Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14](O)[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]([N:40]1[C:36](=[O:46])[C:37]2[C:38](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:39]1=[O:41])[CH3:15]
Reactant: CC(O)c1nc2ccc(F)cn2c(=O)c1Br
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1nc2ccc(F)cn2c(=O)c1Br)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-bromo-7-fluoro-2-(1-hydroxyethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (1.238 g, 4.31 mmol), triphenylphosphine (1.357 g, 5.17 mmol), phthalimide (0.761 g, 5.17 mmol), and THF (28.7 mL) was stirred at rt for 5 min to dissolve all reactants. The mixture was then cooled to 0° C. and to the cooled homogenous mixture was added dropwise over 3 min diisopropyl azodicarboxylate (1.019 mL, 5.17 mmol) at 0° C. After stirring at 0° C. for 30 min, the cooling bath was removed and the mixture was stirred at rt. After 1.5 h, the mixture was partitioned between EtOAc (50 mL) and water (50 mL). The insoluble solid was filtered, washed with water (50 mL) and EtOAc (50 mL), and dried under vacuum to give the desired product 2-(1-(3-bromo-7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)ethyl)isoindoline-1,3-dione as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.92-9.00 (1 H, m), 8.12 (1 H, ddd, J=9.9, 7.1, 2.9 Hz), 7.82-7.92 (4 H, m), 7.75 (1 H, dd, J=9.8, 5.5 Hz), 5.56-5.66 (1 H, m), 1.85 (3 H, d, J=7.0 Hz); Mass Spectrum (ESI) m/e=416.0 [M+1 (79Br)] and 418.0 [M+1 (81Br)]. To the filtrate was added brine (50 mL) and the organic layer was separated, dried over Na2SO4, filtered and concd under reduced pressure to give the crude material as a yellow solid. The yellow solid was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and 50% isocratic of EtOAc for 10 min as eluent to give the desired product 2-(1-(3-bromo-7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)-ethyl)isoindoline-1,3-dione as a light yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.95 (1 H, td, J=3.1, 1.6 Hz), 8.12 (1 H, ddd, J=9.9, 7.1, 2.9 Hz), 7.83-7.93 (4 H, m), 7.71-7.79 (1 H, m), 5.57-5.65 (1 H, m), 1.85 (3 H, d, J=7.0 Hz); Mass Spectrum (ESI) m/e=416.0 [M+1 (79Br)] and 418.0 [M+1 (81Br)].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=3)[N:12]=[C:13]([C:19]([O:21]CC[Si](C)(C)C)=[O:20])[C:14]=2[S:15]([CH3:18])(=[O:17])=[O:16])[CH:6]=[CH:7][CH:8]=1)#[N:2]>FC(F)(F)C(O)=O>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=3)[N:12]=[C:13]([C:19]([OH:21])=[O:20])[C:14]=2[S:15]([CH3:18])(=[O:17])=[O:16])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCc1ccc2c(-c3cccc(C#N)c3)c(S(C)(=O)=O)c(C(=O)OCC[Si](C)(C)C)nn12
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc2c(-c3cccc(C#N)c3)c(S(C)(=O)=O)c(C(=O)O)nn12
Yield: 88.2 %

Procedure:
A solution of 2-(trimethylsilyl)ethyl 4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxylate (1.09) in trifluoroacetic acid (5 mL) was stirred for 1.5 hours under an ice-bath. The reaction was quenched by adding water (20 mL). An yellow crystal was formed upon the addition, which was collected by filtration. The crystal was washed with water (5 mL) and hexane (3 mL) to give 4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxylic acid as an yellow crystal (756 mg, 88.2%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]2[CH2:29][CH2:28][CH:27]([O:30][CH3:31])[CH2:26]2)[CH2:20][CH2:19]1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([F:48])[C:34]=1[OH:49]>>[Cl:32][C:33]1[CH:38]=[C:37]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]3[CH2:29][CH2:28][CH:27]([O:30][CH3:31])[CH2:26]3)[CH2:20][CH2:19]2)[CH:36]=[C:35]([F:48])[C:34]=1[OH:49]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: COC1CCN(C[C@H]2CC[C@H](Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)CC2)C1
Product: COC1CCN(C[C@H]2CC[C@H](Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)cc34)CC2)C1

Procedure:
Following general procedure M, (6-bromo-4-((trans-4-((3-methoxypyrrolidin-1-yl)methyl)cyclohexyl)amino)quinolin-3-yl)(cyclopropyl)methanone (49 mg, 0.10 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (41 mg, 0.15 mmol) to afford the desired product (34 mg, 62%) as an off-white solid. 1H NMR (500 MHz, MeOD+TFA-d) δ 9.35 (br s, 1H), 8.47 (br s, 1H), 8.26 (dd, J=8.8, 1.8 Hz, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.59 (br s, 1H), 7.51 (d, J=11.4 Hz, 1H), 4.50 (br s, 1H), 4.18 (d, J=19.4 Hz, 1H), 3.85-3.74 (m, 2H), 3.36 (s, 3H), 3.22-3.13 (m, 3H), 2.84 (s, 1H), 2.45-2.29 (m, 3H), 2.22-2.05 (m, 4H), 1.80-1.71 (m, 2H), 1.35-1.19 (m, 6H). ESI MS m/z 552 [C31H35ClFN3O3+H]+; HPLC>99% (AUC), tR=11.30 min.
Reaction SMILES: [CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:27][CH3:28])=[N:19][N:20]3[CH:23]3[CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N+:36]([O-:38])=[O:37])[N:31]=1>>[CH2:1]([CH:8]1[N:13]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([N+:36]([O-:38])=[O:37])[N:31]=2)[CH2:12][CH2:11][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:27][CH3:28])=[N:19][N:20]3[CH:23]3[CH2:24][CH2:25][CH2:26]3)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(Cl)n1
Reactant: CCc1nn(C2CCC2)c2cc(N3CCNC(Cc4ccccc4)C3)ccc12
Product: CCc1nn(C2CCC2)c2cc(N3CCN(c4cccc([N+](=O)[O-])n4)C(Cc4ccccc4)C3)ccc12

Procedure:
Prepared using the same procedure described in Example 410 from 6-(3-benzyl-piperazin-1-yl)-1-cyclobutyl-3-ethyl-1H-indazole and 2-chloro-6-nitro-pyridine to afford the intermediate 6-[3-benzyl-4-(6-nitro-pyridin-2-yl)-piperazin-1-yl]-1-cyclobutyl-3-ethyl-1H-indazole {20.5 mg; LC/MS (Method B) 5.09 min, [M+1]+ 497]}. The nitro-intermediate was reduced with sodium hydrosulfite (48 mg, 0.28 mmol) in 50:50 THF/water at room temperature to obtain the title compound as a tan solid (6 mg, 2% overall). LC/MS (Method B) 4.02 min, [M+1]+ 467.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH3:9].[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[F:8][C:4]1[C:3]([CH3:9])=[C:2]([NH:1][C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1c(N)cccc1F
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc(F)c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-amino-3-fluoro-2-methylbenzene (1 equivalent) was dissolved in CH2C2 and acetic anhydride (2.0 equivalents) was added slowly. The solution was stirred at room temperature for 4 hours. The reaction mixture was then quenched with water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with H2O, a 10% HCl solution, H2O, and brine. It was then dried over Na2SO4 and concentrated in vacuo, to yield N-(3-fluoro-2-methylphenyl)acetamide as a pink solid. LC/MS (m/z) 168.2 (MH+), Rt 1.91 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]1[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH2:12]1.C1COCC1>[Pd].CO>[O:15]1[C:14]2([CH2:19][CH2:20][N:11]([C:3]3[CH:4]=[C:5]([NH2:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:12][CH2:13]2)[O:18][CH2:17][CH2:16]1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(N)cc1N1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 12 h
Yield: 123 %

Procedure:
To a solution of 8-(2-Methyl-5-nitro-phenyl)-1,4-dioxa-8-aza-spiro[4.5]decane (100 mg, 0.278 mmol) in the mixed solvent of THF (3 ml) and methanol (3 ml) was added 10% Pd/C, and the reaction mixture was stirred for 12 hours at room temperature under a hydrogen balloon. The reaction mixture is filtered and the filtrate was concentrated under vacuum to give 3-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-methyl-phenylamine [29] (Yield: 84.9 mg, 95.2%) as a off white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=3)[N:11]=[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:9]=2)=[CH:4][CH:3]=1.[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1B(O)O>>[F:23][C:15]1[CH:14]=[C:13]([N:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[O:29][CH:33]=[CH:32][CH:31]=4)=[CH:3][CH:4]=3)=[CH:9][C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:11]2)[CH:18]=[CH:17][C:16]=1[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CCOC(=O)c1cc(-c2ccc(Br)cc2)n(-c2ccc(S(C)(=O)=O)c(F)c2)n1
Reactant: OB(O)c1ccco1
Product: CCOC(=O)c1cc(-c2ccc(-c3ccco3)cc2)n(-c2ccc(S(C)(=O)=O)c(F)c2)n1

Procedure:
The title compound was prepared according to the procedure of Example 85 using ethyl 5-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-1H-pyrazole-3-carboxylate instead of 5-(4-bromophenyl) 1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole and 2-furanboronic acid instead of 3-furanboronic acid in step 2.
Reaction SMILES: [Cl:1]C1C=CC(C(O)=O)=CN=1.[C:11]([O:15][C:16](=[O:29])[NH:17][C:18]1[CH:19]=[N:20][C:21](C(F)(F)F)=[CH:22][C:23]=1[I:24])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16](=[O:29])[NH:17][C:18]1[CH:19]=[N:20][C:21]([Cl:1])=[CH:22][C:23]=1[I:24])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)Nc1cnc(C(F)(F)F)cc1I
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I

Procedure:
The title product was prepared from 6-chloronicotinic acid in the same manner as in the preparation of (4-iodo-6-trifluoromethylpyridin-3-yl)carbamic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9]CC)=[O:8])[N:6]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)C(C)C)C>O1CCOCC1>[N:12]1([C:2]2[S:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)c1csc(Cl)n1
Reactant: C1CCNC1
Agent: CCN(CC)C(C)C
Solvent: C1COCCO1
Product: O=C(O)c1csc(N2CCCC2)n1
Temperature: 60 °C
Yield: 68 %

Procedure:
A mixture of ethyl 2-chlorothiazole-4-carboxylate (500 mg, 2.6 mmol), pyrrolidine (210 mg, 2.98 mmol) and diethylisopropyl amine (1 mL) in p-dioxane (5 mL) was heated to 60° C. for 2 h. After cooling to room temperature, the solvent was concentrated in vacuo and the residue purified by flash chromatography (SiO2, 2 to 5% MeOH in CH2Cl2 as eluent) to give the desired compound as a foam (400 mg, 68% yield, which was used directly for the next step). MS: (ES) m/z 227.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>O>[F:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:12][NH:14][C:4]2=[O:5]
Reactant: NC=O
Reactant: Nc1ccc(F)cc1C(=O)O
Solvent: O
Product: O=c1[nH]cnc2ccc(F)cc12
Temperature: 160 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A mixture of 2-amino-5-fluorobenzoic acid (2.07 g) and formamide (4 ml) was heated at 160° C. for 2 hours, and for a further 2 hours at 180° C. The reaction mixture was allowed to cool and water was added. The reaction product was filtered off and washed with water and with diethyl ether to give 6-fluoro-3,4-dihydroquinazolin-4-one in 78% yield: m.p. 269-271° C.;
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:7]=[CH:8][C:9]=1[O:10]C(=O)C)=[O:3].Cl.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][C@@H:42]([NH2:49])[C:43]3[O:47][N:46]=[C:45]([CH3:48])[N:44]=3)=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)(=[O:28])=[O:27].CCN(C(C)C)C(C)C>>[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][C@@H:42]([NH:49][C:9]([C:4]3[CH:5]=[C:6]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=4)[CH:7]=[CH:8][C:2]=3[OH:3])=[O:10])[C:43]3[O:47][N:46]=[C:45]([CH3:48])[N:44]=3)=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: Cc1noc([C@H](N)Cc2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)n1
Reactant: CC(=O)Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc([C@@H](Cc2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)NC(=O)c2cc(-c3ccc(C(F)(F)F)cc3)ccc2O)n1

Procedure:
4-Hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2(4′-methanesulfonyl-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (49 mg) was prepared from acetic acid 3-chlorocarbonyl-4′-trifluoromethyl-biphenyl-4-yl ester (1.93 mL, 0.1 M CH2Cl2) and 2-(4′-methanesulfonyl-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine hydrochloride (80 mg, 0.175 mmol) and DIEA (92 μL, 0.525 mmol) using standard procedure M. The crude reaction mixture was concentrated and redissolved in THF (3 mL) and MeOH (1 mL). 1 N NaHCO3 (200 μL) and 1N Na2CO3 (50 μL) were added and the hydrolysis was followed by TLC and LCMS. Once complete, the reaction was diluted with EtOAc and the layers were separated. After extraction and drying the combined organics over MgSO4, the crude mixture was concentrated onto silica gel and purified by chromatography using 15% EtOAc in hexanes.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH3:25])[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[C:16](=[C:18]([C:22](O)=[O:23])[CH:19]=[CH:20][CH:21]=3)[N:17]=2)=[CH:9][CH:8]=1.O.[NH3:27]>ClCCl>[C:7]1([CH3:25])[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[C:16](=[C:18]([C:22]([NH2:27])=[O:23])[CH:19]=[CH:20][CH:21]=3)[N:17]=2)=[CH:9][CH:8]=1
Reactant: Cc1ccc(-c2nc3c(C(=O)O)cccc3o2)cc1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-c2nc3c(C(N)=O)cccc3o2)cc1
Temperature: 50 °C
Yield: 69.8 %

Procedure:
Oxalyl chloride (0.04 g, 0.3 mmol) was slowly added to a solution of 2-p-tolylbenzo[d]oxazole-4-carboxylic acid (0.064 g, 0.25 mmol) in dichloromethane (10 mL) with stirring. The reaction mixture was warmed to 50° C. for 4 hr and then cooled to 25° C. The solution was condensed in vacuum and then slowly added to 28% ammonia water (10 mL) and a solid precipitated out immediately. The mixture was warmed to 50° C. and stirred for another 2 hr. Water (20 mL) was added to the mixture and the slurry was cooled to 25° C. The product was filtered and the cake was washed with water, dried to afford 44 mg 2-p-tolylbenzo[d]oxazole-4-carboxamide as a solid (yield 69.8%). 1H-NMR (400 MHz, DMSO-d6) δ 2.46 (s, 3H), 6.01 (s, 1H), 7.34-7.36 (d, J=7.6 Hz, 2H), 7.43-7.47 (t, J=8.0 Hz, 1H), 7.71-7.73 (d, J=8.0 Hz, 1H), 8.15-8.18 (m, 3H), 9.02 (s, 1H); LC-MS (ESI) m/z 253 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=O.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:10][C:9]1[N:8]=[C:6]([C:5]2[CH:26]=[CH:27][CH:28]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:16]2[C:11]=1[CH:12]=[N:13][C:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[N:15]2
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3cccc(OC)c3)nn2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4cccc(OC)c4)n3n2)cc1
Yield: 30.2 %

Procedure:
Applying the Cyclization Procedure 1, 3-(methyloxy)-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide (Intermediate 52) (41 mg, 0.11 mmol), 1,2-dichloroethane (2.2 mL) and phosphorus oxychloride (0.081 mL, 0.87 mmol), to afford 5-methyl-7-[3-(methyloxy)phenyl]-N-[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (12 mg) as a yellow solid. MS m/z 362 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[S:16][C:12]=3[C:11](=[N:23]O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:25].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][NH:23][C:11](=[O:25])[C:12]3[S:16][C:15]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)=[CH:14][C:13]2=3)=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: ON=C1CCC(c2ccc(Cl)cc2)c2cc(-c3ccncc3)sc21
Agent: [Na+]
Product: O=C1NCCC(c2ccc(Cl)cc2)c2cc(-c3ccncc3)sc21
Temperature: 130 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
In a 100 mL round bottomed flask was placed stereo isomeric mixture of 4-(4-chlorophenyl)-2-pyridin-4-yl-5,6-dihydro-1-benzothiophen-7(4H)-one oxime prepared above and then was added polyphosphoric acid (11 g, 46 mmol) and the mixture was stirred for 6 h at 130° C. During this period, the mixture was occasionally mixed by hand. The mixture was allowed to cool to ambient temperature and then was added crushed ice (ca 20 ml) while the reaction mixture is hot. The mixture was stirred for 30 min at rt. A dark brown suspension was obtained, which was basicified by the addition of 5N NaOH (30 mL, pH ca 12). The mixture was extracted with a 1:1 mixture of CH2Cl2 and THF (30 mL×3). The combined organic phase was dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure to obtain title compound (230 mg; 68%) as a yellowish off-white powder, which was only one isomer.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[N:13]=[N:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:16]=1[OH:26])([O-])=O.ClC1C(=O)C2C(C(=[O:39])C=1Cl)=CC=CC=2.C1C2C(=O)C3C(=CC=CC=3)C=2C=CC=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.N(C1C=CC=CC=1)=NC1C=CC=CC=1>CO.O>[OH:26][C:16]1[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=1[N:14]1[N+:13]([O-:39])=[C:7]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:6]2=[N:3]1
Reactant: Cc1cc(N=Nc2ccc(Cl)cc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Agent: O=C1c2ccccc2-c2ccccc21
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cc(-n2nc3cc(Cl)ccc3[n+]2[O-])c(O)c(C(C)(C)C)c1

Procedure:
97% sodium hydroxide 8.2 g was added and dissolved in a mixture of methanol 60 ml and water 20 ml. 2-nitro-4-chloro-2'-hydroxy-3'-t-butyl-5'-methylazobenzene 11.6 g was then added to the resultant solution at 50° to 60° C. over 30 minutes while stirring, and thereafter 2,3-dichloro-1,4-naphthoquinone 0.3 g and 9-fluorenone 0.4 g were added to the solution. Glucose 4 g was then added to the resultant mixture at 40° to 50° C. over two hours, and the mixture was stirred for one hour at the same temperature. As this result, almost all of the azobenzene disappeared to produce 2-(2'-hydroxy-3'-t-butyl-5'-methylphenyl)-5-chlorobenzotriazole-N-oxide.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1([OH:12])[CH2:11][CH2:10][CH2:9]1.[F:13][C:14]([F:18])([F:17])[CH2:15][OH:16].CC(C)([O-])C.[K+]>CN(C=O)C>[F:13][C:14]([F:18])([F:17])[CH2:15][O:16][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1([OH:12])[CH2:11][CH2:10][CH2:9]1
Reactant: OCC(F)(F)F
Reactant: OC1(c2cnccc2Cl)CCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC1(c2cnccc2OCC(F)(F)F)CCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.2 %

Procedure:
To a solution of 1-(4-chloropyridin-3-yl)cyclobutanol (Example 108a, 0.83 g, 4.52 mmol) in dry DMF (20 ml) under an argon atmosphere was added 2,2,2-trifluoroethanol (CAN 75-89-8, 904 mg, 653 μl, 9.04 mmol) and potassium tert-butoxide (533 mg, 4.75 mmol). The reaction mixture was stirred at room temperature for 20 minutes and stirred at 90° C. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethylacetate and extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic phase was collected, dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/(solution 3% Et3N in ethylacetate) to yield the title compound (885 mg, 71%) as a yellow oil. MS (ESI, m/z): 248.5 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=1)=[C:27]=[O:28].N1C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[F:8][C:7]1[CH:6]=[CH:5][C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:23][CH2:24]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)=[CH:3][C:2]=1[NH:1][C:27](=[O:28])[NH:26][C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]([F:37])([F:39])[F:38])=[CH:31][CH:30]=1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CN(c1ccc(F)c(N)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CN(c1ccc(F)c(NC(=O)Nc2ccc(OC(F)(F)F)cc2)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.2 %

Procedure:
N-{5-[(3-Amino-4-fluorophenyl)(methyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (120 mg, 0.34 mmol) produced in Example 1(x) was dissolved in N,N-dimethylformamide (1.5 mL), 1-isocyanato-4-(trifluoromethoxy)benzene (70 μl, 0.46 mmol) was added, and the mixture was stirred at room temperature for 12 hr. 1-Isocyanato-4-(trifluoromethoxy)benzene (70 μL, 0.46 mmol) was further added to the reaction mixture, and the mixture was further stirred at 70° C. for 3 hr. Pyridine (1.5 mL) was added to the reaction mixture, and the mixture was further stirred at 70° C. for 2 hr. The reaction mixture was diluted with ethyl acetate (20 mL), and washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (69 mg, 37%) as a colorless powder.
Reaction SMILES: [CH2:1]([O:13][CH2:14][CH:15](O)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(Cl)([Cl:25])=O>>[Cl:25][CH:15]([CH2:14][O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCOCC(O)Cn1ccnc1
Product: CCCCCCCCCCCCOCC(Cl)Cn1ccnc1

Procedure:
Thionyl chloride (10 ml.) and 1.55 g. of 1-[3'-(n-dodecyloxy)-2'-hydroxypropyl]imidazole are warmed gently for a period of 2 hours and the solution is then evaporated to dryness. The residue is dissolved in 100 ml. of dichloromethane and rendered basic with aqueous potassium carbonate solution. The organic layer is separated, dried over magnesium sulfate and evaporated to yield 1-[2'-chloro-3'-(n-dodecyloxy)propyl]imidazole.