Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:4]1[C:9](=O)[N:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[S:5]1)([CH3:3])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>C1(C)C=CC=CC=1>[CH:1]([CH:4]1[C:9](=[S:21])[N:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[S:5]1)([CH3:3])[CH3:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)CN1C(=O)C(C(C)C)Sc2ccccc21
Solvent: Cc1ccccc1
Product: COC(=O)CN1C(=S)C(C(C)C)Sc2ccccc21

Procedure:
A mixture of methyl 3,4-dihydro-2-isopropyl-3-oxo-2H1,4-benzothiazine-4-acetate (50.0 g), phosphorus pentasulfide (79.5 g), and toluene (450 ml) was refluxed for 5.5 hours with stirring. After cooling, the insoluble matter was removed by filtration, and the solvent was evaporated off. To the residue isopropyl ether (300 ml) was added, and the insoluble matter was removed by filtration. The filtrate was concentrated, and the residue was crystallized from 2-propanol, to give methyl 3,4-dihydro-2- isopropyl-3-thioxo-2H-1,4-benzothiazine-4-acetate as crystals. Yield was 27.0 g (51.0%). Recrystallization from 2-propanol gave yellow prisms. mp 99°-100° C.
Reaction SMILES: [Na].[CH3:2][C:3]([C:5]1[N:6]([CH3:15])[C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[C:16](OCC)(=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[CH3:15][N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[O:14][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:2][C:3](=[O:4])[C:5]1=2
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1c(O)c2ccccc2n1C
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2c(o1)c1ccccc1n2C

Procedure:
To a solution of 6.0g (0.26 mole) of sodium metal in 600ml ab. ethanol was added 18.0g (0.095 mole) of 3-hydroxy-1-methyl-1H-indol-2-yl methyl ketone, followed by 37.6g (0.26 mole) of diethyl oxalate, added over 10 min. The mixture was stirred and heated at reflux for 17 hours, cooled and the red di-sodium salt was filtered and washed with cold hexane. The crude salt was added to a solution of 28ml conc. HCl and 120ml ab. ethanol, heated at reflux for 30 min., and the mixture was filtered while hot. Cooling the filtrate gave the crude product, which was filtered and then dissolved in 400ml of chloroform. The chloroform solution was washed 3 times with dilute aqueous NaHCO3, 1 time with water, dried (MgSO4) and evaporated to leave a grey residue. Recrystallization from 15% CHCl3 in hexane gave yellow needles of mpt. 160°-162°.
Reaction SMILES: ClCCCN(C)[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2=[N:16][N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:8]2[N:7]=1.[I-].[K+].[C-:30]#[N:31].[K+]>C(O)C>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]2[N:8]3[N:7]=[C:6]([CH2:30][NH:31][CH2:13][CH2:14][CH2:15][C:6]#[N:7])[C:15]4[C:10]([C:9]3=[N:16][N:17]=2)=[CH:11][CH:12]=[CH:13][CH:14]=4)=[CH:24][CH:23]=1
Reactant: COc1ccc(-c2nnc3c4ccccc4c(N(C)CCCCl)nn23)cc1
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(-c2nnc3c4ccccc4c(CNCCCC#N)nn23)cc1
Yield: 70 %

Procedure:
The compound of example 106 (2.5 g) is dissolved in ethanol (20 ml) and added of potassium iodide (0.4 g) and potassium cyanide (0.75 g). The mixture is refluxed for about 8 hours. The reaction mixture is then hot filtered, and the filtrate is concentrated to dryness. The residue is taken up with water and extracted with methylene chloride (2×25 ml). The pooled organic layer is dried over sodium sulfate and concentrated to dryness. The residue, which is the compound of the title, crystallizes from methanol. Yield: 70%. M.p. 117°-119° C.
Reaction SMILES: C(O[C:14]1[CH:40]=[CH:39][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23](OCCCCCCCCCCCC)=[CH:22][CH:21]=2)=O)=[CH:16][CH:15]=1)CCCCCCCCCCC.O.[NH2:42][NH2:43]>C(O)CCCC>[C:17]1([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N+:42]=[N-:43])[CH:39]=[CH:40][CH:14]=[CH:15][CH:16]=1
Reactant: NN
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)c2ccc(OCCCCCCCCCCCC)cc2)cc1
Solvent: O
Solvent: CCCCCO
Product: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 4,4′-dihydroxybenzophenone (21.4 g, 100 mmol), 1-bromododecane (49.8 g, 200 mmol), K2CO3 (50 g) in 500 mL of DMF were heated with stirring at 120° C. for 60 hours. After the mixture was cooled to room temperature, 1 L of water was added. The solution was extracted with CH2Cl2 (4×500 mL). The combined organic layers were dried with MgSO4 and the most of the solvent removed under reduced pressure as a white solid formed. The solids were collected by filtration, washed with cold hexanes, and air dried to give 4,4′-didodecyloxybenzophenone (41.2 g, 75%). A mixture of 4,4′didodecyloxybenzophenone (20.6 g) and hydrazine monohydrate (20 mL) in 150 mL of pentanol were heated at reflux for 24 hours. After cooling to room temperature, a white solid precipitated which is collected by vacuum filtration, washed with 20 mL cold ethanol and air dried (19.4 g, 92%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[C:6]([CH:25]=1)[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][C:16]=2[F:24])[CH2:11][CH2:10]1)=[O:8].[NH:32]1[CH:36]=[CH:35][N:34]=[CH:33]1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[Cu]I.O1CCOCC1>[F:24][C:16]1[CH:17]=[C:18]([C:21](=[O:23])[CH3:22])[CH:19]=[CH:20][C:15]=1[N:12]1[CH2:13][CH2:14][N:9]([C:7](=[O:8])[C:6]2[CH:25]=[C:2]([N:32]3[CH:36]=[CH:35][N:34]=[CH:33]3)[CH:3]=[CH:4][C:5]=2[N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[CH2:10][CH2:11]1
Reactant: c1c[nH]cn1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(Br)ccc3N3CCOCC3)CC2)c(F)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(-n4ccnc4)ccc3N3CCOCC3)CC2)c(F)c1
Temperature: 120 °C
Yield: 41.9 %

Procedure:
In a tube were added successively 1-{4-[4-(5-Bromo-2-morpholin-4-yl-benzoyl)-piperazin-1-yl]-3-fluoro-phenyl}-ethanone (example BJ, 0.05 g, 0.1 mmol), imidazole (8.4 mg, 0.12 mmol), cesium carbonate (70 mg, 0.21 mmol), CuI (4 mg, 0.02 mmol), 1,10-phenanthroline (7.3 mg, 0.04 mmol) and dioxane (0.2 ml). The mixture was heated under argon at 120° C. for 12 hours. The reaction mixture was cooled to room temperature and quenched with water/ethyl acetate. The aqueous layer was extracted twice with ethylacetate. The organic layers were combined, dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude oil was chromatographed over silicagel: eluent: CH2Cl2/methanol: 0-5% to provide the title compound as a brown solid (20 mg, 40%), MS (m/e): 478.4 (M+H, 100%)
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)[C:5]#[N:6].O.[NH2:19]N.C(O)(=O)C>C(O)C>[F:14][C:13]([F:16])([F:15])[C:9]1[CH:8]=[C:7]([C:4]2[CH:3]=[N:2][NH:6][C:5]=2[NH2:19])[CH:12]=[CH:11][CH:10]=1
Reactant: CN(C)C=C(C#N)c1cccc(C(F)(F)F)c1
Reactant: NN
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1[nH]ncc1-c1cccc(C(F)(F)F)c1
Reaction time: 5 h
Yield: 97.4 %

Procedure:
To a mixture of 3-(dimethylamino)-2-(3-(trifluoromethyl)phenyl)acrylonitrile (2.93 g, 12.20 mmol) in ethanol (35 ml) was added hydrazine hydrate (3.80 ml, 122 mmol) and acetic acid (6.98 ml, 122 mmol). Upon to reflux; a solution formed. After 5 hours, 0.25 mL of hydrazine hydrate was added and the reaction refluxed an additional 15 hours. The volatiles were removed in vacuo, and the residue partitioned between EtOAc and water. After extracting three times with EtOAc, the combined organics were washed twice with saturated aqueous NaHCO3, dried over Na2SO4, and concentrated in vacuo to cleanly give 4-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (2.7 g, 97% yield) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14](Cl)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>CC(N(C)C)=O.C(#N)C>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:14]2[N:13]=[C:12]([C:18]([F:21])([F:20])[F:19])[C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:16][N:15]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cnc(Cl)nc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(C(=O)Nc3ccc(Cl)cc3)c(C(F)(F)F)n2)CC1

Procedure:
A mixture of 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid (4-chloro-phenyl)-amide (0.8 g, 2.38 mmol, 1.0 equiv; commercially available from Maybridge, UK), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.72 g, 3.57 mmol, 1.5 equiv; commercially available) and triethylamine (0.49 mL, 0.36 g, 3.57 mmol, 1.5 equiv) in anhydrous DMAc (2 mL) and acetonitrile (9 mL) was heated by microwave irradiation to 120° C. for 20 min. The organic phase was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 1.0 g (84%) of the title compound. MS (ISP): 500.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([CH3:19])([CH3:18])[OH:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1>FC(F)(F)C(O)=O.[Pt](=O)=O>[NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([CH3:19])([CH3:18])[OH:17])[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CC(C)(O)Cn1cnc2c(N)nc3ccccc3c21
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)Cn1cnc2c(N)nc3c(c21)CCCC3

Procedure:
Platinum (IV) oxide (0.3g) was added to a suspension of 4-amino-α,α,-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol (0.5 g, 1.95 mmole, U.S. Pat. No. 4,689,338 Example 189) in trifluoroacetic acid (15 mL). The mixture was hydrogenated at 50 psi (3.44×105Pa) overnight. The reaction mixture was filtered to remove the catalyst then concentrated under vacuum. The residue was diluted with water then combined with aqueous sodium bicarbonate. The resulting precipitate was isolated by filtration. The nuclear magnetic resonance spectroscopy indicated the reduced product.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[NH2:7][C@H:8]([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][C:11](=[O:13])[NH2:12].C(Cl)(=O)C(C)=C.Cl.[Cl-].[Na+]>O.C(#N)C>[C:11]([NH2:12])(=[O:13])[C:10]([CH3:1])=[CH2:9].[NH2:7][C@H:8]([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][C:11](=[O:13])[NH2:12]
Reactant: O=C([O-])[O-]
Agent: C=C(C)C(=O)Cl
Agent: Cl
Agent: NC(=O)CC[C@H](N)C(=O)O
Solvent: O
Solvent: CC#N
Product: C=C(C)C(N)=O
Reaction time: 2 h

Procedure:
Potassium carbonate(34.55 g) was dissolved in 100 ml of distilled water, 7.30 g of L-glutamine was dissolved in the solution, and 20 ml of acetonitrile was further added to the solution. The reaction mixture was added dropwise with 10.45 g of methacryloyl chloride over about 10 minutes with vigorous stirring, and further stirred for about 2 hours. The reaction mixture was adjusted to pH 1-2 with concentrated hydrochloric acid, saturated with sodium chloride, and extracted 2 times with 100 ml of ethyl acetate. The obtained aqueous layer was extracted 3 times with 100 ml of ethyl acetate/isopropanol=1/1. The ethyl acetate/isopropanol layers were combined, concentrated, and purified on a silica gel column (30 g of silica gel, eluted with chloroform/methanol=2/1). The corresponding fractions were collected and concentrated (colorless syrup, 7.47 g)
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[CH3:59][O:60][C:61]1[N:66]=[CH:65][C:64](B(O)O)=[CH:63][CH:62]=1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:26][CH2:27]3)=[CH:7][CH:8]=2)[C:3](=[O:32])[C:2]=1[C:64]1[CH:65]=[N:66][C:61]([O:60][CH3:59])=[CH:62][CH:63]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2ccc(F)cc2F)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3ccc(F)cc3F)c3ccc(OCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cn1
Yield: 68 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-{2-[4-(methylsulfonyl)piperazin-1-yl]ethoxy}-1H-inden-1-one obtained in Step 1 of Example 116 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and 6-methoxy-3-pyridinylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (68%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10]CC2C=CC=CC=2)=O)[CH:4]2[CH2:18][CH2:19][N:20]([C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH:3]12.Br.C(O)(=O)C.C1CCN2[C:38](=[N:39]CCC2)[CH2:37]C1.C(CC(OC)=O)#N>>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH2:37][C:38]#[N:39])[CH:4]2[CH2:18][CH2:19][N:20]([C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH:3]12
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC1CCN(C(=O)OCc2ccccc2)C2CCN(c3ncnc4[nH]ccc34)C12
Agent: Br
Agent: COC(=O)CC#N
Solvent: CC(=O)O
Product: CC1CCN(C(=O)CC#N)C2CCN(c3ncnc4[nH]ccc34)C12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the product of Example 20 (30 mg, 0.077 mmol), was added HBr in acetic acid (1.5 mL, 0.10 mmol) and the reaction was stirred at room temperature for 2 hours before being concentrated in vacuo and azeotroped with heptanes (×4) and MeOH/heptanes (×3). The solid was dried under high vacuum and was then dissolved in methanol and passed through a Varian StratoSpheres™ SPE PL-HCO3 MP SPE resin and concentrated in vacuo. The solid was dissolved in MeOH (0.4 mL) and DBU (5.8 μL, 0.038 mmol) and methyl cyanoacetate (15.2 mg, 0.153 mmol) were added and the reaction was stirred at 40° C. for 16 hours. The reaction was concentrated in vacuo and the residue was purified by mass triggered reverse phase HPLC. Lyophilization of the desired fractions gave the title product (TFA salt) as a off-white solid. LRMS calc'd for C17H21N6O [M+H]+, 325; found 325. Jak1 activity: +.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.[Br:16]N1C(=O)CCC1=O.S(=O)(=O)(O)O>>[Br:16][C:7]1[CH:6]=[CH:5][C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][C:2]=1[F:1]
Reactant: Fc1cccc(OCc2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: Fc1cc(OCc2ccccc2)ccc1Br

Procedure:
In analogy to the procedure described in example 8 b], 1-fluoro-3-(phenylmethoxy)-benzene (for the preparation of 1-fluoro-3-(phenylmethoxy)-benzene see: A. A. Durrani, J. H. P. Tyman, J. Chem. Soc., Perkin Trans. 1 1979, 8, 2079-2087) was treated with N-bromosuccinimide in the presence of concentrated sulfuric acid to give 1-bromo-2-fluoro-4-(phenylmethoxy)-benzene as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1B1OC(C)(C)C(C)(C)O1.[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][C:22]=1[F:28].N#N.C([O-])([O-])=O.[Na+].[Na+].Cl>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>[CH3:18][O:19][C:20]([C:21]1[CH:26]=[CH:25][C:24]([C:7]2[CH:6]=[CH:5][C:4]([OH:17])=[CH:3][C:2]=2[CH3:1])=[CH:23][C:22]=1[F:28])=[O:29]
Reactant: Cc1cc(O)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: N#N
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc(O)cc2C)cc1F
Temperature: 90 °C
Yield: 78.7 %

Procedure:
A solution of 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (0.241 g, 1.03 mmol) and 4-bromo-2-fluoro-benzoic acid methyl ester (0.240 g, 1.03 mmol) in 1,4-dioxane (20 mL) is evacuated and re-filled with N2 3 times. To this solution, Pd(PPh3)4 (0.010 g) and aqueous Na2CO3 (1.0 mL, 2.0 M) are added. The resulting mixture is heated at 90° C. for 24 hours under N2. The reaction mixture is cooled to room temperature and neutralized with HCl (1.0 M, 3.0 mL) and concentrated. The residue is extracted with ethyl acetate (30 mL×2), and the combined organic layers are dried over sodium sulfate and concentrated. The residue is purified via silica gel chromatography eluting with 25-30% ethyl acetate in hexanes to give the title compound (0.211 g, 79%). 1H NMR (400 MHz, CDCl3): δ 7.95-7.91 (t, 1H), 7.10-7.04 (m, 3H), 6.74-6.69 (m, 2H), 3.93 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [CH:1]1[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=2[CH:4]=[N:3][CH:2]=1)=[O:8].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1>>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:7]([C:6]2[CH:1]=[CH:2][N:3]=[CH:4][C:5]=2[C:10]([OH:9])=[O:11])=[O:8])=[CH:15][CH:14]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: O=C1OC(=O)c2cnccc21
Product: Cc1ccc(C(=O)c2ccncc2C(=O)O)cc1

Procedure:
Employing 3,4-pyridinecarboxylic anhydride (10.0 g) and 4-methylphenyl magnesium bromide, substantially the same reaction and process as in Reference Example 2 Step 1 were conducted to give 4-(4-methylbenzoyl)-3-pyridinecarboxylic acid as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH3:36].CO>C(Cl)Cl>[NH2:36][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(N)n2)s1
Temperature: 90 °C

Procedure:
A suspension of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (196 mg, 0.364 mmol) and ammonia in methanol 7M (8 ml, 56.0 mmol) was heated in a sealed tube to 90° C. for 24 h. The reaction was diluted with DCM and added silica gel and concentrated. The crude product was chromatographed on silica gel eluting with 100% DCM to 1:1 [DCM:(9:1 EtOAc:MeOH)]. The clean fractions were concentrated to yield the crude product. The crude product was repurified by reverse phase HPLC (a gradient of acetonitrile:water with 0.1% TFA in both). The combined clean fractions were concentrated then partitioned between DCM and saturated NaHCO3. The DCM layer was separated and dried over Na2SO4. The title compound, N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide was obtained (94 mg, 47% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.83 (s, 1H), 7.93 (d, J=5.2 Hz, 1H), 7.55-7.70 (m, 1H), 7.35-7.43 (m, 1H), 7.31 (t, J=6.3 Hz, 1H), 7.14-7.27 (m, 3H), 6.70 (s, 2H), 5.79 (d, J=5.13 Hz, 1H), 1.35 (s, 9H). MS (ESI): 519.9 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1.CO>[C].[Pd].C(O)(=O)C>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([CH:37]2[CH2:42][CH2:41][CH2:40][NH:39][CH2:38]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2cccnc2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCCNC2)ccc1O
Temperature: 80 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
To an acetic acid (15 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-(pyridin-3-yl)benzamido)-4-phenylbenzoate (0.88 g), 10% palladium-carbon (0.44 g) was added, followed by stirring under hydrogen pressure (5 kg/cm2) at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, and methanol and acetic acid were added thereto. The insoluble substance was removed by filtration. The solvent was removed under reduced pressure, and chloroform and a saturated aqueous solution of sodium bicarbonate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.51 g of tert-butyl 2-(2-hydroxy-5-(piperidin-3-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:15](Cl)(Cl)=[O:16].C(=O)=O.Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(Cl)Cl.O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[N:9]=[C:10]([O:12][CH2:13][CH3:14])[O:11][C:15]1=[O:16]
Reactant: CCOC(=O)NNc1ccccc1Cl
Reactant: O=C(Cl)Cl
Agent: Cl
Agent: O=C=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOc1nn(-c2ccccc2Cl)c(=O)o1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Ethyl 3-(2-chlorophenyl)-carbazate (15.2 g.) is added to a 14.8% (w/v) solution (71 cc.) of phosgene in toluene. The solution obtained is then heated gradually until gas ceased to be evolved, whilst condensing the condensable vapours by means of a condenser containing solid carbon dioxide. The temperature of the reaction mixture is then 105° C. The condenser containing solid carbon dioxide is replaced by a coil condenser and the mixture is heated under reflux until the evolution of gas is complete. After cooling, the solution is concentrated under reduced pressure (25 mm. Hg) at 50° C. The residue obtained is dissolved in methylene chloride (71 cc.), then triethylamine (9.5 cc.) is added to the solution and the mixture is stirred overnight at 20° C. Water (71 cc.) is then added in order to dissolve the precipitate of triethylamine hydrochloride. The organic phase is decanted and then washed successively with 0.1N hydrochloric acid (50 cc.) and water (100 cc.). After drying over sodium sulphate, the solvent is removed by evaporation under reduced pressure (25 mm.Hg) at 40° C. The residual solid is recrystallised from petroleum ether, b.p. 35°-60° C., (380 cc.) to give 3-(2-chlorophenyl)-5-ethoxy-1,3,4-oxadiazolin-2-one (13.7 g.), melting at 45° C.