Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:7]=1)[C:3](=[O:5])[CH3:4]>C(O)C.[Pd]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([C:8]2[CH:7]=[C:6]([N:2]([CH3:1])[C:3](=[O:5])[CH3:4])[CH:11]=[CH:10][CH:9]=2)(=[O:13])=[O:14])=[CH:16][CH:17]=1
Reactant: CC(=O)N(C)c1cccc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N(C)c1cccc(S(=O)(=O)c2ccc(N)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
1.50 g (0.00448 mol) of N-methyl-N-[3-(4-nitrobenzenesulphonyl)-phenyl]-acetamide were suspended in 150 ml of ethanol, treated with 0.15 g of Pd/C (10%) and stirred in a H2 atmosphere at room temperature under normal pressure for 2 hrs. Then, the catalyst was filtered off, the filtrate was freed from solvent and the residue was chromatographed on silica gel with ethyl acetate/hexane 2:1. There were obtained 1.19 g (87%) of N-[3-(4-amino-benzenesulphonyl)-phenyl]-N-methyl-acetamide as white crystals; m.p.: 178-180° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=4[F:33])=[O:21])=[C:15]([F:34])[CH:14]=3)[CH:9]=[C:10]([CH:11]=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.[CH:35]([Mg]Br)=[CH2:36]>C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:25][C:24]=4[F:33])=[O:21])=[C:15]([F:34])[CH:14]=3)[CH:9]=[C:10]([CH:11]([OH:12])[CH:35]=[CH2:36])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(C=O)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c12
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)c1cc(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn12
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a stirred solution of 1-[4-(4-amino-7-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl) -2-fluorophenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea (450 mg, 0.95 mmol) dissolved in THF (10 mL), was added vinyl magnesium bromide (9.45 mL, 9.45 mmol, 1.0 M in THF) at rt. The reaction was allowed to stir for 1 hr and then quenched with MeOH (1 mL). The mixture was partitioned between EtOAc (250 mL) and saturated aq. Na2CO3 (100 mL). The organic phase was washed with brine (100 mL), dried (Na2SO4), and concentrated to dryness. Trituration with Et2O afforded 300 mg (63%) of the desired product. 1H-NMR (DMSO-d6) δ 8.65 (d, J=7.8 Hz, 1H), 8.27 (t, J=8.4 Hz, 1H), 7.85 (s, 1H), 7.36-7.27 (m, 5H), 7.13-7.07 (m, 1H), 6.90 (s, 1H), 6.70-6.60 (m, 1H), 4.29 (dd, J=1.5, 5.7 Hz, 1H); MS [M+H]+=505.2; LCMS RT=2.85 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:21][C:18]1[CH:17]=[C:16]([F:22])[CH:15]=[CH:20][C:19]=1[N:10]1[CH2:11][CH2:12][N:8]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:9]1=[O:13]
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Fc1ccc(Br)c(F)c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc(F)cc2F)C1=O
Yield: 61.2 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474 mmol) was reacted with 1-bromo-2,4-difluoro-benzene (0.114 mL, 1.0169 mmol), 1,4-dioxane (20 mL), copper iodide (16 mg, 0.08474 mmol), trans-1,2-diamino cyclohexane (29.4 mg, 0.254 mmol) and potassium phosphate (449.7 mg, 2.118 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 150 mg of the product (61% yield).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][NH:9][C:8]2=[N:13][N+:14]([O-:16])=[O:15])[CH2:2]1.[H-].[Na+].[C:19](Cl)(=[O:21])[CH3:20]>C(#N)C>[CH3:20][C:19]([N:9]1[CH2:10][CH2:11][CH2:12][N:7]([CH2:6][CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)[C:8]1=[N:13][N+:14]([O-:16])=[O:15])=[O:21]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])N=C1NCCCN1CC1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)N1CCCN(CC2CCOC2)C1=N[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 16.9 %

Procedure:
A mixture of 0.30 g of 1-[(tetrahydro-3-furanyl) methyl]-2-(nitroimino)hexahydropyrimidine, 0.07 g of sodium hydride (60%) and 10 ml of acetonitrile was stirred at 50° C. for 30 minutes. After this mixture was cooled on ice, 0.11 g of acetyl chloride was dropwise added thereto over 10 minutes, and the mixture was then stirred at room temperature for 2 hours. After the completion of reaction, insolubles were removed by filtration, and concentration was then carried out under a reduced pressure. The resultant oily substance was purified by silica gel column chromatography (2:1 ethyl acetate/acetone) to obtain 0.06 g of 1-(methylcarbonyl)-2-(nitroimino)-3-[(tetrahydro-3-furanyl)methyl]hexahydropyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>N1C=CC=CC=1>[CH3:12][S:13]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)(=[O:15])=[O:14]
Reactant: Nc1cccc2cccnc12
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc2cccnc12
Yield: 92.2 %

Procedure:
The reaction of 5.0 g (0.0347 mole) of 8-aminoquinoline with 3.97 g (0.0347 mole) of methylsulfonyl chloride was carried out in 10 ml of pyridine at room temperature. After 2 hours from the start of the reaction, the reaction mixture was washed with water, extracted with diethyl ether, purified by column chromatography and concentrated to give 10.32 g (0.032 mole, 92%) of 8-(methylsulfonamido)quinoline. Then, 5.0 g (0.016 mole) of the 8-(methylsulfonamido)quinoline, 3.07 g (0.023 mole) of zinc chloride and 6.98 g (0.069 mole) of triethylamine were suspended in 30 ml of ethanol and allowed to react at room temperature. After 3 hours, the separated yellow powder was filtered, washed with ethanol and purified by column chromatography to give 10.48 g (90.0%) of Compound M as yellow crystals. The maximum PL wavelength of this compound in chloroform was 505 nm.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[C:13]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]([O:37]CC2C=CC(OC)=CC=2)[CH:22]([CH2:30][CH2:31]OS(C)(=O)=O)[C:23]([O:25]C(C)(C)C)=[O:24])=[CH:15][CH:14]=1>CN(C)C=O>[C:13]1([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH:21]([OH:37])[CH:22]([CH2:30][CH2:31][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[C:23]([OH:25])=[O:24])=[CH:17][CH:18]=1
Reactant: COc1ccc(COC(CCc2ccc(-c3ccccc3)cc2)C(CCOS(C)(=O)=O)C(=O)OC(C)(C)C)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(O)C(CCN1C(=O)c2ccccc2C1=O)C(O)CCc1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 27.1 %

Procedure:
Potassium phthalimide (8.8 mg, 60 μmol) was added in one portion to a stirred solution of 1,1-dimethylethyl 5-(4-biphenylyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)-2-{2-[(methylsulfonyl)oxy]ethyl}pentanoate (28.4 mg, 50 μmol) in dimethylformamide (0.5 mL) under nitrogen at room temperature. The resulting solution was heated at 80° C. for 1 h 45 min then cooled to room temperature. The volatiles were evaporated and the residue taken up in dichloromethane (0.5 mL). Trifloroacetic acid (0.5 mL) was added in one portion and the resulting solution stirred for 1 h at room temperature. The volatiles were evaporated and the residue purified by mass directed auto-preparative HPLC to give the title compound as a white solid (6.0 mg, 27%). LC/MS: 3.43 min; z/e 444, calcd (M+1) 444. 1H NMR (400 MHz: CDCl3): 7.85 (2H), 7.70 (2H), 7.55 (1H), 7.50 (1H), 7.45 (2H), 7.30 (1H), 7.25 (4H), 3.85 (3H), 2.95 (1H), 2.75 (1H), 2.60 (1H), 2.20 (1H), 2.05 (1H), 1.90 (2H).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[CH2:9](Br)[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:9]([O:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCBr
Reactant: Cc1cccc(O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1cccc(C)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of 18.7 g (0.17 mol) of 6-hydroxy-2-methylpyridine (commercially available) and 24.0 g (0.17 mol) of n-butyl bromide dissolved in 100 ml of dimethylformamide was added 23.0 g (0.17 mol) of potassium carbonate, and the mixture was stirred at 90°-110° C. for 8 hours. To the mixture was added 300 ml of ice-water, and the mixture extracted with ethyl acetate, followed by a separation of the oily extract obtained by silica gel chromatography (ethyl acetate:hexane=7:97) to give 19.8 g of an oily substance (yield 69.9%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]([F:14])([F:13])[CH3:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([F:28])([F:27])([F:26])([F:25])[F:24])=[CH:19][CH:18]=1>C(O)C>[F:13][C:11]([C:9]1[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=[C:2]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([S:23]([F:28])([F:24])([F:25])([F:26])[F:27])=[CH:19][CH:18]=3)[N:7]2[N:8]=1)([F:14])[CH3:12]
Reactant: Cc1cc(Cl)n2nc(C(C)(F)F)nc2n1
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1
Solvent: CCO
Product: Cc1cc(Nc2ccc(S(F)(F)(F)(F)F)cc2)n2nc(C(C)(F)F)nc2n1
Temperature: 50 °C

Procedure:
A suspension of Intermediate 3 (5.84 g, 25.09 mmol) and 4-aminophenylsulfur pentafluoride (MANCHESTER, 5.5 g, 25.09 mmol) in ethanol (150 mL) was heated at 50° C. for 1 h. Heating resulted in the precipitation of a solid. The reaction mixture was concentrated under vacuum, redissolved in DCM (300 mL) and washed with aq. Na2CO3 (2×350 mL). The organic layer was dried over Na2SO4 and filtered. Then 8 g of silica gel were added and the mixture was concentrated under vacuum to dryness. The residue was purified (silica gel column, eluting with Hexane/EtOAc mixtures from 100:0 to 50:50%) to afford the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:18]([OH:20])=O)=[N:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1.CN(C)C=O.C(Cl)(=O)CC([Cl:30])=O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:18]([Cl:30])=[O:20])=[N:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1
Reactant: O=C(Cl)CC(=O)Cl
Reactant: Cn1nc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1nc(C(=O)Cl)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (939 mg, 2.413 mmol) in dichloromethane (60 mL) in the presence of dimethylformamide (8.0 mL) was cooled to 0° C. Malonyl chloride (1.26 mL, 14.48 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was evaporated and partitioned between ethyl acetate and 1M aqueous ammonium chloride. The aqueous layer was extracted 1× with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl chloride. This crude material was taken into the next step without further purification. MS (EI) for C12H8N3O2ClFI: 408 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:14]([CH:16]=3)[NH2:15])=[N:7][C:6]=2[CH:24]=1.[C:25]1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(OCC)(OCC)OCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]4[N:17]([CH:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)[CH:25]=[N:15][C:14]=4[CH:16]=3)=[N:7][C:6]=2[CH:24]=1
Reactant: Nc1cc(-c2nc3cc(Cl)ccc3o2)ccc1NC1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(OCC)OCC
Product: Clc1ccc2oc(-c3ccc4c(c3)ncn4C3CCOCC3)nc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 973.4 %

Procedure:
To a solution of 5-chloro-2-(2-(tetrahydropyran-4-yl)aminoanilin-5-yl)benzoxazole (see Working Example 100-2) (300 mg, 0.873 mmol) in triethyl orthoformate (5 mL) was added p-toluenesulfonic acid (10 mg), and this was stirred at 100° C. for 2 hours. After the reaction was complete, saturated aqueous sodium hydrogen carbonate solution was added, and this was extracted with chloroform. The organic layer obtained was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude crystals that were washed with diethyl ether and ethyl acetate to yield the title compound (200 mg, 65% yield) as brown crystals.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[N:27]1([S:32](Cl)(=[O:34])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[N:27]1([S:32]([N:21]2[CH2:20][CH2:19][C:16]3([C:15](=[O:24])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=4)[CH2:18][CH2:17]3)[CH2:23][CH2:22]2)(=[O:34])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=S(=O)(Cl)N1CCCC1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Solvent: CC(=O)O
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)N1CCCC1)CC2

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and pyrrolidine-1-sulfonyl chloride. Off-white solid. MS (ESI): 448.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=2)=[O:15])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH-].[Na+]>C1COCC1.Cl>[NH2:23][C:19]1[CH:18]=[C:17]([NH:16][C:14]([NH:13][CH2:12][CH2:11][CH2:10][NH:9][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=2)=[O:15])[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(NCCCNc1nc(Cl)ncc1Br)Nc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1cccc(NC(=O)NCCCNc2nc(Cl)ncc2Br)c1
Reaction time: 24 h

Procedure:
A solution of 1.71 g (3.98 mmol) of 1-[3-(5-bromo-2-chloro-pyrimidin-4-ylamino)-propyl]-3-(3-nitro-phenyl)-urea in 50 ml of THF is mixed at room temperature with 30 ml of a 15% solution of Ti(III)Cl in approximately 10% hydrochloric acid. After 24 hours, another 5 ml of the 15% solution of Ti(III)Cl in approximately 10% hydrochloric acid is added. After another 6 hours, the batch is made basic with 2N NaOH solution and extracted from ethyl acetate. The combined organic phases are filtered through a Whatman filter and concentrated by evaporation. The residue that is obtained is purified by chromatography (DCM/EtOH 9:1). 850 mg (2.13 mmol, corresponding to 54% of theory) of the product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:14]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:23])[C:17]=3[CH:16]=[CH:15]2)([CH2:12][CH3:13])[CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.CN1CCOCC1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[CH2:9][O:10][CH3:11])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(COC)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(COC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(2-(4-chlorophenyl)-1-methoxybutan-2-yl)-1H-indol-4-amine (30 mg) and 4-methylmorpholine (46 mg) in DCM (3 mL) was added methanesulfonyl chloride (16 mg) dropwise. Then the mixture was stirred at room temperature overnight. The solution was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by chromatography on silica gel (20-30% ethyl acetate in hexane) to afford the title compound as a white solid. LC/MS m/z=407.1 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[C:17]=2[F:24])=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(F)=C(F)C=2F)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:26]1([CH2:25][N:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[C:17]=2[F:24])[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:8][N:9]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2F)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: Fc1ccc(NCC2CCCC2)c(F)c1F
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2F)s1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(2,3,4-trifluoro-phenyl)ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(2,3,4-trifluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:10][CH2:9][CH:8]=[CH:7][CH:6]1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:4].[CH3:20][S:21]([NH:24][C:25]1[CH:40]=[CH:39][C:28]2[NH:29][C:30]([CH2:35][C:36](O)=[O:37])=[N:31][S:32](=[O:34])(=[O:33])[C:27]=2[CH:26]=1)(=[O:23])=[O:22].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[O-]CC.[Na+].Cl>CN(C)C=O.C(OCC)(=O)C.C(O)C>[F:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:11]2[CH:6]3[CH:5]([CH2:10][CH2:9][CH:8]=[CH:7]3)[C:3]([OH:4])=[C:35]([C:30]3[NH:29][C:28]4[CH:39]=[CH:40][C:25]([NH:24][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:26][C:27]=4[S:32](=[O:33])(=[O:34])[N:31]=3)[C:36]2=[O:37])=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: COC(=O)C1CCC=CC1NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)C3CCC=CC3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 60 °C
Yield: 24.2 %

Procedure:
2-(4-Fluoro-benzylamino)-cyclohex-3-enecarboxylic acid methyl ester (0.051 g, 0.19 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 mL). (7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.065 g, 0.19 mmol) was added followed by N-methylmorpholine (0.05 mL, 0.43 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.041 g, 0.21 mmol) was added and the mixture was stirred at 25° C. for 3 h. The solution was diluted with ethyl acetate (25 mL) and washed with 1.0 M aqueous hydrochloric acid solution (2×25 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. The oil was dissolved in ethanol (4 mL) and a 21% w/w solution of sodium ethoxide in ethanol (0.3 mL, 0.8 mmol) was added, and the reaction mixture was heated to 60° C. for 2 h. Upon cooling to 25° C., the reaction mixture was acidified to pH 2-3 with 2.0 M aqueous hydrochloric acid solution, upon which the product precipitated while stirring. The solid was collected by vacuum filtration and purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-95% in 9 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2,4a,5,6,8a-hexahydro-quinolin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.025 g, 0.046 mmol, 25%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.65-2.24 (4H, m), 3.04 (3H, s), 4.10-4.21 (1H, m), 5.01 (1H, d, J=16.0 Hz), 5.45 (1H, d, J=10.0 Hz), 5.86 (1H, d, J=8.8 Hz), 7.16 (2H, dd, J=8.8 Hz), 7.42 (2H, m), 7.51 (1H, m), 7.57 (12H, m), 10.20 (1H, s). LC-MS (ESI) calcd for C24H23FN4O6S2 546.10, found 547.3 [M+H+].
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.[Cl:13][C:14]1[C:15]([NH2:20])=[N:16][CH:17]=[CH:18][N:19]=1>C(#N)C.CC(O)C>[Cl:13][C:14]1[C:15]2[N:16]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=3[F:12])[N:20]=2)[CH:17]=[CH:18][N:19]=1
Reactant: Nc1nccnc1Cl
Reactant: O=C(CBr)c1ccc(F)cc1F
Solvent: CC#N
Solvent: CC(C)O
Product: Fc1ccc(-c2cn3ccnc(Cl)c3n2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
A mixture of 2-bromo-1-(2,4-difluorophenyl)ethanone (107.31 g, 442.89 mmol) and 3-chloropyrazin-2-amine (98.00 g, 756.5 mmol) in ACN (800 mL) was stirred at reflux for about 20 h. The reaction mixture was cooled to about 25° C. before the resultant solid was collected. The filtrate solvent was removed in vacuo to yield a brown solid. This filtration was done to negate the bumping associated with the removal of the ACN. The combined solids were then suspended in water (750 mL) and basified, whilst stirring, with 2N NaOH (750 mL). After about 30 min, the product was partitioned between DCM (9×1000 mL) and filtered from the insoluble material to aid extraction process. The organic extracts were combined and stirred with 2.5N HCl (4×750 mL). The organic layer was finally washed with 2.0N NaOH (500 mL) and water (2×500 mL), dried over MgSO4, and filtered through a Florisil® pad (3 inch diameter×3 inch depth) to remove origin material. The Florisil® pad was washed with repeated amounts of solvent until no product was detected by TLC. The organic solvent was removed in vacuo to yield a yellow solid. The solid was suspended in IPA (200 mL) at about 80° C. for about 15 min and then cooled to about 20° C. The solid was collected and washed with ice-cold IPA (2×40 mL), followed by petroleum ether [bp 30-60° C.] (3×80 mL) to remove impurities. The solid was dried in vacuo at about 70° C. overnight to yield the title compound as a yellow powdery solid (69.75 g, 57%): LC/MS (Table 1, Method g) Rt=2.70 min; MS m/z: 266.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[O:15]([C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=1)[CH:25]=[CH:26][C:27](O)=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:27](/[CH:26]=[CH:25]/[C:24]3[CH:30]=[CH:31][CH:32]=[C:22]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:23]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: O=C(O)C=Cc1cccc(Oc2ccccc2)c1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(Oc4ccccc4)c3)nc2n(CC)c1=O
Yield: 62.9 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 4.00 g (16.7 mmol) of 3-phenoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 3.82 g (yield 63%) of Compound 182 as pale yellow needles.