Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2([CH3:15])[CH2:14][O:13]2)=[O:11])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O-:29])=[O:28])=[CH:23][CH:22]=1.[Na+]>C(Cl)(Cl)Cl.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:15][C:12]([OH:13])([C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:5]=1)=[O:11])[CH2:14][S:27]([C:24]1[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=1)(=[O:29])=[O:28]
Reactant: CC1(C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)CO1
Reactant: O=S([O-])c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(O)(CS(=O)(=O)c1ccc(F)cc1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
0.500 g of the epoxyamide (5A) was dissolved in a mixture of 40 ml of chloroform and 40 ml of water and 371 mg of sodium p-fluorobenzenesulfinate was added. Subsequently, 298 mg of tetrabutylammonium bromide was added. The reaction mixture was heated till reflux, while stirring vigorously. The reaction was monitored with HPLC. After 96 hours of reflux, the reaction mixture was cooled to room temperature. 20 ml of chloroform was added and the organic layer was washed with 3×50 ml of water, dried (Na2SO4) and evaporated to dryness. Yield: 860 mg. Purification of the crude product by column chromatography (Merck silica gel 60; eluent: heptane/ethyl acetate=1/1) afforded bicalutamide as white solid. Isolated yield: 380 mg (48%). 1H-NMR: confirmed the structure.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7](O)=[O:8])=[C:5]([CH3:10])[N:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[N:3]=1.[N:22]1([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:1][C:2]1[C:6]([C:7]([N:30]2[CH2:31][CH2:32][CH:27]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:28][CH2:29]2)=[O:8])=[C:5]([CH3:10])[N:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=2)[N:3]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1nn(-c2ccc(OC(F)(F)F)cc2)c(C)c1C(=O)O
Product: Cc1nn(-c2ccc(OC(F)(F)F)cc2)c(C)c1C(=O)N1CCC(N2CCCC2)CC1
Yield: 95 %

Procedure:
In analogy to the procedure described in Example 18], 3,5-dimethyl-1-(4-trifluoromethoxy-phenyl)-1H-pyrazole-4-carboxylic acid and 4-pyrrolidine-1-yl-piperidine gave the title compound in 95% yield as light brown solid. MS: 437.2 (MH+).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([O:12][C:13]2[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)[CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:56][C:57]1[CH:58]=[C:59]([S:63]([NH2:66])(=[O:65])=[O:64])[CH:60]=[N:61][CH:62]=1>CN(C=O)C>[S:63]([C:59]1[CH:58]=[C:57]([NH:56][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:23])([F:24])[F:1])=[CH:4][C:5]=2[O:12][C:13]2[CH:14]=[N:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=2)[CH:62]=[N:61][CH:60]=1)(=[O:65])(=[O:64])[NH2:66]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1Oc1ccc(C(F)(F)F)nc1
Reactant: Nc1cncc(S(N)(=O)=O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1cncc(NC(=O)c2ccc(C(F)(F)F)cc2Oc2ccc(C(F)(F)F)nc2)c1
Temperature: 25 °C

Procedure:
A solution of 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyridin-3-yloxy)benzoic acid (28 mg, 81 μmol), HATU (31 mg, 81 μmol), and Et3N (11 μL, 81 μmol) in DMF (1.0 mL) was stirred at room temperature for 5 min, then 5-aminopyridine-3-sulfonamide (14 mg, 81 μmol) was added. The reaction was stirred at room temperature then overnight at 70° C. The reaction was purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) to give N-(5-sulfamoylpyridin-3-yl)-4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyridin-3-yloxy)benzamide. LC/MS: m/z 507.3 (M+H)+ at 1.61 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[N:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[N:14][CH:15]=3)[N:10]([S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])[CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(c2c[nH]c3ccncc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(c2cn(S(=O)(=O)c3ccccc3)c3ccncc23)CC1

Procedure:
from 3-(1-methyl-4-piperidinyl)-5-azaindole (20 mg, 0.094 mmol), benzenesulfonyl chloride (24 μL, 0.188 mmol) and 1M NaN(TMS)2 (250 μL, 0.25 mmol) in THF (1 mL) at RT.
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])[C@@H:44](/[CH:60]=[CH:61]/[C:62]([N:64]2[CH2:68][CH2:67][C@H:66]([NH:69][C:70]([O:72][CH2:73][C:74]3[CH:79]=[CH:78][C:77]([N+:80]([O-:82])=[O:81])=[CH:76][CH:75]=3)=[O:71])[CH2:65]2)=[O:63])[CH2:43]1>C(#N)C.C(N(C(C)C)CC)(C)C>[N+:57]([C:54]1[CH:53]=[CH:52][C:51]([CH2:50][O:49][C:47]([N:45]2[CH2:46][C@@H:42]([S:41][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[CH2:43][C@@H:44]2/[CH:60]=[CH:61]/[C:62]([N:64]2[CH2:68][CH2:67][C@H:66]([NH:69][C:70]([O:72][CH2:73][C:74]3[CH:75]=[CH:76][C:77]([N+:80]([O-:82])=[O:81])=[CH:78][CH:79]=3)=[O:71])[CH2:65]2)=[O:63])=[O:48])=[CH:56][CH:55]=1)([O-:59])=[O:58]
Reactant: O=C(N[C@H]1CCN(C(=O)/C=C/[C@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@H](/C=C/C(=O)N4CC[C@H](NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 24 h
Yield: 70.5 %

Procedure:
To a solution of 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (1.01 g) in anhydrous acetonitrile (10 ml), a solution of (2R,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-(4-nitrobenzyloxycarbonylamino)pyrrolidin-1-ylcarbonyl-(E)-ethenyl]-pyrrolidine (972 mg) in anhydrous acetonitrile (10 ml) and diisopropylethylamine (0.296 ml) were added under ice cooling. The resulting mixture was allowed to stand at the same temperature for one day. The reaction mixture was concentrated by evaporation under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed successively with water and saline and then dried over anhydrous sodium sulfate. The solvent was distilled off. The residue was subjected to chromatography on a silica gel column and eluted with methylene chloride-acetone of ratio from (6:1) to (1:1). Desired fractions were combined, followed by distilling off, whereby 4-nitrobenzyl (1R,5S,6S)-2-[(2R,4S)-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-(4-nitrobenzyloxycarbonylamino)pyrrolidin-1-ylcarbonyl-(E)-ethenyl]pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (1.079 g) was obtained as a powder.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1>CN(C=O)C>[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Sc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CSc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a mixture of benzenethiol (1.3 mL, 13.1 mmol) and potassium tert-butoxide (1.47 g, 13.1 mmol) in DMF (50 mL) at 0° C. was added 4-(bromomethyl)benzoic acid methyl ester (3.0 g, 13.1 mmol), and the mixture was stirred at room temperature for 1 hour. After stirring at 80-90° C. overnight, the reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in water (30 mL) and extracted with CH2Cl2 (200 mL). The organic layer was dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by MPLC on silica gel (10% EtOAc in hexanes) to afford the titled compound (2.74 g, 81%) as a white solid.
Reaction SMILES: C(O[CH:4]([OH:9])[C:5]([F:8])([F:7])[F:6])C.[C:10]1([CH3:19])[CH:15]=[CH:14][C:13]([C:16]([NH2:18])=[O:17])=[CH:12][CH:11]=1.O1CCOCC1>C(OCC)(=O)C>[CH3:19][C:10]1[CH:15]=[CH:14][C:13]([C:16]([NH:18][CH:4]([OH:9])[C:5]([F:6])([F:7])[F:8])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(C(N)=O)cc1
Reactant: CCOC(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
A 500 mL round-bottom flask was charged with trifluoroacetaldehyde ethyl hemiacetal (12.3 g, 85.0 mmol), p-toluamide (10.0 g, 74.0 mmol), and dioxane (150 mL). The thick white slurry was stirred at ambient temperature for 3 hours, then heated at reflux for 44 hours. The homogeneous solution was cooled and concentrated in vacuo to provide a white solid. The crude material was dissolved in ethyl acetate (50 mL), adsorbed onto silica gel (50 g), and eluted through a medium porosity fritted filter funnel (elution with 25% ethyl acetate/hexanes, then ethyl acetate) to provide 14.1 g of the desired product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:12]#[N:13].F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].[H-].[Na+]>O1CCCC1>[F:11][C:8]1[CH:9]=[CH:10][C:4]2[C:3]([C:12]#[N:13])=[C:2]([NH:1][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:21]([O-:23])=[O:22])[S:6][C:5]=2[CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: N#Cc1c(N)sc2cc(F)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c(Nc2ccccc2[N+](=O)[O-])sc2cc(F)ccc12
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
To a solution of 2-amino-6-fluorobenzo[b]thiophene-3-carbonitrile (15 g), tetrahydrofuran (140 ml) and 2-fluoronitrobenzene (11.3 g) was added portionwise 60% sodium hydride (3.5 g) under ice-cooling and the mixture was stood still at 5° C. for 30 minutes. The precipitated crystals were filtered by suction, washed with isopropyl ether (120 ml) and dried to give 6-fluoro-2-(2-nitroanilino)benzo[b]thiophene-3-carbonitrile (8.0 g).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(O)C.[O:8]1[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:9]1>O>[OH:2][CH2:1][CH2:3][NH:4][CH2:9][CH:10]([OH:8])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCCC1CO1
Reactant: NCCO
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCC(O)CNCCO
Temperature: 80 °C
Yield: 74.6 %

Procedure:
A 300-ml flask equipped with a stirrer and a dropping funnel was charged with 45.8 g (0.75 mol) of ethanolamine and 9 g of ethanol. While stirring the mixture at 80° C., 13.4 g (50 mmol) of 1,2-epoxyoctadecane were added dropwise over 2 hours. Water was added to the resultant reaction mixture, and white crystals formed were collected by filtration, washed with water and then recrystallized from methanol, thereby obtaining 12.3 g (yield: 74.6%) of the title compound (IIc-1).
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].C(#N)C.Br[CH2:31][CH2:32][O:33][CH3:34]>C(OCC)(=O)C>[CH3:34][O:33][CH2:32][CH2:31][O:1][C:2]1[C:11]([O:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COCCBr
Reactant: COC(=O)c1cccc(OC(=O)c2ccccc2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COCCOc1c(OC(=O)c2ccccc2)cccc1C(=O)OC
Temperature: 25 °C
Yield: 87.2 %

Procedure:
To a mixture of methyl 2-hydroxy-3-[(phenylcarbonyl)oxy]benzoate (21.2 g, 78 mmol), potassium carbonate (21.5 g, 156 mmol) and acetonitrile (370 mL) was added 1-bromo-2-(methyloxy)ethane (12.1 mL, 116 mmol). The resulting mixture was heated at reflux 18 hour. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (400 mL), filtered and concentrated. The residue was then diluted with ethyl acetate (200 mL) and washed with 5% sodium hydroxide solution, water and brine (100 mL each), dried over sodium sulfate, filtered, concentrated, and the residue was chromatographed (silica gel, 30-50% ethyl acetate-hexane) to provide methyl 2-{[2-(methyloxy)ethyl]oxy}-3-[(phenylcarbonyl)oxy]benzoate, (22.5 g, 68 mmol, 87% yield). 1H NMR (400 MHz, CDCl3): 8.25-8.23 (d, d, 2H), 7.76-7.74 (d, d, 1H), 7.68-7.64 (d, d, 1H), 7.55-7.51 (d, d, 2H), 7.40-7.38 (d, d, 1H), 7.23-7.19 (d, d, 1H), 4.17-4.15 (m, 2H), 3.92 (s, 3H), 3.58-3.55 (m, 2H), 3.14 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5]([OH:7])=[O:6].[CH:12](O)([CH3:14])[CH3:13]>OS(O)(=O)=O>[CH:12]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([CH3:11])[N:10]=[C:2]([Cl:1])[CH:3]=1)([CH3:14])[CH3:13]
Reactant: CC(C)O
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Agent: O=S(=O)(O)O
Product: Cc1cc(C(=O)OC(C)C)cc(Cl)n1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a suspension of 2-chloro-6-methyl-isonicotinic acid (20.0 g, 117 mmol) in isopropanol (80 mL), H2SO4 (5 mL) is added dropwise. The mixture becomes warm (40° C.). The mixture is stirred for 24 h at rt, then at 90° C. for 28 h before the solvent is removed in vacuo. The residue is dissolved in diethyl ether (200 mL), washed with sat. aq. NaHCO3-solution (3×50 mL) followed by brine (3×50 mL), dried over Na2SO4, filtered and concentrated to give 2-chloro-6-methyl-isonicotinic acid isopropyl ester (21.0 g) as a colourless oil which slowly crystallises; LC-MS: tR=0.97 min, [M+1]+=214.05.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:16])[C:9]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH2:5][NH2:6].[N:17]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][N:24]=[CH:25]2)=[C:18]=[O:19]>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:16])[C:9]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH2:5][NH:6][C:18]([NH:17][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][N:24]=[CH:25]2)=[O:19]
Reactant: O=C=Nc1cccc2cnccc12
Reactant: NCc1cc(F)c(N2CCOCC2)c(F)c1
Solvent: CCOCC
Product: O=C(NCc1cc(F)c(N2CCOCC2)c(F)c1)Nc1cccc2cnccc12

Procedure:
The product from Example 177A (500 mg, 2.19 mmol) in diethyl ether (5 mL) was treated with an ethereal solution of 5-isocyanatoisoquinoline. The resulting waxy precipitate was collected by filtration and air-dried to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.79 (s, 1H), 8.54 (d, 1H, J=6.1 Hz), 8.26 (dd, 1H, J=7.8 Hz, 1.0 Hz), 7.94 (d, 1H, 6.1 Hz), 7.76 (d, 1H, 8.2 Hz), 7.60 (t, 3H, J=7.6 Hz), 7.10 (t, 1H, J=6.0 Hz), 7.03 (m, 2H), 4.31 (d, 2H), 3.68 (m, 4H), 3.07 (m, 4H); MS (ESI+) m/z 399 (M+H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH:6]1[C:11](=[O:12])[NH:10][C:9](=[O:13])[NH:8][C:7]1=[O:14])[CH3:2].[OH-].[Na+].[Br:17]Br>O>[Br:17][C:6]1([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:7](=[O:14])[NH:8][C:9](=[O:13])[NH:10][C:11]1=[O:12]
Reactant: CCOCCC1C(=O)NC(=O)NC1=O
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOCCC1(Br)C(=O)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.3 %

Procedure:
To a mixture of 5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-trione (27.8 g, 139 mmol) and 1.5 L of water was added 1M sodium hydroxide solution (140 mL) and bromine (7.2 mL, 22.2 g, 139 mmol) at 0° C. After warming to room temperature, the mixture was stirred for 48 hours, filtered, and the solids were washed with water, then ether, then hexanes and dried in vacuo, affording 23 g of 5-bromo-5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-trione.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([CH:8]1[CH2:13][CH:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[C:34]([Cl:40])=[CH:35][CH:36]=[CH:37][C:38]=1[Cl:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1c(Cl)cccc1Cl)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(c1c(Cl)cccc1Cl)N1CCC(NCc2ccnc3ccccc23)CC1Cc1ccccc1

Procedure:
138 mg (0.230 mmol) of (2R*,4S*)-2-benzyl-1-(2,6-dichlorobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 40 with 18.4 mg (0.460 mmol) of sodium hydroxide in 1.5 ml of tetrahydrofuran and 1.5 ml of methanol. The title compound ##STR68## is obtained (56 mg, 48%) as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.50, FD-MS: M+ =503, 505.
Reaction SMILES: C[Si](C)(C)[N-:3][Si](C)(C)C.[Li+].[Cl:11][C:12]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15].Cl>CCCCCC.C(OCC)C>[Cl:11][C:12]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]([NH2:3])=[NH:15]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: N#Cc1cccc(F)c1Cl
Agent: Cl
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOCC
Product: N=C(N)c1cccc(F)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
320 ml (0.32 mmol) of a 1 molar solution of lithium hexamethyl disilazide (LiHMDS) in hexane are placed in 800 ml diethyl ether and combined at ambient temperature with 25.0 g (0.161) 2-chloro-3-fluoro-benzonitrile. The mixture is stirred for 2 h at ambient temperature and after cooling to 0° C. it is combined with 280 ml 3 normal hydrochloric acid. The precipitate formed is suction filtered, washed with water and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[C:10]([O:22][CH3:23])[CH:9]=2)=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([O:22][CH3:23])[C:11]([O:16][CH2:17][C:18]([F:19])([F:20])[F:21])=[C:12]([O:14][CH3:15])[CH:13]=2)=[N:6][CH:7]=1)(=[O:36])[CH:34]=[CH2:35]
Reactant: C=CC(=O)Cl
Reactant: COc1cc(-c2ccc(N)cn2)cc(OC)c1OCC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccc(-c2cc(OC)c(OCC(F)(F)F)c(OC)c2)nc1
Temperature: 0 °C

Procedure:
To a solution of 5-amino-2-[3,5-dimethoxy-4-(2,2,2-trifluoroethoxy)phenyl]pyridine (melting point: 176.0-177.5° C.)(28.2 g, 85.4 mmol) synthesized by a similar procedure to that described in Reference Example 11 in methylene chloride (550 mL) was added N,N-diisopropylethylamine (18.0 mL, 103 mmol). To the ice-cold stirred solution was added acryloyl chloride (7.00 mL, 86.0 mmol) dropwise over about 10 minutes. A saturated aqueous sodium hydrogencarbonate was added, and the resulting mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Chloroform-hexane (1:2, 300 mL) was added to the residue and the resulting precipitate was collected by filtration to yield crude 5-acryloylamino-2-[3,5-dimethoxy-4-(2,2,2-trifluoroethoxy)phenyl]pyridine was obtained as colorless needles (melting point: 207.0-209.0° C.)(38.2 g).
Reaction SMILES: [Cl:1][CH:2]([Cl:28])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([CH2:24]O)=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:27])[CH3:26])=[O:4].CCN(C(C)C)C(C)C.CS([Cl:42])(=O)=O>C(Cl)Cl>[Cl:28][CH:2]([Cl:1])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([CH2:24][Cl:42])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:26])[CH3:27])=[O:4]
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(CO)nc3)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)O[C@H](c2ccc(-c3ccc(CCl)nc3)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.5 %

Procedure:
To a cooled (ice-water) solution of the product of step 1 (800 mg, 1.87 mmol) and DIPEA (0.675 mL, 3.75 mmol) in DCM (10 mL) is slowly added methanesulfonyl chloride (0.150 mL, 1.87 mmol). The reaction mixture is stirred at room temperature for 6 hours. The reaction is diluted with DCM (10 mL), washed with water (2×10 mL) dried over Na2SO4 and concentrated under reduced pressure to give the title compound (813 mg): LCMS m/z (Cl): 445 [M+H].
Reaction SMILES: [CH3:1][OH:2].[Na].[NH2:4][C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([CH2:12][CH2:13][CH3:14])[N:6]=1.O>C(Cl)(Cl)Cl>[NH2:4][C:5]1[CH:10]=[C:9]([O:2][CH3:1])[N:8]=[C:7]([CH2:12][CH2:13][CH3:14])[N:6]=1
Reactant: CCCc1nc(N)cc(Cl)n1
Reactant: CO
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCc1nc(N)cc(OC)n1

Procedure:
To a mixture of 25 ml of methanol and 1.1 g (0.048 mole) of sodium was added 5.1 g (0.030 mole) of 4-amino-6-chloro-2-(n-propyl)pyrimidine, and the resulting mixture was heated at reflux for four days. The mixture was allowed to cool to about 20° C., at which time water and chloroform were added thereto. The layers were separated, and the aqueous layer was extracted with additional chloroform. The organic layers were combined, dried over magnesium sulfate, and evaporated to provide a residue. The residue was recrystallized from cyclohexane with treatment with decolorizing charcoal to provide white solid 4-amino-6-methoxy-2-(n-propyl)pyrimidine, m.p. 97°-99° C. The structural assignment was supported by nuclear magnetic resonance and infrared spectral analyses.
Reaction SMILES: OS(O)(=O)=O.[Cl:6][C:7]1[S:8][C:9]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[C:10]([CH2:12][OH:13])[N:11]=1.C([OH:23])(C)C>CC(C)=O.O.[Na+].[Cl-]>[Cl:6][C:7]1[S:8][C:9]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[C:10]([C:12]([OH:23])=[O:13])[N:11]=1
Reactant: CC(C)O
Reactant: CC(C)OC(=O)c1sc(Cl)nc1CO
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)OC(=O)c1sc(Cl)nc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3 mL H2SO4 and 12 mL water were cooled in an ice water bath, and 2.3 g (23 mmol) CrO3 was added portionwise. The solution was added dropwise to a cooled (ice water bath) solution of 2.74 g (11.6 mmol) of isopropyl 2-chloro-4-(hydroxymethyl)-1,3-thiazole-5-carboxylate (Intermediate 13) in acetone (50 mL) The resulting mixture was stirred 4 hours with warming to room temperature. Isopropanol (2 mL) was added and stirring was continued for 15 min. The solution was diluted with water, saturated with NaCl and extracted 3 times with EtOAc. The EtOAc was washed with brine, dried (MgSO4) and concentrated to give 2.86 g of an oil. NMR: 1.3 (d, 6H), 5.1 (m, 1H), 14.1 (s, 1H).