Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.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>[Cl:10][C:4]1[CH:3]=[C:2]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[F:11])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: OB(O)c1ccccc1F
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: C1CCOC1
Product: N#Cc1ccc(-c2ccccc2F)cc1Cl
Yield: 99.3 %

Procedure:
A mixture of 4-bromo-2-chlorobenzonitrile (2.2 g, 10 mmol) and 2-fluorobenzeneboronic acid (1.82 g, 13 mmol) in tetrahydrofuran (30 ml) was treated with 2M sodium carbonate (13 ml) then degassed with nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.58 g, 0.5 mmol) was added and this mixture was heated under reflux for 12 h. The resulting mixture was partitioned between dichloromethane and water. The organics were washed with water, brine, dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo. Purification of the residue by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (5-15%) gave 3-chloro-2′-fluorobiphenyl-4-carbonitrile as a white solid (2.3 g, 99%): δH (400 MHz, CDCl3) 7.17-7.57 (5H, m), 7.64-7.75 (2H, m).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[Br:21][C:22]1[CH:23]=[C:24]([C:28]2[O:29][C:30]([CH3:35])=[C:31]([CH2:33]I)[N:32]=2)[CH:25]=[CH:26][CH:27]=1>>[Br:21][C:22]1[CH:23]=[C:24]([C:28]2[O:29][C:30]([CH3:35])=[C:31]([CH2:33][O:1][CH:2]3[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=4[C:12]([OH:14])=[O:13])[CH2:3]3)[N:32]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Reactant: Cc1oc(-c2cccc(Br)c2)nc1CI
Product: Cc1cccc(COC2CCCC(OCc3nc(-c4cccc(Br)c4)oc3C)C2)c1C(=O)O

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-(3-bromophenyl)-4-iodomethyl-5-methyloxazole as starting materials in the procedure of Example XXXI, gave the product 51 of molecular weight 514.42, (C26H28BrNO5), MS(ESI): 514.30, 516.30 (M+H+).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[NH2:46][C:47]1[CH:59]=[C:58]([CH2:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH:57]=[CH:56][C:48]=1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([NH:46][C:47]2[CH:59]=[C:58]([CH2:60][CH2:61][C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)[CH:57]=[CH:56][C:48]=2[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[CH:3][N:4]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Reactant: Brc1cncc2ccccc12
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1Nc1cncc2ccccc12
Temperature: 25 °C
Yield: 40.4 %

Procedure:
To toluene 1.0 mL solution of 4-bromoisoquinoline 0.12 g were added 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg, tert-butyl 2-amino-4-phenethylbenzoate 59 mg, cesium carbonate 0.13 g, palladium acetate 0.90 mg and tris(dibenzylideneacetone)dipalladium(0) 3.7 mg at room temperature, and it was heated and refluxed for 7 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol/L hydrochloric acid were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution sequentially, and the solvent was removed under reduced pressure. Ethyl acetate and hexane were added to the obtained residue, and solid matter was filtrated to give tert-butyl 2-((isoquinolin-4-yl)amino)-4-phenethylbenzoate 34 mg of a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([NH2:14])[N:11]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[N:17]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1>C(N)(C)C>[CH:18]([NH:19][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([NH2:14])[N:11]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[N:17]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1)([CH3:23])[CH3:16]
Reactant: Nc1cc(-c2ccc(Cl)nc2)cc2nc(-c3ccccn3)nn12
Solvent: CC(C)N
Product: CC(C)Nc1ccc(-c2cc(N)n3nc(-c4ccccn4)nc3c2)cn1
Yield: 82.7 %

Procedure:
A solution of 0.16 g (0.00035 mol) 7-(6-chloro-pyridin-3-yl)-2-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine in 80 ml isopropylamine were stirred at 150° C. for 150 hours in an autoclav. Removal of the amine and chromatography on silicagel with dichloro-methane/methanol 9/1 gave 0.05 g (29%) 7-(6-isopropylamino-pyridin-3-yl)-2-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine as beige solid, MS m/e (%): 346 (M+H+,100).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:28]=[CH:27][CH:26]=[CH:25][C:13]=2[C:14]([NH:16][CH2:17][CH2:18][CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[I-:34].[K+].[OH-].[Na+]>O>[I:34][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:28]=[CH:27][CH:26]=[CH:25][C:13]=2[C:14]([NH:16][CH2:17][CH2:18][CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: Nc1ccc(S(=O)(=O)Nc2ccccc2C(=O)NCCCn2ccnc2)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: O=C(NCCCn1ccnc1)c1ccccc1NS(=O)(=O)c1ccc(I)cc1
Temperature: 95 °C

Procedure:
A solution of 2-(4-aminobenzenesulphonamido)-N-(3-imidazol-1-ylpropyl)benzamide (11.0 g; hereinbefore prepared in Example 16) in a mixture of concentrated hydrochloric acid (9.5 ml) and water (50 ml) was cooled to between 0° C. and 5° C. whilst a solution of sodium nitrite (2.09 g) in water (15 ml) was added dropwise over 15 minutes. A solution of potassium iodide (4.58 g) in water (10 ml) was then added over 30 minutes, maintaining a temperature between 0° C. and 10° C. The mixture was then heated at 95° C. for 15 minutes. The resultant solution was cooled and adjusted to pH 8 by dropwise addition of 10% w/v aqueous sodium hydroxide solution. The solid precipitate was collected, washed with water and recrystallised from ethyl acetate to give 2-(4-iodobenzenesulphonamido)-N-(3-imidazol-1-ylpropyl)benzamide in the form of a pale-yellow solid, m.p. 162°-166° C. (yield: 3.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][NH:6][C:7]([C:9]1([C:12]([F:15])([F:14])[F:13])[CH2:11][CH2:10]1)=[O:8].C1N=CN([C:25](N2C=NC=C2)=[S:26])C=1>C(Cl)Cl>[Cl:19][C:18]1[CH:17]=[CH:16][C:4]([CH2:5][NH:6][C:7]([C:9]2([C:12]([F:13])([F:14])[F:15])[CH2:10][CH2:11]2)=[O:8])=[CH:3][C:2]=1[N:1]=[C:25]=[S:26]
Reactant: Nc1cc(CNC(=O)C2(C(F)(F)F)CC2)ccc1Cl
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Reaction time: 12 h

Procedure:
A solution of N-(3-amino-4-chlorobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (5.21 g; 17.79 mmol) in DCM (40 mL) was added to a solution of TCDI (3.80 g; 21.34 mmol) in DCM (30 mL) at 0° C. After 12 h at rt, the mixture was concentrated and the residue was purified by column chromatography to give the sub-title compound. Yield: 5.00 g (84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:22](=O)[CH2:23][CH2:24][C:25]([O:27]C)=O)[CH:19]=3)[CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.O.[NH2:31][NH2:32]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:22]4[CH2:23][CH2:24][C:25](=[O:27])[NH:31][N:32]=4)[CH:19]=3)[CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)CCC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(OC)cc1)C2
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)NC2Cc3ccc(C4=NNC(=O)CC4)cc3C2)cc1

Procedure:
5.0 g (12 mmol) of methyl 4-(2-p-methoxybenzenesulphonamido-indan-5-yl)-4-oxobutyrate and 3.0 g (60 mmol) of 99% hydrazine hydrate in 25 ml of glacial acetic acid are boiled for 30 minutes. The mixture is evaporated, water is added to the residue, and the reaction product is filtered off with suction and recrystallised from n-propanol.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][C@@:11]1([NH:30]C(=O)OC(C)(C)C)[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:18][CH:17]=2)[CH2:12]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.CCCCCCC>ClCCl>[NH2:30][C@:11]1([CH2:10][CH2:9][P:4](=[O:5])([O:3][CH2:1][CH3:2])[O:6][CH2:7][CH3:8])[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:18][CH:17]=2)[CH2:12]1
Reactant: CCCCCCCCc1ccc([C@H]2CC[C@@](CCP(=O)(OCC)OCC)(NC(=O)OC(C)(C)C)C2)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCc1ccc([C@H]2CC[C@](N)(CCP(=O)(OCC)OCC)C2)cc1
Reaction time: 1 h
Yield: 48.4 %

Procedure:
Tert-butyl (1R,3S)-1-(2-(diethoxyphosphoryl)ethyl)-3-(4-octylphenyl)cyclopentylcarbamate (0.2 g, 0.372 mmol) was dissolved in dichloromethane (1.860 ml) in a sealed vial to give a colorless solution. TFA (1.860 ml) was added and the reaction stirred for about 1 h. Solvents were removed under reduced pressure. Methylene chloride (25 mL) and saturated sodium bicarbonate (25 mL) were added and the layers separated and extracted with methylene chloride (2×10 mL). The combined extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated to a yellow oil. The oil was dissolve in ether (15 mL). 1 M HCl in dioxane (3 mL) was added. Solvents were removed under reduced pressure. The solid was redissolved in water and lyophilized. The resulting white/tan solid was suspended in ether and the resulting solid was collected by vacuum filtration and washed with ether then heptane to provide diethyl 2-((1R,3S)-1-amino-3-(4-octylphenyl)cyclopentyl)ethylphosphonate (0.0787 g, 0.180 mmol, 48.4% yield) as a white solid on drying under vacuum: LCMS (method a) Rt=3.46 min.; MS m/z: 438.48 (M+H)+.
Reaction SMILES: C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.[Br:26][C:27]1[CH:28]=[C:29]([NH:42][C:43]2[N:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:46]=[CH:45][N:44]=2)[CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:32]=1.Br[C:54]1[S:58][CH:57]=[N:56][CH:55]=1.[F-].[K+]>C1COCC1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].O>[Br:26][C:27]1[CH:28]=[C:29]([NH:42][C:43]2[N:48]=[C:47]([C:49]([F:50])([F:51])[F:52])[CH:46]=[CH:45][N:44]=2)[CH:30]=[C:31]([C:54]2[S:58][CH:57]=[N:56][CH:55]=2)[CH:32]=1
Reactant: CC1(C)OB(c2cc(Br)cc(Nc3nccc(C(F)(F)F)n3)c2)OC1(C)C
Reactant: Brc1cncs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccnc(Nc2cc(Br)cc(-c3cncs3)c2)n1
Temperature: 75 °C
Yield: 65.9 %

Procedure:
A solution of Pd(OAc)2 (19 mg, 0.085 mmol) and butyl di-1-adamantyl phosphine (61 mg, 0.18 mmol) in THF (12.8 mL) was stirred for 15 min. Intermediate 10 (755 mg, 1.70 mmol), 5-bromo-1,3-thiazole (760 μL, 8.50 mmol), potassium fluoride (296 mg, 5.10 mmol), and water (4.25 mL) were then added, and the mixture was heated to 75° C. overnight. After cooling to rt, the mixture was diluted with 100 mL EtOAc and washed with 100 mL brine. A bright yellow solid remained undissolved on the walls of the separatory funnel, which was thus rinsed with 100 mL THF. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Purification by Chromatography on silica gel (40 g; dry load; 100:0 to 50:50 hexanes:EtOAc over 25 minutes) provided N-[3-bromo-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (449 mg, 1.12 mmol, 66%) as an off-white solid. MS APCI: [M+H]+ m/z 403.0. 1H NMR (400 MHz, (CD3)2CO): δ 9.46 (s, 1H); 9.03 (s, 1H); 8.89 (d, J=4.9 Hz, 1H); 8.32-8.26 (m, 2H); 8.16 (s, 1H); 7.59 (s, 1H); 7.33 (d, J=4.9 Hz, 1H). rhSYK activity=++
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]4[CH:33]=[CH:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]=4)=[CH:18][CH:17]=3)=[CH:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)=[O:4]>[OH-].[Na+].O1CCCC1.CO.O>[CH3:14][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:13]=2)[C:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:20][CH:21]=2)=[CH:10]1
Reactant: COC(=O)c1ccc2c(Cc3ccc(OCc4ccc5ccccc5n4)cc3)cn(C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cn1cc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c2ccc(C(=O)O)cc21
Reaction time: 8 h
Yield: 59.7 %

Procedure:
A solution of the methyl ester (Example 10, part ii) (1.73 g) in aqueous sodium hydroxide (2M, 5.9 ml), tetrahydrofuran (20 ml) and methanol (10 ml) was refluxed with stirring overnight. The reaction mixture was cooled, diluted with water until turbid and washed with diethyl ether (2×). The aqueous phase was acidified with acetic acid and the resulting precipitate filtered, washed with water and dried in vacuo at 50° C. to give the product as a white solid (1 g). A small amount was crystallised from tetrahydrofuran/ethanol m.p. 208°-212° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([OH:3])=[O:2].C(N1C=CN=C1)(N1[CH:19]=[CH:18]N=C1)=O.CCO.[H-].[Na+]>C1COCC1>[CH2:18]([O:2][C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)=[O:3])[CH3:19]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2[nH]ccc2c1
Reaction time: 2 h
Yield: 127.7 %

Procedure:
Combine 5-carboxyindole (4.8 g, 29.8 mmol) in 150 mL THF and carbonyldiimidazole (9.7 g, 59.6 mmol) and stir overnight at ambient temperature. Treat the reaction mixture with 25 mL EtOH and 1.2 g (29.8 mmol) of a 60% oil dispersion of NaH and stir for 2 hours. Concentration under vacuum gives a residue. Partition the residue between 150 mL EtOAc and 100 mL brine. Separate the layers, dry the organic layer over MgSO4, filter, and concentrated to an oil. Chromatograph on silica gel eluting with 1% MeOH in CHCl3 to give 7.2 g of an oil. Crystallize the oil from toluene gives the title compound: Analysis for C11H11NO2: calcd: C, 69.83; H, 5.86; N, 7.40. found: C, 69.82; H, 5.90; N, 7.38. ISMS 190 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:21]([OH:23])=O)=[N:6][CH:7]=1.[CH3:24][S:25]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)=[N:11][C:10]=2[C:21]([NH:32][C:31]2[CH:30]=[CH:29][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:34][CH:33]=2)=[O:23])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(NC(=O)c2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazole-4-carboxylic acid (intermediate A 4.1, 15 mg, 0.043 mmol), 4-(methylsulfonyl)aniline (7.32 mg, 0.043 mmol) and DIPEA (0.015 ml, 0.086 mmol) in 0.6 mL of DMF was added BOP (22.7 mg, 0.051 mmol). The reaction was stirred at room temperature for 1 h and purified by reverse phase HPLC to give 5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-N-[4-(methylsulfonyl)phenyl]-1,3-oxazole-4-carboxamide: 1H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 8.38 (d, J=2.5 Hz, 1H), 8.08 (m, 2H), 7.94 (s, 4H), 7.61 (dd, J=8.4, 2.5 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.19 (m, 2H), 3.06 (s, 3H); HRMS exact mass calc for C22H15ClFN3O4S2 [M+H]+: 504.0245; observed: 504.0249.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[CH3:21][C:22]1[NH:27][C:26](=[O:28])[CH:25]=[CH:24][CH:23]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]3[C:4]=2[CH2:3][N:27]2[C:22]([CH3:21])=[CH:23][CH:24]=[CH:25][C:26]2=[O:28])=[CH:15][CH:16]=1
Reactant: Cc1cccc(=O)[nH]1
Reactant: Fc1ccc2nc(-c3ccc(Cl)cc3)c(CCl)n2c1
Agent: Cl
Product: Cc1cccc(=O)n1Cc1c(-c2ccc(Cl)cc2)nc2ccc(F)cn12

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 91 from 3-(chloromethyl)-2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridine hydrochloride and 6-methylpyridin-2(1H)-one. 1H-NMR (CDCl3, 400 MHz, δ) 8.75 (dd, J=2.2, 4.6 Hz, 1H), 7.55 (m, 3H), 7.45 (m, 2H), 7.16 (m, 2H), 6.55 (d, J=9.1 Hz, 1H), 5.87 (d, J=6.8 Hz, 1H), 5.84 (s, 2H), 1.74 (s, 3H) ppm; m/e 368 (M+H)+
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(C1C=CC=CC=1NC(=O)C1C=CC=CN=1)#N.[C:34]([C:38]1[CH:43]=[C:42](I)[CH:41]=[C:40]([I:45])[C:39]=1[O:46][CH3:47])([CH3:37])([CH3:36])[CH3:35]>CS(C)=O.[Cu]I.CC#N>[C:34]([C:38]1[CH:43]=[C:42]([N:1]2[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]2=[O:3])[CH:41]=[C:40]([I:45])[C:39]=1[O:46][CH3:47])([CH3:37])([CH3:35])[CH3:36]
Reactant: COc1c(I)cc(I)cc1C(C)(C)C
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: [Cu]I
Agent: N#Cc1ccccc1NC(=O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Solvent: CC#N
Product: COc1c(I)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 60 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
Uracil (33.3 g, 297 mmol, 1.2 equiv.), K3PO4 (106 g, 500 mmol, 2.1 equiv.), CuI (4.6 g, 24.2 mmol, 0.1 equiv.), and N-(2-cyanophenyl)picolinamide (6.4 g, 28.7 mmol, 0.12 equiv.) were charged to a flask and inerted with argon. The 1-tert-butyl-3,5-diiodo-2-methoxybenzene was solvent switched into MeCN, dissolved in 1 L DMSO and sparged with argon and added to the solids. The reaction was heated to 60° C. for 16 h. After cooling, the reaction was diluted with 2 L EtOAc and washed with 2.6 L water (back extracted with 3×1 L EtOAc). The combined organic layers were washed with 2×1 L of 0.25M (CuOAc)2 then 2×830 mL 15% NH4Cl then 800 mL brine. The organic layer was then concentrated and chased with 1 L heptane, then triturated with refluxing 85:15 (v/v) heptane:iPrOAc for 4 h. After cooling, the product was collected by filtration and washed with an additional 330 mL of 85:15 v/v heptanes:EtOAc to yield after drying 66.9 g (70% yield) of the product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:13][C:14]1[CH:21]=[N:20][CH:19]=[CH:18][C:15]=1[CH:16]=O.CS(C)=O>O>[F:13][C:14]1[CH:21]=[N:20][CH:19]=[CH:18][C:15]=1[C:16]1[S:12][C:3]2[C:2]([N:1]=1)=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][N:4]=2
Reactant: O=Cc1ccncc1F
Reactant: Nc1cc(C(F)(F)F)cnc1S
Solvent: O
Solvent: CS(C)=O
Product: Fc1cnccc1-c1nc2cc(C(F)(F)F)cnc2s1
Temperature: 170 °C
Reaction time: 2 h
Yield: 39.7 %

Procedure:
A mixture of 0.90 g of 3-amino-5-(trifluoromethyl)-pyridine-2-thiol, 0.58 g of 3-fluoroisonicotinaldehyde and 5 ml of DMSO was stirred at 170° C. for 2 hours. The reaction mixture was cooled down to room temperature, then, to the reaction mixture was added water, and the resultant mixture was extracted with ethyl acetate twice. The combined organic layers were washed with water and saturated saline, dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to obtain 0.55 g of 2-(3-fluoropyridin-4-yl)-6-(trifluoromethyl)thiazolo[5,4-b]pyridine (hereinafter, referred to as the present compound 9).
Reaction SMILES: [F:1][C:2](=[C:10]([F:12])[F:11])[CH2:3][CH2:4][CH:5]([OH:9])[CH2:6][CH2:7]O.[OH-].[Na+].[C:15]1([N:21]2[C:25]([SH:26])=[N:24][N:23]=[N:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2](=[C:10]([F:12])[F:11])[CH2:3][CH2:4][CH:5]([OH:9])[CH2:6][CH2:7][S:26][C:25]1[N:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:22]=[N:23][N:24]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: OCCC(O)CCC(F)=C(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: OC(CCSc1nnnn1-c1ccccc1)CCC(F)=C(F)F
Reaction time: 0.5 h
Yield: 75 %

Procedure:
Compound 3 (3.87 g) was dissolved in toluene (50 mL) and a 2N aqueous solution of sodium hydroxide (50 mL), and tetrabutylammonium bromide (700 mg) and tosyl chloride chloride (4.10 g) were added thereto under ice cooling, followed by stirring for 30 min. To the reaction solution 1-phenyl-1H-tetrazole-5-thiol (4.60 g) was added, followed by stirring at 60° C. overnight. The reaction solution was poured into water and extracted with tert-butyl methyl ether. The organic layer was washed with saturated brine; dried with sodium sulfate; and concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→7:3) to obtain the title compound (5.43 g) having the following physical properties:
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:22]=3[F:31])=[N:19][CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1.C(Cl)Cl>[F:31][C:22]1[C:23]([C:27]([F:30])([F:28])[F:29])=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]1[C:15]([N:12]2[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)=[N:16][CH:17]=[CH:18][N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2-c2cccc(C(F)(F)F)c2F)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Fc1c(-c2nccnc2N2CCNCC2)cccc1C(F)(F)F
Reaction time: 19 h

Procedure:
Add 4 M HCl in 1,4-dioxane (5 mL) to a solution of 3′-(2-fluoro-3-trifluoromethyl-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (0.101 g, 0.237 mmol) in DCM (10 mL) and stir for 19 hr. Concentrate, dissolve the residue in methanol (20 mL) and purify by SCX chromatography (pre-wash column with methanol), load material, elute with 2 M ammonia in methanol, and concentrate to give the title preparation as a yellow solid (0.0985 g). MS (ES): m/z=327 [M+H]+.