Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([CH2:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:17]1(=[O:23])[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]1>CO.O>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:18]2[C:17](=[O:23])[CH2:22][CH2:21][CH2:20][CH:19]=2)=[CH:6][C:7]([CH2:10][CH3:11])=[CH:8][N:9]=1
Reactant: O=C1C=CCCC1
Reactant: CCc1cnc(Cl)c(C=O)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CO
Product: CCc1cnc(Cl)c(C(O)C2=CCCCC2=O)c1
Yield: 95 %

Procedure:
The clear solution of 2-Chloro-5-ethylnicotinaldehyde (10 mmol, 1.69 g) and imidazole (10 mmol) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclohexen-1-one (10.2 mmol., 1.0 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 95% yield (2.43 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[O:29]([C:31]#[N:32])[K]>CC#N.O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:31](=[O:29])[NH2:32])[CH2:21]3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: N#CO[K]
Reactant: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCNC3)n2)c1
Solvent: CC#N
Solvent: O
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCN(C(N)=O)C3)n2)c1
Reaction time: 4 h
Yield: 6.8 %

Procedure:
To a mixture of 2-(3-acetamidophenylamino)-4-(piperidin-3-ylmethylamino)pyrimidine-5-carboxamide (40 mg, 0.104 mmol) in CH3CN (2 mL), a solution of KOCN (50 mg, 0.617 mmol) in H2O (1 mL) was added. The mixture was stirred at 70 C for 4 h. It was then purified by HPLC to give the titled compound (3 mg). MS 427.4 (M+H); UV 202.2, 248.6 nm.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:52])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:49][CH3:50])([C:27]3[CH:32]=[CH:31][C:30]([C:33]#[C:34][C:35]([O:44]COC)([C:40]([F:43])([F:42])[F:41])[C:36]([F:39])([F:38])[F:37])=[C:29]([CH3:48])[CH:28]=3)[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])[CH:17]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:8][O:9][C:10](=[O:52])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:25][CH3:26])([C:27]3[CH:32]=[CH:31][C:30]([C:33]#[C:34][C:35]([OH:44])([C:36]([F:37])([F:39])[F:38])[C:40]([F:42])([F:43])[F:41])=[C:29]([CH3:48])[CH:28]=3)[CH2:49][CH3:50])=[CH:20][C:19]=2[CH3:51])[CH:17]=1
Reactant: CCC(CC)(c1ccc(C#CC(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)(c1ccc(C#CC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.4 %

Procedure:
Trifluoroacetic acid (0.20 mL) was added to a solution of [5-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 80-(1); 36.0 mg, 0.0566 mmol) in dichloromethane (1.0 mL) at 0° C., and the mixture was stirred at room temperature for three hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (34.3 mg, 99%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:25]=[CH:24][C:13]3[C@:14]4([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C[Si](C([Si](C)(C)C)(C(F)(F)F)C(N)=O)(C)C>O1CCOCC1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:25]=[CH:24][C:13]3[C@:14]4([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH:16]=[CH:15]4)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3cccc([N+](=O)[O-])c3)ccc12
Agent: C[Si](C)(C)C(C(N)=O)(C(F)(F)F)[Si](C)(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@]12C=CC(=O)N[C@@H]1CCc1cc(-c3cccc([N+](=O)[O-])c3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.9 %

Procedure:
To a suspension of (+)-(4aR)-(10bR)-8-(3-nitrophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3one (264 mg, 0.786 mmol), in 3.0 mL of 1,4-dioxane was added DDQ (196 mg, 1.1 equiv.) followed by bistrimethylsilyltrifluoromethyl acetamide (911 mg, 4.5 equiv.), and the solution was stirred at room temperature for 2 h, then heated at 100° for 20 h. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed with 2M sodium hydroxide. The organic phase was washed with brine, dried over sodium sulfate, concentrated and chromatographed on silica gel (ethyl acetate eluent) to give, after trituration from ether/hexanes, 55 mg (21%) of the title compound as an orange solid. mp 205°-206°. FDMS m/e=334. α[D]589 =+57.23 (c=0.66, chloroform).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]=[C:16]([C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=2)[C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>C1(C)C=CC=CC=1.C(O)C>[Br:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]([C:24]2[CH:25]=[CH:26][C:27]([Br:30])=[CH:28][CH:29]=2)=[CH:15][CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:8][CH:9]=2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)CCc1ccc(OCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(O)CCc1ccc(OCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.1 %

Procedure:
To a solution of 3-{4-[3,3-bis-(4-bromo-phenyl)-allyloxy]-phenyl}-propionic acid ethyl ester (example 5) (1.0 g, 2.0 mmol) in toluene (20 mL) and ethanol (50 mL) was added 1N NaOH (10.0 mL) and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was concentrated in vacuo and 1N HCl added. The product was extracted with ethyl acetate (x 3). The organic layers were combined, washed with water, dried (MgSO4), filtered and concentrated in vacuo. The residue was recrystalised from warm ethanol (100 mL), witch was concentrated to 60 mL, and cooled, to give 600 mg (56%) of the title compound.
Reaction SMILES: C([N:6]1[CH:12]([CH3:13])[C:11]2[CH:14]=[C:15]([S:17](=[O:20])(=[O:19])[NH2:18])[S:16][C:10]=2[S:9](=[O:22])(=[O:21])[CH2:8][CH2:7]1)(=O)C(C)C.C(O)C.C([O-])(O)=O.[Na+].[ClH:31]>O>[ClH:31].[CH3:13][CH:12]1[C:11]2[CH:14]=[C:15]([S:17](=[O:19])(=[O:20])[NH2:18])[S:16][C:10]=2[S:9](=[O:22])(=[O:21])[CH2:8][CH2:7][NH:6]1
Reactant: CC(C)C(=O)N1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc2C1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1NCCS(=O)(=O)c2sc(S(N)(=O)=O)cc21
Temperature: 100 °C
Yield: 80 %

Procedure:
A suspension of 4-isobutyryl-5(R,S)-methyl-7-sulfamoyl-2,3,4,5-tetrahydrothieno[3,2-f]-1,4-thiazepine-1,1-dioxide (500 mg, 1.5 mmol) in water (8 mL) and concentrated HCl (4 mL) containing ethanol (3 mL) was warmed at 100° C. for 2 days. The cooled solution was made weakly basic with NaHCO3 and the product was extracted into ethyl acetate. The extract was dried (Na2SO4), filtered through a pad of charcoal and the solvent evaporated. Trituration of this residue afforded 361 mg (80%) of title compound, mp 236°-238° C. dec.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][O:15][CH3:16])[C:9]2[C:8](=[O:17])[N:7]([CH3:18])[CH:6]=[N:5][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[CH:29][C:30]3[O:34][CH:33]=[N:32][C:31]=3[CH:35]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:34]1[C:30]2[CH:29]=[CH:28][C:27]([C:2]3[N:11]=[C:10]([NH:12][CH2:13][CH2:14][O:15][CH3:16])[C:9]4[C:8](=[O:17])[N:7]([CH3:18])[CH:6]=[N:5][C:4]=4[CH:3]=3)=[CH:35][C:31]=2[N:32]=[CH:33]1
Reactant: CC1(C)OB(c2ccc3ocnc3c2)OC1(C)C
Reactant: COCCNc1nc(Cl)cc2ncn(C)c(=O)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COCCNc1nc(-c2ccc3ocnc3c2)cc2ncn(C)c(=O)c12
Temperature: 140 °C

Procedure:
To a solution of 7-chloro-5-(2-methoxyethylamino)-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (15.0 mg, 0.0559 mmol) in 1,4-dioxane (0.5 mL) were added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (15.0 mg, 0.0612 mmol), 2M aqueous Na2CO3 solution (83.7 μL, 0.167 mmol), and a catalytic amount of Pd(PPh3)4. The reaction mixture was purged with N2 and heated at 140° C. by a microwave reactor for 15 minutes. The mixture was then cooled, quenched with H2O (5 mL) and extracted with ethyl acetate (3×2.5 mL). The combined organic layers were evaporated under vacuum and the residue was purified by preparatory LC/MS to provide 7-(benzo[d]oxazol-5-yl)-5-(2-methoxyethylamino)-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one, which was completely decomposed to the title compound at room temperature; HPLC-MS calculated for C18H19N5O4 (M+H+) 370.1, found 370.1.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]([OH:24])=O)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[NH:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[NH:28]>>[CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]4[O:24][N:28]=[C:27]([N:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)[N:26]=4)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N=C(NO)N1CCCCC1
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Product: c1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](Cc4nc(N5CCCCC5)no4)CS3)cc2c1
Yield: 54 %

Procedure:
The compound (140 mg, 0.41 mmol) prepared in Example 42 and N-hydroxypiperidinecarboxamidine instead of N-hydroxycyclopentanecarboxamidine were reacted according to the same procedure as Example 172 to give the title compound (100 mg, Yield 54%).
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=[O:2].Br[C:11]1[CH:12]=[C:13]2[C:26]3[CH:16]([CH2:17][C@@H:18]4[C@@H:23]([C:24]=3[CH:25]=1)[CH2:22][C@H:21]([NH:27][C:28](=[O:34])[N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:20][N:19]4[CH3:35])[CH2:15][N:14]2[Si](C(C)(C)C)(C)C>>[CH2:32]([N:29]([CH2:30][CH3:31])[C:28]([NH:27][C@H:21]1[CH2:22][C@H:23]2[C@@H:18]([CH2:17][CH:16]3[C:26]4[C:13](=[CH:12][CH:11]=[C:25]([OH:2])[C:24]2=4)[NH:14][CH2:15]3)[N:19]([CH3:35])[CH2:20]1)=[O:34])[CH3:33]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(Br)cc4c3C(C[C@H]2N(C)C1)CN4[Si](C)(C)C(C)(C)C
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(O)ccc4c3C(CN4)C[C@H]2N(C)C1

Procedure:
With nitrobenzene and 3-(13-bromo-1-tert-butyldimethylsilyl-2,3-dihydro-6-methyl-8α-ergolinyl)-1,1-diethylurea:
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:4]=2[O:3]1.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[CH:15][C:16]([OH:18])=[O:17])=[CH:10][C:4]=2[O:3]1
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Reactant: O=C(O)CC(=O)O
Agent: Cl
Agent: O=C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc2c(c1)OC(F)(F)O2
Temperature: 25 °C

Procedure:
A mixture of 10.0 g (53.7 mmol) 2,2-difluoro-benzo[1,3]dioxole-5-carbaldehyde, 6.24 g (60.0 mmol) malonic acid, 0.46 g (5.40 mmol) piperidine and 40 ml pyridine was kept at reflux temperature until carbon dioxide development ceased (3 h). After cooling to room temperature the reaction mixture was poured onto 100 g ice and 30 ml 6N HCl. The precipitate was isolated, washed with water and dried. Yield: 8.60 g (70%) 3-(2,2-Difluoro-benzo[1,3]dioxol-5-yl) -acrylic acid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[CH2:36]([NH2:38])[CH3:37].O>C1COCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:38][CH2:36][CH3:37])[N:3]=3)[N:25]=2)=[CH:30][CH:31]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: CCN
Solvent: O
Solvent: C1CCOC1
Product: CCNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At RT, 100 mg (0.17 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.17 ml (0.33 mmol) of ethylamine (2M solution in THF) were stirred in 2 ml of THF for 30 min. Another 0.17 ml (0.33 mmol) of ethylamine (2M solution in THF) was then added, and the mixture was stirred at RT for 2 h. About 15 ml of water were added to the reaction mixture, and the precipitate formed was filtered off, washed with water and dried under high vacuum. This gave 81 mg (89% of theory) of the desired target compound.
Reaction SMILES: [C:1]([N:3]=[C:4](OCC)[CH2:5][CH2:6][CH2:7][CH3:8])#[N:2].[C:12]([C:14]1[CH:27]=[CH:26][C:17]2[O:18][C:19]([CH3:25])([CH3:24])[C@@H:20]([OH:23])[C@H:21]([NH2:22])[C:16]=2[CH:15]=1)#[N:13]>C(OCC)(=O)C>[C:12]([C:14]1[CH:27]=[CH:26][C:17]2[O:18][C:19]([CH3:25])([CH3:24])[C@@H:20]([OH:23])[C@H:21]([NH:22][C:4](=[N:3][C:1]#[N:2])[CH2:5][CH2:6][CH2:7][CH3:8])[C:16]=2[CH:15]=1)#[N:13]
Reactant: CCCCC(=NC#N)OCC
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Solvent: CCOC(C)=O
Product: CCCCC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Reaction time: 2 h

Procedure:
To 3.35 g of ethyl N-cyanovalerimidate, 4.37 g of 6-cyano-3,4-dihydro-2,2-dimethly-trans-4-amino-2H-benzo[b]pyran-3-ol was added, and the mixture was reacted under stirring at a temperature of from 100° to 120° C. for 2 hours. The reaction mixture was cooled, then dissolved in 100 ml of ethyl acetate, washed twice with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The residual oily substance was purified by silica gel column chromatography to obtain 1.25 g of the above identified compound as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[N:10]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:55][C:56]([F:68])([F:67])[C:57]1[CH:62]=[CH:61][C:60]([C:63]2([NH2:66])[CH2:65][CH2:64]2)=[CH:59][CH:58]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([NH:66][C:63]3([C:60]4[CH:61]=[CH:62][C:57]([C:56]([F:55])([F:67])[F:68])=[CH:58][CH:59]=4)[CH2:65][CH2:64]3)=[O:21])=[CH:22][CH:23]=2)[N:10]=1
Reactant: NC1(c2ccc(C(F)(F)F)cc2)CC1
Reactant: O=C(O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NC1(c2ccc(C(F)(F)F)cc2)CC1)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Yield: 20 %

Procedure:
The title compound was prepared according to the procedure described in Example-17 by using 4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoic acid (Intermediate-9, 0.100 g, 0.290 mmol), THF (5 mL), di-isopropyl ethyl amine (2.0 mL), TBTU (0.193 g, 0.590 mmol) and 1-[4-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-13, 0.073 g, 0.350 mmol) to afford 0.030 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.35 (s, 4H), 7.36 (d, J=7.8 Hz, 2H), 7.46-7.70 (m, 5H), 8.01 (s, 4H), 9.30 (s, 1H), 12-13 (br s, 1H); MS (m/z): 515.23 (M−H)−.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[N:13]=[CH:14][N:15](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:16]=2)([OH:11])[CH3:10])=[CH:5][C:4]=1[F:36])#[N:2].[C:37]([O:41][CH3:42])(=[O:40])[CH2:38]O.C(N(CC)C(C)C)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[CH3:42][O:41][C:37](=[O:40])[CH2:38][N:13]1[C:12]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:36])[CH:5]=2)([OH:11])[CH3:10])=[CH:16][N:15]=[CH:14]1
Reactant: CC(O)(c1ccc(C#N)c(F)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COC(=O)CO
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cn1cncc1C(C)(O)c1ccc(C#N)c(F)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-(4-cyano-3-fluorophenyl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol from Step F (200 mg, 0.42 mmol), methyl glycolate (35 mg, 0.39 mmol), and N,N-diisopropylethylamine (65 mg, 0.51 mmol) in dry CH2Cl2 (10 mL), under argon, at −78° C., was added trifluoromethanesulfonic anhydride (110 mg, 0.39 mmol) dropwise. The mixture was allowed to warm slowly to ambient temperature, then the solvent was removed in vacuo. The residue was dissolved in MeOH (10 mL) and the solution was heated to reflux for 1 hr, then concentrated to dryness. The residue was purified by silica gel chromatography, eluting with 4% MeOH—0.4% NH4OH in CHCl3, to yield the titled product as a white solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10].[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[Cl:29])[NH2:25].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH:25][C:24]1[CH:26]=[CH:27][C:28]([Cl:29])=[C:22]([Cl:21])[CH:23]=1)=[O:10]
Reactant: O=C(Cl)c1cccnc1Oc1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1cccnc1Oc1cccc(C(F)(F)F)c1

Procedure:
In the manner as in Example 1, 2.75 grams (0.009 mole) of 2(3-trifluoromethylphenoxy)nicotinoyl chloride, 1.5 grams (0.009 mole) 3,4-dichloroaniline, 0.9 grams (0.009 mole) triethylamine and 125 milliliters toluene were combined to yield 2.3 grams (59.8% of theoretical yield) of the desired product, a waxy solid. The structure was confirmed by mass spectrometry.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.Cl>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:11]1([C:2]2[CH2:3][C:4]3[C:9]([CH:1]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1Cc2ccccc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: C1=C(c2ccccc2)Cc2ccccc21
Temperature: 25 °C
Yield: 64.3 %

Procedure:
A solution of 2-indanone (13.47 g, 102 mmol) in anhydrous benzene (100 mL) is added to phenylmagnesium bromide (3.0M in diethyl ether, 50.9 mL, 153 mmol) at 5° C. over 2.5 hours. The reaction was allowed to warm to room temperature over 30 minutes. The solution was cooled to 0° C. and 150 mL of water are added. The resultant mixture was diluted with 200 mL of hexanes, neutralized with 5M HCl, and washed with brine (2×100 mL). The aqueous layer was extracted with hexanes (2×50 mL), and the combined organic layers were dried (MgSO4), filtered, and the solvent removed in vacuo from the filtrate to yield a brown oil. This oil and p-toluenesulfonic acid (0.50 g) were dissolved in benzene (250 mL) in a round-bottom flask below a Soxhlet extractor containing 4 Å molecular sieves. After refluxing for 2.5 hours, the solution was filtered and cooled to 5° C. overnight. The product, a white flaky solid, was collected by filtration, and was washed with 50 mL of cold benzene. Additional product is obtained by concentrating the filtrate, cooling, and filtering the crystals (12.60 g, 64.3% yield). 1H NMR (400 Mhz, 20° C., CDCl3) δ7.62 (d,J=7.3 Hz, 2H), 7.47 (d,J =7.3 Hz, 1H), 7.39 (m, 3H), 7.27 (m, 2H), 7.22 (s,1H), 7.18 (t,J=7.4 Hz,1H), 3.78 (S, 2H). 13C{1H} NMR (100 Mhz, 20° C., CDCl3): δ146.3, 145.3, 143.1, 135.9, 128.6, 127.5, 126.5, 126.4, 125.6, 124.7, 123.6, 120.9, 38.9.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>O>[F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][S:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:24])=[O:23]
Reactant: Nc1cc(F)ccc1F
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(F)ccc1F)c1ccccc1
Temperature: 40 °C

Procedure:
0.194 mole (25 g) of 2,5-difluoroaniline is added to 125 ml of pyridine. 0.2 mole (25.5 ml) of benzenesulphonyl chloride is added, while the temperature is between 35° C. and 45° C. The temperature is maintained at 40° C. for 1 hour after the addition is completed, and then the reaction mixture is poured onto 1 kg of ice and water to which 100 ml of concentrated hydrochloric acid have been added. The expected product precipitates. After filtration and washing, it is treated with a normal sodium hydroxide solution in order to remove insoluble material. The soda-containing filtrate is neutralized with concentrated hydrochloric acid. The expected product, which has precipitated, is filtered off, washed to neutrality and recrystallized from acetic acid. It melts at 115° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:27]=[CH:26][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1.C(N(CC)C(C)C)(C)C.O1CCCC1.[C:42](O)(=[O:46])[C@H:43]([CH3:45])[OH:44].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>>[OH:44][C@@H:43]([CH3:45])[C:42]([N:1]1[CH2:4][CH:3]([C:5]2[CH:27]=[CH:26][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1)=[O:46]
Reactant: C[C@H](O)C(=O)O
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CNC4)ccc2-3)n(C(C)C)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CN(C(=O)[C@H](C)O)C4)ccc2-3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
To a solution of 8-Azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.811 g, 0.000786 mol) and N,N-diisopropylethylamine (0.274 mL, 0.00157 mol) in tetrahydrofuran (5.0 mL, 0.062 mol) was added simultaneously L-lactic acid (0.0708 g, 0.000786 mol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.329 g, 0.000865 mol). The reaction was stirred at room temperature overnight. The mixture was partitioned between saturated sodium bicarbonate and methylene chloride and extracted 3 times with methylene chloride. The organic phases were combined, dried with MgSO4, and concentrated. The crude was purified by reverse-phase HPLC to give 490 (191.2 mg) as a colorless solid. MS(ESI+) 454.2. 1H NMR (400 MHz, DMSO) δ 8.34 (d, J=8.2, 1H), 7.22 (m, 1H), 7.06 (s, 1H), 5.84-5.66 (m, 1H), 5.09 (dd, J=11.1, 5.8, 1H), 4.65 (m, 1H), 4.37 (t, J=5.0, 2H), 4.28 (m, 2H), 4.16 (quin, J=6.5, 1H), 3.94-3.78 (m, 2H), 3.43 (t, J=5.0, 2H), 2.32 (s, 3H), 1.52 (d, J=6.6, 6H), 1.21 (d, J=6.7, 3H)