Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[Cl:31]>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:27]2[CH:28]=[CH:29][C:30]([Cl:31])=[C:25]([Cl:24])[CH:26]=2)=[N:3][CH:4]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccc(Cl)c(Cl)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3,4-dichlorophenol: 1H-NMR (CDCl3) δ 8.52 (1H, d, J=2.6 Hz), 8.13 (1H, d, J=2.8 Hz), 8.00 (2H, dd, J=6.7, 1.9 Hz), 7.93 (1H, d, J=7.4 Hz), 7.51 (1H, d, J=8.7 Hz), 7.42 (2H, d, J=8.1 Hz), 7.30 (1H, d, J=2.6 Hz), 7.03 (1H, dd, J=8.7, 2.6 Hz), 5.42–5.31 (1H, m), 3.90 (3H, s), 1.60 (3H, d, J=6.9 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:16][C:11]=3[O:10][CH:9]=2)=[CH:4][CH:3]=1.[N:22]1C=CC=C[CH:23]=1.Cl>C(Cl)(Cl)Cl>[C:23]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:16][C:11]=3[O:10][CH:9]=2)=[CH:4][CH:3]=1)#[N:22]
Reactant: COC(=O)Cc1ccc2occ(-c3ccc(Br)cc3)c2c1
Reactant: c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)Cc1ccc2occ(-c3ccc(C#N)cc3)c2c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A stirred mixture of 40 g. of cuprous cyanide and 99 g. (0.29 mole) of methyl 3-(4-bromophenyl)benzofuran-5-acetate in 30 ml. of pyridine is heated at 160°-175° C. under a nitrogen atmosphere for 20 hours, cooled to about 100° C., and then a solution of 200 g. of ferric chloride, 100 ml. of concentrated hydrochloric acid and 200 ml. of ice water is added. To this mixture is added 300 ml. of chloroform, and stirring is continued for one hour. The solid is separated by filtration and washed with chloroform. The filtrate and washings are combined, dried, then evaporated to provide a residue which is recrystallized from an N,N-dimethylformamide-water mixture to provide methyl 3-(4-cyanophenyl)-benzofuran-5-acetate.
Reaction SMILES: [CH3:1][N:2]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)C(=O)C(F)(F)F.[OH-].[Na+]>CO>[CH3:1][NH:2][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1
Reactant: CN(Cc1ccc([N+](=O)[O-])cc1)C(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.5 %

Procedure:
To a solution of N-methyl-N-(4-nitrobenzyl)trifluoroacetoamide (11.82 g) in methanol (200 ml) was added 1N aqueous solution of sodium hydroxide (50 ml) at room temperature. The mixture was stirred at room temperature for 24 hours, and concentrated under reduced pressure. The mixture was extracted with ethyl acetate and dried over magnesium sulfate. The mixture was concentrated under reduced pressure, to give methyl(4-nitrobenzyl)amine (6.78 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br)#[N:2].Cl.[CH3:12][CH:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:14].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:14][CH:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:23][CH2:24][N:25]([CH2:6][C:5]2[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=2)[C:1]#[N:2])[CH2:26][CH2:27]1)[CH3:12]
Reactant: CC(C)Oc1ccccc1N1CCNCC1
Reactant: N#Cc1cccc(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)Oc1ccccc1N1CCN(Cc2cccc(C#N)c2)CC1

Procedure:
A solution of 3-cyanobenzyl bromide (10.0 g, 0.051 mol), commercially available from Aldrich Chemical, and acetonitrile (250 mL) was added to a mixture of N-[2-(methylethoxy)phenyl]piperazine hydrochloride (13.10 g, 0.051 mol, prepared according to Martin, G. E., et al, J. Med. Chem., 1989, 32, 1052), K2CO3 (21.15 g, 0.153 mol) and acetonitrile (250 mL) and the resulting mixture was stirred at reflux under nitrogen for 6.75 hours. The reaction was cooled, concentrated to dryness, and the residue partitioned between CH2Cl2 and aqueous NaHCO3. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated to give a gummy residue. This material was chromatographed on silica gel (CH3OH:CH2Cl2 /2:98 eluant) to produce 3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]benzonitrile as a yellow gum, 10.86 g. A solution of this material (10.36 g, 0.031 mol) and anhydrous ether (500 mL) was added dropwise to a slurry of LiAIH4 (1.17 g, 0.031 mol) in anhydrous ether (500 mL) under N2 at room temperature. The reaction was stirred at reflux for 5.5 hours at which point additional LiAIH4 (1.17 g, 0.031 mol) was added. After stirring at reflux for 12 hours, the reaction was cooled in an ice bath and treated slowly with H2O (100 mL), 20% aqueous NaOH (100 mL), and H2O (100 mL) in that order, followed by extraction with diethyl ether. The ether layer was separated, dried over anhydrous Na2SO4, filtered, and evaporated to give 3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]benzyl amine as a pale yellow gum, 8.07 g.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].O[C:9]1[CH:10]=[C:11]([C@@:15]23[CH2:24][C:23](=[O:25])[CH2:22][CH2:21][C@@H:20]2[CH2:19][N:18]([CH3:26])[CH2:17][CH2:16]3)[CH:12]=CC=1.N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.O.C1(C)C=CC=CC=1>[C:5]([O:4][C:1]1[CH:12]=[C:11]([C@@:15]23[CH2:24][C:23](=[O:25])[CH2:22][CH2:21][C@@H:20]2[CH2:19][N:18]([CH3:26])[CH2:17][CH2:16]3)[CH:10]=[CH:9][CH:2]=1)(=[O:7])[CH3:6]
Reactant: CN1CC[C@]2(c3cccc(O)c3)CC(=O)CC[C@@H]2C1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)Oc1cccc([C@]23CCN(C)C[C@H]2CCC(=O)C3)c1
Reaction time: 2 h

Procedure:
3.77 ml (40 mmol) of acetic anhydride are added dropwise to a stirred mixture of 5.19 g (20 mmol) of octahydro-4a-(3-hydroxyphenyl)-2-methyl-cis-6(2H)-isoquinoline (see Example 3), 3.22 ml (40 mmol) of pyridine and 20 ml of toluene at 5°. The mixture is then kept at 22° for 2 hours. 20 ml of water is added to the mixture at 5°, and the mixture is stirred for 30 minutes at 22°. 40 ml of methylene chloride are added. Whilst being stirred, the aqueous phase of the resultant twophase mixture is adjusted to pH 7 by the addition of 4 g of sodium carbonate. The aqueous phase is then separated and extracted with methylene chloride. The organic phases are washed with water, dried, concentrated by evaporation and dried in a high vacuum. The title compound is obtained as a viscous oil which is crystallized as the hydrogen fumarate from isopropanol; M.Pt. 194° (decomposition).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:22](=[O:24])[CH3:23])[C:14]4[C:19]([C:20]=3[CH:21]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)O1.[Br:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29](Br)[CH:28]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.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>[Br:26][C:27]1[CH:28]=[C:29]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]([C:22](=[O:24])[CH3:23])[C:14]4[C:19]([C:11]=3[CH:10]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:30]=[CH:31][CH:32]=1
Reactant: Brc1cccc(Br)c1
Reactant: CC(=O)n1c2ccccc2c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)n1c2ccccc2c2cc(-c3cccc(Br)c3)ccc21
Temperature: 25 °C
Yield: 23 %

Procedure:
A mixture solution of 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazol-9-yl)ethanone (10.00 g, 29.8 mmol), 1,3-dibromobenzene (17.59 g, 74.6 mmol), Pd(PPh3)4 (0.689 g, 0.597 mmol) and K2CO3 (12.37 g, 89 mmol) in toluene (100 mL) and water (20 mL) was refluxed under N2 overnight. After cooling to room temperature, the organic phase was isolated and the solvent was evaporated. The residue was purified by column chromatography on silica gel with hexane/DCM (1/1, v/v) as eluent to yield 1-(3-(3-bromophenyl)-9H-carbazol-9-yl)ethanone (2.5 g, 23%) as a white solid.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]([F:35])([C:31]([F:34])([F:33])[F:32])[CH2:29][OH:30]>O>[F:27][C:28]([F:35])([C:31]([F:34])([F:33])[F:32])[CH2:29][O:30][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: OCC(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3OCC(F)(F)C(F)(F)F)nc2c1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g of potassium carbonate and 3 ml of 2,2,3,3,3-pentafluoropropanol was heated to reflux while stirring for 5.5 hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.33 g of 2-[3-(2,2,3,3,3-pentafluoropropoxy)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 75”).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([N:18]=COC)=[C:16]([S:22]([C:24]([F:27])([F:26])[F:25])=[O:23])[C:15]([C:28]2[N:32]=[CH:31][O:30][N:29]=2)=[N:14]1.Cl.O.C(=O)([O-])O.[Na+]>CC(C)=O>[NH2:18][C:17]1[N:13]([C:3]2[C:4]([Cl:12])=[CH:5][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]=2[Cl:1])[N:14]=[C:15]([C:28]2[N:32]=[CH:31][O:30][N:29]=2)[C:16]=1[S:22]([C:24]([F:27])([F:26])[F:25])=[O:23]
Reactant: COC=Nc1c(S(=O)C(F)(F)F)c(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Nc1c(S(=O)C(F)(F)F)c(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 100 %

Procedure:
1-(2,6-Dichloro-4-trifluoromethylphenyl)-5-methoxymethylideneamino-3-(1,2,4-oxadiazol-3-yl)-4-trifluoromethylsulfinylpyrazole (151 mg, 0.29 mmol) was dissolved in 5 ml of acetone and 1.2 N hydrochloric acid (0.12 ml, 0.14 mmol) was added, and then the mixture was stirred at room temperature. Seven hours after stirring, 1.2 N hydrochloric acid (0.12 ml, 0.14 mmol) was further added, followed by stirring at room temperature for 3 days. Furthermore, 1.2 N hydrochloric acid (0.12 ml, 0.14 mmol) was added, followed by heating to 50° C. and stirring for another 9 hours. After 5 ml of water and 2 ml of an aqueous saturated sodium hydrogencarbonate solution were added, acetone was distilled off and extracted with 40 ml ethyl acetate. The ethyl acetate layer was washed twice with 30 ml of an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 136 mg (0.29 mmol) of the title compound as a yellowish crystal.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)CCC.Br[C:21]1[C:22]([CH:27]=[O:28])=[N:23][CH:24]=[CH:25][CH:26]=1>C1(C)C=CC=CC=1.CCOC(C)=O.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>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[C:22]=1[CH:27]=[O:28]
Reactant: O=Cc1ncccc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=Cc1ncccc1-c1cccnc1
Temperature: 90 °C
Yield: 28.8 %

Procedure:
A mixture of 3-tributylstannanyl-pyridine (255 mg, 0.693 mmol), 3-Bromo-pyridine-2-carbaldehyde (123 mg, 0.660 mmol), and Pd(PPh3)4 (53.1 mg, 0.046 mmol) in toluene (4 mL) was heated to 90° C. for 23 h and cooled to room temperature. The reaction mixture was diluted with EtOAc (50 mL), washed with brine (3×20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (Hexanes/EtOAc, 70:30, then 0:100) afforded [3,3′]Bipyridinyl-2-carbaldehyde (35 mg, 29%) as a yellow oil.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:20])[CH2:6][NH:7][C:8]([C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([Cl:19])=[CH:14][CH:13]=2)=[O:9].Cl>C1COCC1>[Cl:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:8]([NH:7][CH2:6][C:5]([OH:20])=[O:4])=[O:9])=[CH:18]2
Reactant: COC(=O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1N NaOH (35 ml) was added to a suspension of [(5-chloro-1H-indole-2-carbonyl)-amino]-acetic acid methyl ester (8.0 g, 30 mmol) in THF (100 ml) and the resulting mixture stirred for 18 hours at 25° C. The solution was acidified with 6N HCl (7 mL), the mixture concentrated, the solids suspended in water, filtered, and washed with water (7.42 g, 98%): HPLC (60/40) 2.89 minutes (100%;)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:43])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[CH:31]=1)=O)(C)(C)C>>[CH3:14][C:12]1[C:11]([C:15]([F:16])([F:17])[F:18])=[CH:10][C:9]2[NH:19][C:26](=[O:43])[CH2:27][C:28]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([C:36]4[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=4)[CH:31]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cc(C(=O)CC(=O)OC(C)(C)C)ccn2)ccn1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(-c2cc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)ccn2)ccn1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (102 mg, 0.35 mmol) and 3-(2′-methyl-[2,4′]bipyridinyl-4-yl)-3-oxo-propionic acid tert-butyl ester (Example K59) (109 mg, 0.35 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (80 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([NH:12][C@H:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]([OH:16])=[O:15])=[O:11])[S:7][C:6]=2[CH:24]=1.C(OC(=O)[C@H](CC1C=CC=CC=1)N)(C)(C)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([NH:12][C@@H:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]([OH:16])=[O:15])=[O:11])[S:7][C:6]=2[CH:24]=1
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1cc2ccc(F)cc2s1
Agent: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cc2ccc(F)cc2s1

Procedure:
Following the 13a synthetic method, using B1 (110.65 mg, 0.5 mmol) instead of A1 gave 13b as colorless oil; (154.68 mg, 90.1%). [α]D25: +15.7 (c=0.26, CHCl3); 1H-NMR (300 MHz, acetone-d6): δ 8.08 (d, J=8.1 Hz, 1H), 8.03 (s, 1H), 7.96-7.91 (m, 1H), 7.80-7.76 (m, 1H), 7.39-7.18 (m, 6H), 4.98-4.92 (m, 1H), 3.36-3.15 (m, 2H); 13C NMR (300 MHz, acetone-d6): δ 172.17, 163.11, 161.48, 159.86, 142.28, 139.43, 137.51, 136.19, 129.23, 128.32, 126.89, 126.76, 126.60, 124.43, 114.09, 108.67, 54.12, 37.02; HRMS (ESI): calcd for: C18H14FNO3S [M−H]−=342.0606, obsd [M−H]−=342.0593.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]2[CH:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[N:12]=[C:6]2[CH:5]=1)(=O)[NH2:2].C(Cl)Cl.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[C:1]([C:4]1[CH:9]=[CH:8][N:7]2[CH:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[N:12]=[C:6]2[CH:5]=1)#[N:2]
Reactant: COC(=O)c1cn2ccc(C(N)=O)cc2n1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cn2ccc(C#N)cc2n1
Temperature: 0 °C
Yield: 29.1 %

Procedure:
To a suspension of methyl 7-carbamoylimidazo[1,2-a]-pyridine-2-carboxylate (1.5 g), methylene chloride (30 ml) and pyridine (2.7 g) was dropwise added trifluoroacetic anhydride (3.6 g) over the period of 5 minutes under cooling with stirring, and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was poured into ice water (30 ml) and extracted with 5% solution of methanol in chloroform. The organic layer was dried over magnesium sulfate and concentrated. The residue was subjected to a column chromatography on silica gel (50 g) and eluted with 20% solution of methanol in chloroform. The fractions containing the object compound were combined and concentrated to give methyl 7-cyanoimidazo[1,2-a]pyridine-2-carboxylate (0.4 g).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:21])=[O:5])C.[NH2:22][CH2:23][C:24]([OH:26])=[O:25]>C[O-].[Na+].CO>[OH:21][C:7]1[C:8]2[S:14][C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:12][C:9]=2[CH:10]=[N:11][C:6]=1[C:4]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:5]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2nc(-c3ccccc3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2nc(-c3ccccc3)sc2c1O
Temperature: 25 °C
Yield: 52.1 %

Procedure:
A mixture of 7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (63 mg, 0.21 mmol) and glycine (317 mg, 4.22 mmol) in 0.5 M sodium methoxide/methanol (8 mL) was refluxed for 3 days before it was cooled to room temperature and concentrated in vacuo. Water (20 mL) was added and the suspension was adjusted to pH=10 with 1N HCl (3 mL). The mixture was extracted twice with dichloromethane. And the remaining aqueous layer was acidified to pH=3 with 1N HCl (1.5 mL). The white precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (36 mg): 1H NMR (DMSO-d6, 200 MHz): δ=9.49 (br s, 1H), 8.91 (s, 1H), 8.18 (m, 2H), 7.63 (m, 2H), 4.03 (d, J=5.8 Hz, 2H); MS: (+) m/z 329.9 (M+1)
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:15]([O:22][C:23]1[C:28]2[C:29]([OH:32])=[N:30][O:31][C:27]=2[CH:26]=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O[CH2:34][CH2:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:15]([O:22][C:23]1[C:28]2[C:29]([O:32][CH2:34][CH2:35][CH:36]3[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[CH2:40][CH2:41]3)=[N:30][O:31][C:27]=2[CH:26]=[CH:25][CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: Oc1noc2cccc(OCc3ccccc3)c12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CCOc2noc3cccc(OCc4ccccc4)c23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.3 %

Procedure:
Diisopropyl azodicarboxylate (3.2 mL, 17 mmol) was added to a mixture of 4-(benzyloxy)-1,2-benzisoxazol-3-ol (2.7 g, 11 mmol, EXAMPLE 7, Step 1), tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (3.1 g, 14 mmol), and triphenylphosphine (4.3 g, 17 mmol) in toluene (11 mL) at 0° C. The mixture was stirred at room temperature for 16 h, and concentrated in vacuo to give a yellow oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 4:1) to give 3.8 g (76%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([I:22])=[N:17][N:16]=[C:15]3I)=[O:11])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].[O:28]1CCOCC1.Cl>O>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([I:22])=[N:17][N:16]=[C:15]3[OH:28])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: C1COCCO1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc2c(I)nnc(I)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc2c(I)nnc(O)c2c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of 1,4-di-iodo-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (0.15 g, 0.264 mmol), 2N NaOH (1.32 mL, 2.64 mmol) and dioxane (3 mL) was stirred at 50° C. for 16 h. The reaction mixture was diluted with water, acidified with conc. HCl to ˜pH 4 and extracted with EtOAc (×3). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated to afford 1-iodo-4-hydroxy-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (27 mg), 1H NMR (600 MHz, CDCl3) δ: 7.20 (d, 1H), 7.31 (t, 1H), 7.72 (d, 1H), 7.96 (d, 1H), 8.00 (s, 1H), 8.33 (dd, 1H), 8.86 (s, 1H), 10.40 (s, 1H), 12.39 (s, 1H) ppm. m/z 460.07; and 4-iodo-1-hydroxy-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (27 mg), 1H NMR (500 MHz, CDCl3) δ: 7.27 (d, 1H), 7.38 (t, 1H), 8.00 (m, 2H), 8.24 (m, 2H), 8.30 (d, 1H), 10.32 (s, 1H), 12.34 (s, 1H) ppm. m/z 460.07.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C>[F:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(F)c(F)c1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(F)c(F)cc1O
Yield: 49.4 %

Procedure:
In a flask was dissolved 3,4-Difluorophenol (3.10 g, 23.7 mmole) in acetic acid (15 ml). To the stirred solution was added dropwise a solution of fuming HNO3 (1.25 g, 29.7 mmole) in acetic acid (6 ml). The temperature was kept under 50° C. during the entire addition. After completed addition, the mixture was stirred for another hour. The reaction mixture was then poured onto ice-water, giving precipitation of a yellowish solid. The solid was collected by filtration, and dried. The solid was purified on silica (Heptane:EtOAc 5:1), giving the sub-title compound (2.05 g, 50%) as a yellow oil, which crystallizes on standing.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14]C(=O)C.S(=O)(=O)(O)O.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][C:3]=1[CH2:13][NH2:14]
Reactant: CC(=O)NCc1cc(-c2cc[nH]n2)ccc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NCc1cc(-c2cc[nH]n2)ccc1Cl
Temperature: 120 °C

Procedure:
A mixture of N-[[2-chloro-5-(1H-pyrazol-3-yl)phenyl]methyl]acetamide (i.e. the product of Step B) (2.0 g, 8.0 mmol), sulfuric acid (1.5 mL) and water (7.0 mL) was heated to 120° C. for 15 h. The reaction mixture was then cooled to ambient temperature, basified with 10% NaOH solution and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4) and concentrated to yield the title product as a solid (1.0 g), which was used in the next step without further purification.