Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][CH2:6][CH2:7][C:8]#[N:9])#[N:2].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>[I-].[Na+].C(#N)C>[CH2:10]([N:5]([CH2:6][CH2:7][C:8]#[N:9])[CH2:4][CH2:3][C:1]#[N:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCc1ccccc1
Reactant: N#CCCNCCC#N
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: N#CCCN(CCC#N)Cc1ccccc1
Yield: 81.3 %

Procedure:
A mixture of 50.0 g (0.406 mol) of bis(2-cyanoethyl)amine, 51.45 g (0.406 mol) of benzyl chloride, 1.0 g (6.7 mmol) of sodium iodide, 22.05 g (0.208 mol) of sodium carbonate and 150 mL of acetonitrile was stirred mechanically and heated at reflux under nitrogen for 5 h. The cooled reaction mixture was filtered and the solids were washed with acetonitrile (3×50 mL). The combined filtrates were concentrated by rotary evaporation. A solution of the residue in 100 mL of CH2Cl2 was washed with saturated aqueous Na2S2O3 (2×20 mL) and saturated aqueous NaCl (2×50 mL). The combined aqueous layers were extracted with CH2Cl2 (3×30 mL). The combined CH2Cl2 solutions were dried over MgSO4, filtered and concentrated by rotary evaporation. The residual solvent was removed under vacuum (0.5 mm), yielding 70.4 g (89%) of product as a light yellow oil. 1H NMR (CDCl3 /TMS) δ 7.34 (m, 5 H), 3.70 (s, 2 H), 2.88 (t, J=6.8 Hz, 4 H), 2.44 (t, J=6.8 Hz, 4 H). 13C NMR (CDCl3) δ 137.5, 128.3, 127.4, 118.4, 57.7, 49.1, 16.4. IR (film, cm- 1) 3070 (w), 3050 (m), 3020 (s), 2930 (s), 2830 (s), 2240 (s), 1595 (m), 1575 (w), 1485 (s), 1445 (s), 1415 (s), 1360 (br), 1250 (br), 1125 (s), 1070 (s), 1020 (s), 960 (s), 730 (s), 690 (s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]([F:44])([F:43])[F:42])[C:32]([C:45]([O:47][CH3:48])=[O:46])=[CH:31][CH:30]=1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:28][C:29]3[CH:34]=[C:33]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:41]([F:42])([F:43])[F:44])[C:32]([C:45]([O:47][CH3:48])=[O:46])=[CH:31][CH:30]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: COC(=O)c1ccc(CBr)cc1-c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)cc1-c1ccccc1C(F)(F)F

Procedure:
179 mg (0.58 mmol) of the compound from Example 5A and 285 mg (0.88 mmol) of cesium carbonate were suspended in 5 ml of acetonitrile, and 340 mg (0.58 mmol) of the compound from Example 108A were added. The mixture was stirred under reflux for 4 h. The precipitated solid was then filtered off and the filtrate was concentrated under reduced pressure to a volume of about 1.5 ml. After addition of 0.5 ml of 1 N hydrochloric acid, the mixture was directly purified chromatographically [Method 19]. This gave 231 mg (65% of theory) of the target compound.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]([NH:33][C:34](=[O:48])[C@@H:35]2[CH2:39][C@@H:38]([NH2:40])[CH2:37][N:36]2[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:24]=1.[OH:49][C@H:50]([CH2:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:51](O)=[O:52]>ClCCl.C(Cl)(Cl)Cl>[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]([NH:33][C:34](=[O:48])[C@@H:35]2[CH2:39][C@@H:38]([NH:40][C:51](=[O:52])[C@H:50]([OH:49])[CH2:54][CH2:55][C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[CH2:37][N:36]2[C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N)C[C@H]1C(=O)Nc1cnc2ccccc2c1
Reactant: O=C(O)[C@H](O)CCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)[C@H](O)CCc2ccccc2)C[C@H]1C(=O)Nc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
1-Hydroxybenzotriazole (147 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (766 mg) were added to a stirred solution of trans-4-amino-N-tert-butoxycarbonyl-L-proline 3-quinolylamide(E, 1.30 g) and (R)-2-hydroxy-4-phenylbutanoic acid (F, 720 mg) in dichloromethane (40 mL) at 0° C. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with chloroform and washed with saturated sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1, v/v) to give the title compound (1.85 g) as a colorless foam: 1H NMR (400 MHz, CDCl3) δ 1.45 (m, 9H), 1.70 (m, 2H), 1.94 (m, 1H), 2.15 (m, 1H), 2.75 (m, 2H), 3.29 (m, 1H), 3.80 (m, 1H), 4.11 (m, 1H), 4.53 (m, 1H), 4.60 (m, 1H), 6.76 (m, 1H), 7.15-7.26 (m, 5H), 7.48 (m, 1H), 7.57 (m, 1H), 7.73 (m, 1H), 7.95 (d, J=16.8 Hz, 1H), 8.68 (s, 1H), and 8.69 (s,1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].Br[CH2:14][C:15](=[O:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:17]=[C:15]([CH3:16])[CH2:14][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: CC(=O)CBr
Reactant: COC(=O)Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1OCC(C)=O

Procedure:
Following a procedure similar to that described in Preparation 3, but using 15.6 g of methyl 2-hydroxyphenylacetate, 34 g of bromoacetone, 25 g of potassium carbonate and 170 ml of dimethylformamide, the title compound was obtained having an Rf=0.39 (thin layer chromatography over silica gel, using a 3:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[C:34]([OH:36])=[O:35]>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[C:34]([OH:36])=[O:35])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 37.1 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (2.92 g, 6.36 mmol) (The compound was synthesized according to the procedure as described in WO2010069147A) was reacted with morpholine-3-carboxylic acid hydrochloride (1.07 g, 6.36 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (1.2 g, 37%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:15][O:16][CH2:17][S:18][CH3:19])[C:10]([O:12]CC)=[O:11])[N:8]=1)=[O:2].[OH-].[Na+].Cl>CO>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:15][O:16][CH2:17][S:18][CH3:19])[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2]
Reactant: CCOC(=O)C(=NOCSC)c1csc(NC=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSCON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 30 °C
Reaction time: 2.5 h
Yield: 51.9 %

Procedure:
A mixture of ethyl 2-(2-formamidothiazol-4-yl)-2-methylthiomethoxyiminoacetate (syn isomer, 2.4 g.), 1 N aqueous sodium hydroxide (23.8 ml.) and methanol (19.8 ml.) was stirred at 30° C. for 2.5 hours. The resultant solution was adjusted to pH 7 with 10% hydrochloric acid and methanol was distilled off in vacuo. The aqueous solution was adjusted to pH 1 with 10% hydrochloric acid under ice cooling, and extracted with ethyl acetate three times. The extracts were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give 2-(2-formamidothiazol-4-yl)-2-methylthiomethoxyiminoacetic acid (syn isomer, 1.13 g.), mp. 157° C. (dec.).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH:22][C:23]2[C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][N:26]=[C:25]([NH:33][C:34]3[CH:39]=[N:38][C:37]([C:40]#[N:41])=[CH:36][N:35]=3)[CH:24]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[C:40]([C:37]1[N:38]=[CH:39][C:34]([NH:33][C:25]2[CH:24]=[C:23]([NH:22][CH2:21][CH:18]3[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]3)[C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][N:26]=2)=[N:35][CH:36]=1)#[N:41]
Reactant: COC(=O)c1cnc(Nc2cnc(C#N)cn2)cc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cnc(Nc2cnc(C#N)cn2)cc1NCC1CCNCC1
Reaction time: 0.33 h
Yield: 74.8 %

Procedure:
TFA (0.1 mL) was added to a solution of methyl 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-6-(5-cyanopyrazin-2-ylamino)nicotinate (20 mg, 0.04 mmol) in dichloromethane (1 mL) at room temperature. After 20 minutes, the solution was evaporated to dryness and purified by ion exchange chromatography on SCX-II acidic resin (500 mg) eluting with methanol, then 2M ammonia-methanol. The basic fractions were combined and solvent was evaporated to give methyl 6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)-nicotinate compound as a yellow solid (11 mg, 70%).
Reaction SMILES: C[Si]([PH:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])([O-:9])[O:6][CH2:7][CH3:8])(C)C.[CH:17]([C:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:20])=[CH2:18].C(Cl)(Cl)Cl>O>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]([CH2:17][CH2:18][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6][CH2:7][CH3:8])=[O:20])=[CH:26][CH:25]=1
Reactant: C=CC(=O)c1ccc(Cl)cc1
Reactant: CCOC(OCC)[PH]([O-])(OCC)[Si](C)(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(OCC)P(=O)(CCC(=O)c1ccc(Cl)cc1)OCC
Reaction time: 1 h

Procedure:
17.7 g of ethyl trimethylsilyl(diethoxymethyl)phosphonite is added dropwise to a stirred solution of 11.7 g of 4-chlorophenyl vinyl ketone under an atmosphere of nitrogen, at room temperature. The reaction mixture is stirred for a period of 1 hour, 25 ml of chloroform is added followed by 10 ml of water and this mixture is vigorously stirred for a period of 0.5 h. The organic layer is then separated, dried over magnesium sulphate and concentrated under reduced pressure to give ethyl 2-4-chlorobenzoyl-ethyl(diethoxymethyl)phosphinate as an oil, 31P=+45.5 ppm (CDCl3).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[Cl:10][CH2:11][CH2:12][CH2:13]I.O>CN(C)C=O>[Cl:10][CH2:11][CH2:12][CH2:13][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCI
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCOc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-hydroxypyridine (5.00 g, 52.58 mmol) in N,N-dimethylformamide (DMF) (55 mL) was slowly added to a cold (0-5° C.), stirring slurry of sodium hydride (2.52 g of an 80% dispersion in mineral oil, 84.0 mmol) in DMF (10 mL). The mixture was allowed to warm to ambient temperature and further stirred for 1 h. To this slurry was added 1-choro-3-iodopropane (12.90 g, 63.10 mmol), and the resulting dark-brown mixture was stirred at ambient temperature for 48 h. Cold water was added and the mixture was extracted with chloroform (4×100 mL). The combined chloroform extracts were washed with water (2×50 mL), dried (Na2SO4), filtered, and concentrated by rotary evaporation. Water (150 mL) was added, and the mixture was basified with 20% NaOH solution (5.0 mL). The alkaline solution was extracted with methyl t-butyl ether (MTBE) (5×100 mL). The combined MTBE extracts were washed with water (4×100 mL), dried (Na2SO4), filtered, and concentrated by rotary evaporation to give 4.90 g (54.3%) of an oil. 1H NMR (CDCl3, 300 MHz): δ 8.34 (s, 1H), 8.24 (s, 1H), 7.22 (t, 2H, J=2.13 Hz), 4.18 (t, 2H, J=5.85 Hz), 3.77 (t, 2H, J=6.19 Hz), 2.27 (p, 2H, J=6.03 Hz). 13C NMR (CDCl3, 75 MHz): δ 154.99, 142.38, 138.07, 123.93, 121.09, 64.60, 41.22, 32.11. EI-MS: m/z (relative intensity) 171 (M+, 27.25%), 136 (4.66%), 95 (100.00%), 78 (17.98%), 41 (37.74%), 39 (34.23%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH3:21])[C:16](=[O:22])[CH2:15]2)[C:3]=1[CH3:23].[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[C:32]([NH2:36])[CH:33]=[N:34][CH:35]=2)[CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:36][C:32]1[CH:33]=[N:34][CH:35]=[C:30]([N:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)[CH:31]=1)=[C:3]([CH3:23])[C:4]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH3:21])[C:16](=[O:22])[CH2:15]1)=[N:5]2
Reactant: CCN1CCN(c2nc3cc(F)cc(F)c3c(Br)c2C)CC1=O
Reactant: Nc1cncc(N2CCOCC2)c1
Solvent: Cc1ccccc1
Product: CCN1CCN(c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)CC1=O

Procedure:
Essentially prepared according to Procedure H using 4-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)-1-ethylpiperazin-2-one (31.0 mg, 0.081 mmol) and 5-morpholinopyridin-3-amine in toluene to give 4-(5,7-difluoro-3-methyl-4-((5-(4-morpholinyl)-3-pyridinyl)amino)-2-quinolinyl)-1-ethyl-2-piperazinone. 1H NMR (400 MHz, CDCl3) δ ppm 7.85 (1H, d, J=2.2 Hz), 7.75 (1H, d, J=2.0 Hz), 7.57 (1H, d, J=6.7 Hz), 7.28-7.36 (1H, m), 6.93 (1H, s), 6.83 (1H, ddd, J=13.3, 8.7, 2.5 Hz), 4.11 (2H, s), 3.81-3.92 (4H, m), 3.72 (2H, t, J=5.3 Hz), 3.43-3.56 (4H, m), 3.19-3.30 (4H, m), 2.20 (3H, s), 1.18 (3H, t, J=7.2 Hz). Mass Spectrum (ESI) m/e=483.3 (M+1).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:21])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]#[N:19])[C:15]([NH2:20])=[N:14]2)=[CH:8][CH:7]=1>O.CO>[NH2:20][C:15]1[C:16]([C:18]#[N:19])=[CH:17][N:13]([CH2:12][C:9]2[CH:10]=[CH:11][C:6]([C:5]([OH:21])=[O:4])=[CH:7][CH:8]=2)[N:14]=1
Reactant: COC(=O)c1ccc(Cn2cc(C#N)c(N)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1cn(Cc2ccc(C(=O)O)cc2)nc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a solution of NaOH (343 mg, 8.58 mmol) in a mixture of water (10 ml) and MeOH (20 ml) the ester 95 (732 mg, 2.86 mmol) was added. The reaction mixture was refluxed 2 min and stirred for additional 2 hrs at ambient temperature. MeOH was removed under reduced pressure and remaining aqueous solution was acidified with conc. HCl (pH 3-4) to form a precipitate which was collected by filtration to afford the title compound (96) (640 mg, 92% yield). LRMS: 242.2 (calc.), 241.1 (found).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]([OH:16])[CH:15]=1)[C:12](=[O:17])[C:11]1[C:6](=[CH:7][CH:8]=[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]3=1)[O:5]2.[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl>CC(C)=O>[OH:16][C:14]1[CH:15]=[C:2]([O:1][CH2:22][CH:24]2[CH2:25][O:26]2)[CH:3]=[C:4]2[C:13]=1[C:12](=[O:17])[C:11]1[C:6](=[CH:7][CH:8]=[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]3=1)[O:5]2
Reactant: O=c1c2c(O)cc(O)cc2oc2ccc3ccccc3c12
Reactant: ClCC1CO1
Solvent: CC(C)=O
Product: O=c1c2c(O)cc(OCC3CO3)cc2oc2ccc3ccccc3c12
Temperature: 57.5 °C
Yield: 40.4 %

Procedure:
The compound 9,11-dihydroxy-12H-benzo[a]xanthen-12-one (0.1 g, 0.18 mmol) synthesized in Step 1 of Examples 14 and 15, CS2CO3 (0.36 g, 0.54 mmol), and anhydrous acetone (20 mL) were charged to a dry round-bottom flask. Under stirring, epichlorohydrin (0.2 g, 1.08 mmol) was added thereto using a syringe. The reaction liquid was stirred with reflux at a temperature of 55 to 60° C. under a nitrogen atmosphere (48 h). Solid of the reaction mixture was filtered and removed. The filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:3 (v/v)) to give a yellow solid compound 11-hydroxy-9-(oxiran-2-ylmethoxy)-12H-benzo[a]xanthen-12-one (24.3 mg, 20.3%) and a yellow solid compound 9,11-bis(oxiran-2-ylmethoxy)-12H-benzo[a]xanthen-12-one (32 mg, 22.1%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[C:14]1([C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[S:9][C:5]=2[CH2:4][NH2:1])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: [N-]=[N+]=NCc1sc2ccccc2c1-c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1sc2ccccc2c1-c1ccccc1
Temperature: 60 °C
Yield: 130.8 %

Procedure:
A solution of 2-azidomethyl-3-phenylbenzo[b]thiophene (244 mg, 0.92 mmol) in THF (10 mL) was treated with a solution of triphenylphosphine (302 mg, 1.15 mmol) in water (1 mL) under a nitrogen atmosphere. The mixture was heated at 60° C. for 2 h then cooled to RT. The volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge then washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording the title compound (288 mg, quantitative). LCMS (Method C): RT 2.15 min [M−N3]+ 223.0.
Reaction SMILES: [CH2:1]([OH:5])[C:2]#[C:3][CH3:4].Cl[C:7]1[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][S:10][N:11]=1.O>O1CCCC1>[CH2:1]([O:5][C:7]1[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][S:10][N:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCO
Reactant: Clc1nsnc1-c1cccnc1
Solvent: C1CCOC1
Solvent: O
Product: CC#CCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-butyn-1-ol (530 mg, 7.5 mmol) and sodium-hydride (180 mg, 7.5 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [C:1]([C:9]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:10]=1[NH:11][C:12](=[O:17])C(Cl)(Cl)Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.C([O-])(=O)C.[NH4+:34]>O>[C:2]1([C:1]2[C:9]3[C:10](=[CH:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=3)[NH:11][C:12](=[O:17])[N:34]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cc(C(F)(F)F)ccc1NC(=O)C(Cl)(Cl)Cl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CS(C)=O
Product: O=c1nc(-c2ccccc2)c2cc(C(F)(F)F)ccc2[nH]1
Temperature: 75 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
A mixture of 1.08 g of 2′-benzoyl-2,2,2-trichloro-4′-trifluoromethylacetanilide, 10 ml of DMSO and 1.18 g of ammonium acetate was stirred at 75° C. for 1 hour. After cooling, 100 ml of water was added to the mixture. Precipitated crystals were collected by filtration. The collected substance was dissolved in a mixture of hexane:ethyl acetate=1:1, dehydrated using anhydrous magnesium sulfate, and then concentrated to obtain 765 mg of the titled compound. 1H NMR (CDCl3): 7.58-7.68 (3H, m), 7.75 (1H, d, J=8.8 Hz), 7.79-7.83 (2H, m), 7.93 (1H, dd, J=8.8, 1.7 Hz), 8.17 (1H, br. s), 13.37 (1H, br. s).
Reaction SMILES: C(O[CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[C:10](/[C:14](/[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[CH:15]/[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:9]=1)(=O)C.[N-:29]=[N+:30]=[N-:31].[Na+]>C1COCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:17]1([CH2:16]/[CH:15]=[C:14](/[C:10]2[N:9]=[C:8](/[CH:7]=[CH:6]/[CH2:5][N:29]=[N+:30]=[N-:31])[CH:13]=[CH:12][CH:11]=2)\[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CC(=O)OC/C=C/c1cccc(/C(=C/CN2CCCC2)c2ccc(C)cc2)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(/C(=C\CN2CCCC2)c2cccc(/C=C/CN=[N+]=[N-])n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.8 %

Procedure:
A solution of 3-(6-[3-pyrrolidino-1-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-prop-2E-en-1-yl acetate (136 mg, 0.365 mmol) in a mixture of THF/water (5:1, 5 ml) was treated with sodium azide (28 mg, 0.44 mmol) and tetrakis(triphenylphosphine) palladium(0) (17 mg, 0.015 mmol). The reaction was stirred at room temperature for 18 hours. Solvent was removed under reduced pressure to leave a dark brown residue. The product was purified by column chromatography on silica-gel eluting with 5% methanol/DCM. Product containing fractions were combined and solvent removed under reduced pressure to yield {3-(6-[3-pyrrolidino-1-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-prop-2E-enyl}-azide as a brown gum (110 mg, 85%). 1H-NMR; δ (CDCl3), 7.67 (1H, m), 7.56 (1H, m), 7.40 (2H, m), 7.24 (2H, d, J=8.2 Hz), 7.19 (1H, t, J=6.8 Hz), 7.10 (2H, m), 6.91 (1H, dt, J=15.8, 6.6 Hz), 6.73 (2H, m), 4.02 (2H, d, J=8.8 Hz), 3.35 (2H, m), 2.70 (2H, m), 2.41 (3H, s) and 1.82 (4H, m).
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])=[CH:13][C:12]=1[CH:23]1[CH2:32][C:31]([CH3:34])([CH3:33])[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:35](O)=[O:36])[CH:29]=2)[NH:24]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])=[CH:13][C:12]=1[CH:23]1[CH2:32][C:31]([CH3:33])([CH3:34])[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:35]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:36])[CH:29]=2)[NH:24]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)CC(c2cc(N3CCOC3=O)ccc2Cl)Nc2ccc(C(=O)O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(c2cc(N3CCOC3=O)ccc2Cl)Nc2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
To a suspension of 60% sodium hydride (176 mg, 4.4 mmol) in N,N-dimethylformamide (3 mL) was added cyclopropanesulfonic acid amide (530 mg, 4.4 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A29. A solution of 2-[2-chloro-5-(2-oxo-oxazolidin-3-yl)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (250 mg, 0.62 mmol) and 1,1′-carbonyldiimidazole (203 mg, 1.25 mmol) in N,N-dimethylformamide (2 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B29. Solution B29 was added to Solution A29 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid {2-[2-chloro-5-(2-oxo-oxazolidin-3-yl)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-amide (85 mg, 27%) as a white solid: MS (ESI) M+1=504.0.