), 7.44-7.89 (m, 2H, ArH), 9.08 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH:18]=2)[N:13]=[CH:12]1.CN(C=O)C.S(Cl)(Cl)=O.[NH2:38][C:39]1[O:43][N:42]=[CH:41][CH:40]=1>C(Cl)Cl.N1C=CC=CC=1>[O:43]1[C:39]([NH:38][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N:11]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)[CH:18]=4)[N:13]=[CH:12]3)[CH:4]=2)=[CH:40][CH:41]=[N:42]1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Reactant: Nc1ccno1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccno2)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 19.9 %

Procedure:
To a stirred slurry of 4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoic acid (0.3 g) and DMF (0.05 ml) in methylene chloride (30 ml) at 35° C. was added thionyl chloride (0.3 ml). The resultant yellow solution was stirred at 45° C. for 1.5 hours. The reaction mixture was concentrated to give a yellow/orange solid. The solid was stirred in methylene chloride (30 ml) at room temperature with 5-aminoisoxazole (0.11 g) and pyridine (0.2 ml) for 18 hours. The reaction mixture was washed with saturated NaHCO3 solution, brine and concentrated. The residue was purified by column chromatography on a silica column using initially methylene chloride and then a 9:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (70 mg); NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 2.25 (s, 3H), 2.49 (m, 4H), 3.30 (m, 4H), 6.43 (d, 1H), 7.50 (d, 1H), 7.62 (s, 1H), 7.65 (m, 2H), 8.08 (s, 1H), 8.10 (m, 1H), 8.13 (s, 1H), 8.50 (d, 1H), 12.04 (s, 1H); Mass Spectrum: M+H+ 444.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:8]1[C:9]([N+:20]([O-:22])=[O:21])=[CH:10][C:11]([N+:17]([O-:19])=[O:18])=[C:12]([CH:16]=1)[C:13](O)=[O:14])[CH2:5][CH2:6][Cl:7].O=S(Cl)[Cl:25]>CN(C=O)C>[Cl:1][CH2:2][CH2:3][N:4]([C:8]1[C:9]([N+:20]([O-:22])=[O:21])=[CH:10][C:11]([N+:17]([O-:19])=[O:18])=[C:12]([CH:16]=1)[C:13]([Cl:25])=[O:14])[CH2:5][CH2:6][Cl:7]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(N(CCCl)CCCl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(N(CCCl)CCCl)c([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
Treatment of (6) with excess SOCl2 containing a drop of DMF under reflux for 20 min, followed by concentration to dryness and azeotroping with benzene, gave crude 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzoyl chloride (VI: X=Cl; Y1 =Cl). This was dissolved in Me2CO (20 mL), cooled to 0° C., treated with excess 40% aqueous methylamine. The product was purified by chromatography on silica gel, elution with EtOAc/petroleum ether (1:1) giving N-methyl [N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzamide (8) (Ib: X=Cl, R=CONHMe), mp (EtOAc/petroleum ether) 180.5° C. 1H NMR (CD3COCD3) δ 8.53 (s, 1 H, ArH3), 7.75 (br, 1 H, CONH), 7.56 (s, 1 H, H-6), 3.88-3.80 (m, 8 H, NCH2CH2Cl), 2.90, 2.89 (2 s, 3 H, CONHMe). 13C NMR δ 165.89 (CONH), 148.43 (C-5), 140.05, 138.26 (C-2,4), 138.94 (C-1), 125.05, 122.45 (C-3,6), 54.20 (CH2N), 42.10 (CH2Cl), 26.69 (CONHCH3). Anal. (C12H14Cl2N4O5) C,H,N,Cl.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([CH3:16])[N:12]=2)=[CH:7][CH:6]=1)C=C.[C:17]1(OC2C=CC=CC=2)[CH:22]=CC=C[CH:18]=1>C(OCC)C>[CH2:22]([C:10]1[CH:9]=[C:8]([C:11]2[O:15][N:14]=[C:13]([CH3:16])[N:12]=2)[CH:7]=[CH:6][C:5]=1[OH:4])[CH:17]=[CH2:18]
Reactant: C=CCOc1ccc(-c2nc(C)no2)cc1
Reactant: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: C=CCc1cc(-c2nc(C)no2)ccc1O
Reaction time: 0.2 h

Procedure:
5-(4-allyloxyphenyl)-3-methyl-1,2,4-oxadiazole (1.2 g) and diphenyl ether (5 ml) were warmed gently to give a solution. This stirred solution, under an atmosphere of argon, was immersed in an oil bath at 265° C. for 12 minutes. This procedure was repeated three times. The deep red solutions were combined, diluted with diethyl ether (100 ml) and extracted with aqueous 1M sodium hydroxide (3×20 ml). The alkaline extracts were combined, washed with ether (3×30 ml), cooled in ice-water, acidified with aqueous 5M hydrochloric acid (15 ml), and extracted with ether (3×60 ml). The ether extracts were combined, washed with saturated brine (25 ml), dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography on silica gel using 20% ethyl acetate/n-pentane as eluent, to give 2-allyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenol as a solid m.p. 135°-137° C.; microanalysis, found: C, 66.7; H, 5.8; N, 12.5%; C12H12N2O2 requires: C, 66.7; H, 5.6; N, 13.0%; NMR: 2.3-2.35(3H,s), 3.3-3.4(2H,d), 5.0-5.15(2H,m), 5.85-6.1(1H,m), 6.95-7.05(1H,d), 7.75-7.8(2H,m) and 10.4-10.5(1H,s); m/z 217 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[N:36]([CH3:40])[CH:35]=[CH:34]3)=[CH:4][C:5]2[N:9]=[C:8]([O:10][C:11]3[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])[N:7](COCC[Si](C)(C)C)[C:6]=2[CH:30]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[OH-].[Na+]>C1COCC1.CCOC(C)=O.OS([O-])(=O)=O.[K+]>[Cl:1][C:2]1[C:3]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[N:36]([CH3:40])[CH:35]=[CH:34]3)=[CH:4][C:5]2[N:9]=[C:8]([O:10][C:11]3[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])[NH:7][C:6]=2[CH:30]=1
Reactant: COC(=O)c1cc(Oc2nc3cc(-c4ccc5c(ccn5C)c4)c(Cl)cc3n2COCC[Si](C)(C)C)ccc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Oc2nc3cc(-c4ccc5c(ccn5C)c4)c(Cl)cc3[nH]2)ccc1C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 5-[(6-chloro-5-(1-methyl-1H-indol-5-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]-2-methylbenzoate (335 g, 5.81 mmol) in THF (60 mL) was added TBAF (1.0 M in THF) (26 mL, 26.1 mmol) dropwise via syringe. The reaction was heated at 80° C. for 45 min. TBAF (3 mL) was added and heating continued for 4 h. The reaction was cooled and diluted with EtOAc (200 mL) and saturated aqueous KHSO4 (˜pH 3). The aqueous phase was extracted with EtOAc (100 mL). The combined organic layers were washed with H2O and brine, dried (Na2SO4), filtered, and concentrated. The residue was dissolved in MeOH (100 mL) and treated with 2.5 N aqueous NaOH (46 mL, 115 mmol). The reaction was heated at 45° C. for 1 h. Volatiles were removed and the residue was dissolved in H2O (150 mL). The aqueous phase was washed with EtOAc (2×100 mL), acidified to pH ˜1 with 2 N aqueous HCl and extracted with EtOAc (2×100 mL). The combined organics were washed with H2O and brine, dried (Na2SO4), filtered, and concentrated. Trituration of the solid residue with Et2O and filtration afforded the title compound as an off-white solid. LC-MS: m/e 432.6 (M+H)+ (2.0 min). 1H NMR (500 MHz, CD3OD): δ 7.85 (d, 1H), 7.54 (d, 1H), 7.47 (s, 1H), 7.44-7.37 (m, 3H), 7.35 (s, 1 H), 7.22 (dd, 1H), 7.18 (d, 1H), 6.45 (d, 1H), 3.83 (s, 3H), 2.61 (s, 3H).