Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][CH:8]=[CH2:9])[CH:5]=[O:6])[CH2:2][CH3:3].[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([CH:4]([CH2:7][CH2:8][CH3:9])[CH:5]=[O:6])[CH2:2][CH3:3]
Reactant: C=CCC(C=O)CCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC(C=O)CCC

Procedure:
A Parr hydrogenation bottle was charged with 10% palladium on carbon (0.1 equivalent) and ethyl acetate. A solution of 2-propylpent 4 enal, prepared as in Example 5, in ethyl acetate was added. The mixture was hydrogenated at 300N/m2 hydrogen in a Parr hydrogenation apparatus at room temperature until hydrogen uptake ceased. The catalyst was removed by filtration through celite. The filtrate was concentrated to give the desired product as a colorless oil. The product was used without further purification.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43](O)=[O:44])=[CH:31][CH:32]=2)[N:27]=1.C(N(CC)C(C)C)(C)C.[NH2:55][C@@H:56]([CH2:61][C:62]1[CH:67]=[CH:66][C:65]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)=[CH:64][CH:63]=1)[C:57]([O:59][CH3:60])=[O:58]>CN(C)C=O>[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]2)[C:33]2[C:28](=[CH:29][C:30]([C:43]([NH:55][C@@H:56]([CH2:61][C:62]3[CH:67]=[CH:66][C:65]([C:68]4[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=4)=[CH:64][CH:63]=3)[C:57]([O:59][CH3:60])=[O:58])=[O:44])=[CH:31][CH:32]=2)[N:27]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc2c(N3CCN(C)CC3)nc(N)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.6 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (42 mg, 0.11 mmol) was added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (20 mg, 0.07 mmol) in N,N-dimethylformamide (2 mL) and N,N-diisopropylethylamine (24 uL, 0.14 mmol). The methyl (2S)-2-amino-3-biphenyl-4-ylpropanoate (36 mg, 0.14 mmol) was added. The reaction was stirred for 2 h. at r.t., and was purified by RP-HPLC (pH=2) to afford the desired product (5 mg, 10%) as a white solid TFA salt. Analytical LCMS (M+H)+: m/z=525.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=2[C:22]#[N:23])(=[O:19])=[O:18])=[CH:13][CH:12]=1.[OH-:28].[Na+].O.Cl>C(O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][C:14]([S:17]([C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=2[C:22]([NH2:23])=[O:28])(=[O:18])=[O:19])=[CH:15][CH:16]=1
Reactant: [OH-]
Reactant: N#Cc1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)cc1
Temperature: 78 °C
Yield: 52 %

Procedure:
2-({4-[(E)-2-(2,4-Difluorophenyl)vinyl]phenyl}sulfonyl)benzonitrile (Example 47, 100 mg, 0.26 mmol) was dissolved in ethanol (0.26 mL) and 4N sodium hydroxide (0.11 mL, 0.26 mmol) was added. The reaction was heated to 78° C. for 12 hours. After cooling, water and ethyl acetate were added. The aqueous layer was acidified with HCl and extracted with ethyl acetate (×2). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with ethyl acetate, to yield the title compound as a white solid (54 mg, 52%). δH (400 MHz, d6 DMSO): 8.09 (1H, dd, J=0.9, 7.8 Hz), 7.99 (2H, d, J=8.5 Hz), 7.95 (1H, s), 7.86 (1H, q, J=8.2 Hz), 7.80 (2H, d, J=8.5 Hz), 7.74–7.62 (2H, m), 7.58 (1H, s), 7.47–7.27 (4H, m), 7.15 (1H, td, J=1.7, 8.5 Hz); m/z (ES+) 400 [MH+], 383 [(MH+)-17].
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:10][C@@H:11]1[C@@H:19]([CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:18](=[O:27])[O:17][CH2:16][C@H:15]([NH:28][C:29](=[O:39])[C:30]2[C:35]([OH:36])=[C:34]([O:37][CH3:38])[CH:33]=[CH:32][N:31]=2)[C:14](=[O:40])[O:13][C@H:12]1[CH3:41])(=[O:9])[CH:6]([CH3:8])[CH3:7].N1C=CC=CC=1>C(Cl)Cl>[C:5]([O:10][C@@H:11]1[C@@H:19]([CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:18](=[O:27])[O:17][CH2:16][C@H:15]([NH:28][C:29](=[O:39])[C:30]2[C:35]([O:36][C:1](=[O:3])[CH3:2])=[C:34]([O:37][CH3:38])[CH:33]=[CH:32][N:31]=2)[C:14](=[O:40])[O:13][C@H:12]1[CH3:41])(=[O:9])[CH:6]([CH3:7])[CH3:8]
Reactant: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](CC3CCCCC3)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](CC3CCCCC3)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1OC(C)=O
Temperature: 22 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
Acetyl chloride (9 μL, 0.125 mmol) was added to a solution of (3S,6S,7R,8R)-8-(cyclohexylmethyl)-3-(3-hydroxy-4-methoxypicolinamido)-6-methyl-4,9-dioxo-1,5-dioxonan-7-yl isobutyrate (50 mg, 0.100 mmol) and pyridine (40 μL, 0.480 mmol) in CH2Cl2 (1 mL), and the reaction was stirred at ambient temperature (about 22° C.) overnight. The solution was loaded directly onto a pre-packed SiO2 column for purification by column chromatography (0→30% EtOAc/CH2Cl2) to afford the title compound (28 mg, 52%) as a white solid: mp 164-170° C.; 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J=7.5 Hz, 1H), 8.35 (d, J=5.4 Hz, 1H), 7.03 (d, J=5.5 Hz, 1H), 5.47 (br s, 1H), 5.25-5.11 (m, 1H), 5.03 (t, J=9.9 Hz, 1H), 4.97-4.84 (m, 1H), 3.92 (s, 3H), 3.72 (br s, 1H), 2.69 (dd, J=16.8, 7.0 Hz, 1H), 2.60 (sept, J=14.0, 7.0 Hz, 1H), 2.40 (s, 3H), 1.83-1.54 (m, 6H), 1.36-1.02 (m, 14H), 0.94-0.67 (m, 2H); HRMS-ESI (m/z): calcd for C28H38N2O10, 562.2526; found, 562.2516.
Reaction SMILES: [F:1][C:2]1[CH2:7][CH2:6][CH:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]2)[CH2:4][CH:3]=1.[F:17][C:18]1[CH:23]=[C:22]([CH2:24][CH2:25][CH3:26])[CH:21]=[C:20]([F:27])[C:19]=1O.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[F:17][C:18]1[CH:23]=[C:22]([CH2:24][CH2:25][CH3:26])[CH:21]=[C:20]([F:27])[C:19]=1[O:15][C:14]([C@H:11]1[CH2:10][CH2:9][C@H:8]([CH:5]2[CH2:6][CH2:7][C:2]([F:1])=[CH:3][CH2:4]2)[CH2:13][CH2:12]1)=[O:16]
Reactant: CCCc1cc(F)c(O)c(F)c1
Reactant: O=C(O)[C@H]1CC[C@H](C2CC=C(F)CC2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCc1cc(F)c(OC(=O)[C@H]2CC[C@H](C3CC=C(F)CC3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The crude product from b), 0.79 g of 1-fluoro-4-(trans-4-carboxycyclohexyl)cyclohex-l-ene, was cooled to 0°C. under nitrogen together with 0.66 g of 2,6-difluoro-4-propylphenol and 60 mg of dimethylaminopyridine in 10 ml of methylene chloride and treated within 45 minutes with a solution of 1.0 g of dicyclohexyl-carbodiimide in 5 ml of methylene chloride. After stirring at room temperature for 30 minutes the white suspension was filtered over a Celite/silica gel pad. The filtrate was evaporated completely and gave 1.5 g of trans-4-(1-fluoro-cyclohex- 1 -en-4-yl)cyclohexanecarboxylic acid 2,6-difluoro-4-propylphenyl ester, which gave 0.62 g of white crystals by repeated recrystallization from hexane. M.p. (C/N) 58.40°C., c.l.p. (N/I) 96.1°C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1.[C@H:18]12[CH2:24][C@H:21]([NH:22][CH2:23]1)[CH2:20][N:19]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(CC)CC)C>C(#N)C>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([N:7]2[C:3]([CH2:2][N:22]3[CH2:23][C@@H:18]4[CH2:24][C@H:21]3[CH2:20][N:19]4[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[N:4][N:5]=[N:6]2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: FC(F)(F)c1ccc(-n2nnnc2CCl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2Cc1nnnn1-c1ccc(C(F)(F)F)cc1
Temperature: 120 °C

Procedure:
To a solution of 5-(chloromethyl)-1-[4-(trifluoromethyl)phenyl]-1H-tetrazole (500 mg, 1.90 mmol, commercially available from UkrOrgSynthesis, Kiev, Ukraine) in acetonitrile (10 mL) was added 1,1-dimethylethyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (377 mg, 1.90 mmol, commercially available, for example from Sigma Aldrich Corporation) and triethylamine (0.796 mL, 5.71 mmol). The mixture was then heated to 120° C. for 20 min in a microwave reactor.
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[Cl:9][C:10]1=[C:11]([Cl:17])[C:12]([O:14][C:15]1=O)=[O:13].C(O)(=O)C>CCOCC>[CH:1]1([N:8]2[C:15](=[O:14])[C:10]([Cl:9])=[C:11]([Cl:17])[C:12]2=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: NC1C=CCCCC1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C1C(Cl)=C(Cl)C(=O)N1C1C=CCCCC1
Yield: 70.7 %

Procedure:
A mixture of 2-cycloheptenylamine (1.01 g), dichloromaleic anhydride (1.67 g) and acetic acid (10 ml) was heated under reflux for 3 hours. After cooling, ether (20 ml) was added to the reaction mixture which was then washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous sodium chloride solution in this order. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The deposited crystal was purified by recrystallization from hexane to obtain 1.67 g of N-(2-cycloheptenyl)dichloromaleinimide [Compound (217)].
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([S:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)[CH2:8][CH2:9][CH3:10])[CH3:7]
Reactant: COc1ccc(S)cc1
Reactant: CCCC(Br)C(=O)OCC
Product: CCCC(Sc1ccc(OC)cc1)C(=O)OCC

Procedure:
2-(4-Methoxy-phenylsulfanyl)-pentanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl 2-bromovalerate (8.23 g, 39.3 mmol) and 4-methoxythiophenol (5 g, 35.7 mmol), 10.46 g (100%); clear oil; MS: 269 (M+H)+.
Reaction SMILES: [Al].[Li].[Si:3]([O:10][C:11]1[CH:12]=[C:13]([CH:20]=[CH:21][CH:22]=1)[C:14]([O:16][CH2:17][CH2:18][Cl:19])=O)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH:23]12[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[C:24]1=O)[CH2:30]2>[Cl-].[Cl-].[Cl-].[Ti+3].C(OCC)(=O)C.CCCCCC>[Si:3]([O:10][C:11]1[CH:12]=[C:13]([C:14](=[C:24]2[CH:25]3[CH2:31][CH:29]4[CH2:28][CH:27]([CH2:32][CH:23]2[CH2:30]4)[CH2:26]3)[O:16][CH2:17][CH2:18][Cl:19])[CH:20]=[CH:21][CH:22]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)OCCCl)c1
Agent: [Ti+3]
Agent: [Al]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(OCCCl)=C2C3CC4CC(C3)CC2C4)c1
Temperature: 25 °C
Yield: 77 %

Procedure:
##STR34## A 100 mL three-necked flask fitted with a reflux condenser, was dried by means of a hot air gun and nitrogen purging. This was charged with dry THF 200 mL and cooled in an ice-bath. Titanium trichloride (24.5 g, 0.16 mol) followed by lithium aluminum hyride (3.0 g, 0.08 mol) was added in small portions with vigorous stirring. The cooling bath was removed and the black mixture was allowed to warm to room temperature. Triethylamine (15 mL) was added dropwise and the reaction mixture was refluxed for 1 hour. A solution of 2-chloroethyl 3-(tert-butyldimethylsilyloxy)benzoate (5.0 g, 0.015 mol) and adamantanone (7.1 g, 0.05 mol) was added dropwise to the refluxing mixture over a 1 hour period. TLC analysis (ethyl acetate/hexane, 10:90) after 1 hour of refluxing showed conversion to a new material. The reaction mixture was cooled, extracted with hexane. After the evaporation of solvent, the crude material was chromatographed using (ethyl acetate/hexane, 3:97) to give 5.0 g (74%) of alkene 7 as a white oil: 1H NMR (CDCl3) δ 0.194 (s, 6H), 0.982 (s, 9H), 1.78-1.98 (m, 12H), 2.65 (bs, 1H), 3.34 (bs, 1H), 3.55 (t, 2H, J=5.7 Hz), 3.66 (t, 2H, J=5.7 Hz), 6.85-7.29 (m, 4H); 13C NMR (CDCp3) δ -4.46, 18.21, 25.66, 28.28, 30.20, 32.39, 38.94, 39.20, 42.61, 68.95, 119.62, 121.04, 122.50, 129.09, 132.78, 136.40, 141.11, 155.49; MS m/e (rel. intensity) 432 (100) 331 (22), 235 (13), 199 (10), 151 (19), 105 (17), 73 (44), 57 (14); MS exact mass: calcd. 432.2251, found 432.2247.
Reaction SMILES: O[CH:2]([NH:7][C:8](=[O:17])[C:9]1[C:10](=[CH:12][CH:13]=[C:14]([Cl:16])[CH:15]=1)[OH:11])[C:3](Cl)([Cl:5])[Cl:4]>C(O)(=O)C.[Zn]>[Cl:5][C:3]([Cl:4])=[CH:2][NH:7][C:8](=[O:17])[C:9]1[C:10](=[CH:12][CH:13]=[C:14]([Cl:16])[CH:15]=1)[OH:11]
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1cc(Cl)ccc1O
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C(NC=C(Cl)Cl)c1cc(Cl)ccc1O
Temperature: 80 °C
Reaction time: 4 h
Yield: 116.7 %

Procedure:
Thirty (30) g (0.09 mol) of N-(1'-hydroxy-2',2',2'-trichloroethyl)-5-chlorosalicylamide were dissolved in 150 ml of acetic acid. Nine point two (9.2) g (0.14 mol) of zinc powder were added into the solution under stirring at the temperature from 20° to 40° C and the reaction was continued for 4 hours at the same temperature. The temperature was finally raised at 80° C and then excess zinc was removed by filtration. The filtrate was cooled to obtain 28 g of crystals of N-(2',2'-dichlorovinyl)-5-chlorosalicylamide was obtained. Melting point of it was 208°-210° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[C:27]#[CH:28]>>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[C:27]#[C:28][C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1c(Cl)cccc1Cl
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Product: O=C(NCCC(O)c1cccc(C#Cc2c(Cl)cccc2Cl)c1)C(F)(F)F

Procedure:
Sonogashira reaction of 25 with 1,3-dichloro-2-ethynyl-benzene gave N-(3-(3-(2-(2,6-dichlorophenyl)ethynyl)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide as dark brown oil. Yield (0.32 g, 37%). This compound could not be separated completely from the starting bromide and was used directly in the step.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:11])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[BrH:16]>O.[Cu]Br>[Br:16][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: Br
Reactant: Nc1ccc2c(c1)C(=O)OC2
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C1OCc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 84 %

Procedure:
6-Amino-1(3H)-isobenzofuranone (3.0 g, 20 mmol) obtained from Example 26-(1) was dissolved in a mixture of 47% aqueous hydrobromic acid solution (15 ml) and water (15 ml), then the mixture was cooled to 0° C., and a solution of sodium nitrite (1.45 g, 21 mmol) in water (7 ml) was slowly added thereto. Further, a solution of copper (I) bromide (3.6 g, 25 mmol) dissolved in 47% aqueous hydrobromic acid solution (10 ml) was added to the reaction mixture, and the resulting mixture was stirred at 80° C. for 20 minutes. After cooling the mixture, the liberated product was collected by filtration and then washed with water. The obtained pale brown solid was dissolved in ethyl acetate, then the insoluble material was removed by filtration, and the filtrate was washed successively with a 1N aqueous solution of hydrochloric acid, an aqueous solution of sodium hydrogen carbonate, and an aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to afford the title compound (3.57 g, 84% yield) as a crystalline solid.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].Cl[C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[CH:13][C:12]=1[N+:24]([O-:26])=[O:25].Cl.[N+](=C)([O-])[O-]>C1COCC1.O>[C:15]([C:14]1[CH:22]=[CH:23][C:11]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[C:12]([N+:24]([O-:26])=[O:25])[CH:13]=1)([OH:17])=[O:16]
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)CC(=O)OC
Agent: C=[N+]([O-])[O-]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Yield: 87.3 %

Procedure:
Sodium hydride (13.5 g of a 60% dispersion in oil, 0.34 mol) was washed with petroleum ether (×3) under nitrogen and suspended in dry THF (400 mL). A solution of dimethyl malonate (40.4 mL, 0.35 mol) in THF (50 mL) was added dropwise over 45 min with water-bath cooling, keeping the internal temperature below 30° C., and the resulting gel was broken up with more dry THF (300 mL). The above t-Butyl 4-chloro-3-nitrobenzoate (21.7 g, 84 mmol) was added and the mixture was stirred at reflux under nitrogen for 15 h. The red-brown solution was cooled, poured into water, and aqueous HCl (2 N, ca. 60 mL) added slowly until the red nitronate color was dispersed. The THF was evaporated and the aqueous phase extracted with CH2Cl2 (×3), the extracts were dried (Na2SO4) and evaporated. Formic acid (100 mL) was added to the residue and the mixture was stirred at 50° C. for 4 h (when tlc analysis showed no remaining t-butyl ester). The formic acid was evaporated and the residue was taken up in EtOAc and washed with water (×3). The organic layer was extracted with aqueous NaHCO3 (×2), and the aqueous phase was acidified (conc. HCl), and extracted with CH2Cl2 (×2). The organic layer was dried (Na2SO4), evaporated, and the resulting cream solid recrystallized from benzene (ca. 250 mL) to give dimethyl (4-carboxy-2-nitrophenyl)malonate as cream prisms (21.8 g, 87%), mp 147-149° C. 1H NMR ((CD3)2SO) d 13.77 (br s, 1 H, CO2H), 8.52 (d, J=1.7Hz, 1 H, H-3), 8.28 (dd, J=8.1, 1.7 Hz, 1 H, H-5), 7.70 (d, J=8.1 Hz, 1 H, H-6), 5.62 (s, 1 H, ArCH), 3.71 (s, 6 H, CO2Me); 13C NMR ((CD3)2SO) d 166.9, 165.1, 148.2, 134.0, 133.1, 132.3, 132.1, 125.5 (CO2Me, C-1,2,3,4,5,6), 54.3 (ArCH), 52.9 (OMe). Anal. Calculated for C12H11NO8 : C, 48.5; H, 3.7; N, 4.7. Found: C, 48.7; H, 3.5; N, 4.7%.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([NH:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[CH2:11]([N:18]([CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[Cl:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](C)(C)OCCNCc1ccccc1
Reactant: O=C(O)c1cccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCN(Cc1ccccc1)C(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 58.3 %

Procedure:
To a solution of 2-chloronicotinic acid (7.88 g), N-benzyl-2-{[tert-butyl(dimethyl)silyl]oxy}ethanamine (13.3 g) synthesized by known method (e.g., the method described in WO99/31085) and HOBt-H2O (11.5 g) in DMF (50 mL) was added WSC.HCl (14.4 g), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 10→33% ethyl acetate/hexane) to give N-benzyl-N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-chloronicotinamide (11.8 g, 58%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[C:11]2[CH:12]=[C:13]([N:16]3[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[NH:18][C:17]3=[O:27])[CH:14]=[CH:15][C:10]=2[S:9][N:8]=1.[C:28](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:28][N:18]1[C:19]([C:23]([F:26])([F:25])[F:24])=[CH:20][C:21](=[O:22])[N:16]([C:13]2[CH:14]=[CH:15][C:10]3[S:9][N:8]=[C:7]([C:3]4[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=4)[C:11]=3[CH:12]=2)[C:17]1=[O:27]
Reactant: Cn1cccc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cccc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 0 °C
Yield: 21.5 %

Procedure:
To a mixture of 3-[3-(1-methylpyrrol-2-yl)-1,2-benzisothiazol-5-yl]-6-(trifluoromethyl)uracil(1.35 g, 3.44 mmol), dry dimethylformamide and potassium carbonate (0.710 g, 5.14 mmol) is added iodomethane (0.730 g, 5.14 mmol). The resultant mixture is stirred overnight at room temperature and poured into ice water. Filtration and drying affords the title compound as a pink foam (0.300 g, 21.4%) which is identified by NMR spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([NH:23][S:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[C:10]1[S:14][C:13]([NH:15]C(=O)OC(C)(C)C)=[N:12][CH:11]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:15][C:13]1[S:14][C:10]([C@H:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[NH:23][S@@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])=[CH:11][N:12]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc([C@H](NS(=O)C(C)(C)C)c2ccc(F)cc2Cl)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)N[C@H](c1cnc(N)s1)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
To a solution of (R)-tert-Butyl 5-((2-chloro-4-fluorophenyl)(1,1-dimethylethylsulfinamido)methyl)thiazol-2-ylcarbamate (1.6 g, 3.5 mmol) in CH2Cl2 (6 mL) was added TFA (6 mL). The reaction was stirred at room temperature for 2 h. The TFA and CH2Cl2 were removed under vacuum. The crude product was re-dissolved in CH2Cl2, washed with aqueous NaHCO3 solution, dried over MgSO4 and concentrated. The crude product was recrystallized from EtOAc to provide (R)-N-((S)-(2-aminothiazol-5-yl)(2-chloro-4-fluorophenyl)methyl)-2-methylpropane-2-sulfinamide as colorless solid (672 mg, 53%). 1H NMR (400 MHz, CDCl3) δ 7.56 (dd, J=8.7, 5.9 Hz, 1H), 7.16 (dd, J=8.4, 2.6 Hz, 1H), 7.06 (td, J=8.2, 2.6 Hz, 1H), 6.89 (d, J=0.8 Hz, 1H), 6.07 (d, J=4.6 Hz, 1H), 5.22 (d, J=2.9 Hz, 2H), 4.06 (d, J=4.6 Hz, 1H), 1.28 (s, 9H); HPLC ret. time 2.28 min, 10-99% CH3CN, 5 min run; ESI-MS 362.3 m/z (MH+).
Reaction SMILES: C(N)C1C=CC=CC=1.[N:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1.[F:17][C:18]1[CH:40]=[CH:39][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[CH:29]=[C:30]([CH:35]=[CH:36][N:37]=3)[C:31](OC)=[O:32])[C:24]2=[O:38])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[CH:29]=[C:30]([CH:35]=[CH:36][N:37]=3)[C:31]([NH:16][CH2:15][C:12]3[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=3)=[O:32])[C:24]2=[O:38])=[CH:39][CH:40]=1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: NCc1ccncc1
Solvent: NCc1ccccc1
Product: O=C(NCc1ccncc1)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 42 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace benzylamine with pyridin-4-ylmethanamine to react with methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate, 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(pyridin-4-ylmethyl)isonicotinamide was obtained as a colorless solid in 42% yield: mp 205-207° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.33 (t, J=6.0 Hz, 1H), 8.62 (s, 1H), 8.49-8.47 (m, 2H), 8.39 (d, J=5.4 Hz, 1H), 7.37-7.26 (m, 5H), 7.18-7.13 (m, 2H), 4.47 (d, J=5.7 Hz, 2H), 4.39 (s, 2H), 3.94 (t, J=7.5 Hz, 2H), 3.38-3.32 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 165.9, 160.4, 156.8, 153.6, 150.1, 148.6, 143.1, 133.6, 133.6, 130.4, 130.3, 122.6, 116.0, 115.7, 115.2, 110.4, 46.6, 42.3, 41.6, 41.2; MS (ES+) m/z 406.0.