Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:11][C@H:12]([C:14]([N:16]([C:21]1[CH:25]=[CH:24][S:23][CH:22]=1)[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH3:13])(OCC1C=CC=CC=1)=O.Br>C(O)(=O)C>[NH2:11][C@H:12]([C:14]([N:16]([C:21]1[CH:25]=[CH:24][S:23][CH:22]=1)[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH3:13]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)O)c1ccsc1
Agent: Br
Solvent: CC(=O)O
Product: C[C@H](N)C(=O)N(CC(=O)O)c1ccsc1

Procedure:
In a manner described in example 5B, N-carbobenzyloxy-L-alanyl-N-(3-thienyl)glycine was treated with anhydrous hydrogen bromide in acetic acid to yield the hydrobromide salt of L-alanyl-N-(3-thienyl)glycine.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12].[CH3:13][NH2:14]>C(O)C>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][NH:14][CH3:13]
Reactant: CN
Reactant: COc1ccccc1OCCBr
Solvent: CCO
Product: CNCCOc1ccccc1OC
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 1-(2-bromoethoxy)-2-methoxybenzene (7d) (7.7 g, 33 mmol) in a 33% solution of methylamine in ethanol was heated at 80° C. in a sealed tube for 16 h. After cooling to room temperature, the solvents were evaporated in vacuo. A 2N aqueous solution of sodium hydroxide was added to the remaining oil and the resulting slurry was extracted with ethyl acetate (2×250 mL). The collected organic phases were dried (Na2SO4) and the solvents evaporated in vacuo giving 5.9 g (98%) of the title compound as an oil: 1H NMR (CDCl3) δ 1.85 (broad s, 1H), 2.50 (s, 3H), 3.00 (t, 2H), 3.85 (s, 3H), 4.10 (t, 2H), 6.85-6.95 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1I.[C:23]([C:25]1[CH:26]=[C:27]([NH:31][C:32]([C:34]2[O:35][CH:36]=[CH:37][C:38]=2[CH3:39])=[O:33])[CH:28]=[CH:29][CH:30]=1)#[CH:24].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:24]#[C:23][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32]([C:34]2[O:35][CH:36]=[CH:37][C:38]=2[CH3:39])=[O:33])[CH:26]=1
Reactant: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(I)c1
Reactant: C#Cc1cccc(NC(=O)c2occc2C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3occc3C)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.9 %

Procedure:
The solution of methyl 5-{N-[(6-amino-5-iodopyridin-3-yl)carbonyl]-S-methylsulfonimidoyl}pentanoate, (565 mg, 1.28 mmol) in anhydrous DMF (7 mL) was degassed with anhydrous nitrogen and then to the solution was added 3-methyl-furan-2-carboxylic acid (3-ethynyl-phenyl)-amide (376.5 mg, 1.3 eq), bis(triphenylphosphine)palladium(II) dichloride (90.3 mg, 0.1 eq), triphenyl phosphine (8.4 mg, 0.025 eq), triethylamine (0.75 mL, 4 eq) and lastly copper(I) iodide (50 mg, 0.2 eq) under anhydrous nitrogen atmosphere. The reaction mixture was stirred at RT for about 15 minutes and then partitioned between saturated aq NaHCO3 and EtOAc. The organic layer was washed one more time with saturated aq NaHCO3, then with aq NH4Cl (1×), brine (1×), and dried with anhydrous Na2SO4 overnight. The upper solution layer was decanted and concentrated. The oily residue was subject to gradient column chromatography. Concentration of the product eluting fractions gave the title compound as white foam (480 mg, 70%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([OH:23])[C:9]2[C@@H:15]3[CH:16]=[C:17]([CH3:20])[CH2:18][CH2:19][C@H:14]3[C:13]([CH3:22])([CH3:21])[O:12][C:10]=2[CH:11]=1.[N+](C1C=CC=CC=1S[NH:34][CH2:35][CH2:36][C:37]([O-:39])=[O:38])([O-])=O>ClCCl.C1(S)C=CC=CC=1.C(O)(C(F)(F)F)=O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([OH:23])[C:9]2[C@@H:15]3[CH:16]=[C:17]([CH3:20])[CH2:18][CH2:19][C@H:14]3[C:13]([CH3:22])([CH3:21])[O:12][C:10]=2[CH:11]=1.[NH2:34][CH2:35][CH2:36][C:37]([O-:39])=[O:38]
Reactant: O=C([O-])CCNSc1ccccc1[N+](=O)[O-]
Agent: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21
Agent: Sc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCC(=O)[O-]

Procedure:
THC N-(2-nitrophenylsulfenyl)-β-alaninate (35.8 mg, 0.0665 mmol) was dissolved at ambient temperature in dry dichloromethane containing 10% (v/v) of thiophenol and 1.5% (v/v) of TFA (150 μL). After 10 min the mixture was quenched by addition of 180 μL 3% triethylamine in DCM (at 0° C.). The solution of crude product was chromatographed directly on silica gel with dichloromethane-methanol (gradient 1:0, 30:1, 20:1, 10:1, 7:1). The combined fractions containing the product were diluted with chloroform, concentrated at 25° C. to ˜3 mL, diluted with chloroform and concentrated again to ˜0.5 mL. The solution of product was diluted with chloroform again (˜5 mL) and concentrated to dryness. The remaining oil was immediately dissolved in chloroform, concentrated to dryness (11.47 mg, 45%), and immediately dissolved in chloroform to afford a stock solution of THC β-alaninate (ALL00133) stored at −20° C.
Reaction SMILES: [CH:1]1([C:6]2[NH:11][C:10](=[O:12])[C:9]([CH:13]([NH:16][C:17](=O)[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH3:15])=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>>[C:18]([C:17]1[N:8]2[C:9]([C:10](=[O:12])[NH:11][C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:7]2)=[C:13]([CH2:14][CH3:15])[N:16]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CCC(NC(=O)C(C)(C)C)c1nnc(C2CCCC2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(C(C)(C)C)n2nc(C3CCCC3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 1, 200 mg (0.65 mmol) crude N-[1-(3-cyclopentyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]-2,2-dimethylpropanamide, 165 mg (1.1 mmol) phosphoric trichloride are stirred at reflux for 4 hours, proportionate amounts of the solvents are used. The product is purified by chromatography (preparative HPLC).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].CS(O)(=O)=O.[C:23]1([CH2:29][CH:30]2[NH:34][CH2:33][C:32](=[O:35])[CH2:31]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:34]1[CH:30]([CH2:29][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:31][C:32](=[O:35])[CH2:33]1)=[O:7]
Reactant: O=C1CNC(Cc2ccccc2)C1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Product: O=C1CC(Cc2ccccc2)N(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Yield: 12.5 %

Procedure:
3,5-di(trifluoromethyl)benzoyl chloride (0.03 mol) was added to intermediate 23 (0.027 mol). The mixture was stirred and triethylamine (0.1 mol) was added. The mixture was stirred at RT for 18 hours and then washed with water, NaOH and a saturated NaCl solution. The organic layer was separated, washed with a saturated NaCl solution, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated, yielding 1.4 g of (±)-1-[3,5-bis(trifluoromethyl)benzoyl]-5-(phenylmethyl)-3-pyrrolidinone (intermnediate 24).
Reaction SMILES: [N+:1]([C:4]1[CH:45]=[CH:44][C:7]([O:8][CH2:9][C:10]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-])=O)=[CH:37][CH:36]=2)([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=2)[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>O1CCCC1.[Pd]>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:10]([CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:45][CH:44]=2)([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:33][O:34][C:35]2[CH:36]=[CH:37][C:38]([NH2:41])=[CH:39][CH:40]=2)=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(OCC(COc2ccc([N+](=O)[O-])cc2)(COc2ccc([N+](=O)[O-])cc2)COc2ccc([N+](=O)[O-])cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(OCC(COc2ccc(N)cc2)(COc2ccc(N)cc2)COc2ccc(N)cc2)cc1
Yield: 90 %

Procedure:
A mixture of 1,3-bis(4-nitrophenoxy)-2,2-bis[(4-nitrophenoxy)methyl]propane (15.43 grams, 24.87 mmol; prepared as described in Part B of this Example) and Pd/C 10% (1.58 grams, obtained from Aldrich Chemical Co.) was stirred for 70 hours in tetrahydrofuran (400 milliliters) under 180 pounds per square inch of hydrogen gas. The mixture was then filtered over CELITE, and the solvent was removed by evaporation under reduced pressure. The residue was recrystallized from nitrobenzene/benzene to afford pure 1,3-bis(4-aminophenoxy)-2,2-bis[(4-aminophenoxy)methyl]propane (11.17 grams, 22.31 mmol, 90 percent yield) as small light brown crystals: mp 210–211° C.; IR (KBr) 3434, 3351, 3050, 2932, 1625, 1511, 1467, 1232, 1041, 1172, 831, 523 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 6.66 (d, 8H, 3J=8.4 Hz), 6.47 (d, 8H, 3J=8.4 Hz), 4.62 (s, 8H), 4.03 (s, 8H); 13C NMR (100 MHz, DMSO-d6) δ 150.14, 142.73, 115.76, 114.86, 67.06, 44.59; MS (FAB, 3-nitrobenzyl alcohol) m/e 500.3; Anal. Calcd for C33H24N4O4: C, 69.58; H, 6.44; N, 11.19. Found: C, 69.33; H, 6.78; N, 10.91.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
A mixture of 5-fluoro-2-nitrophenol (28 g, 0.178 mol), benzyl bromide (33.53 g, 0.195 mol) and K2CO3 (30.8 g, 0.223 mol) in anhydrous DMF (150 mL) was stirred at room temperature for 12 h. After the reaction was complete, the reaction mixture was poured into a mixture of ether (1000 mL) and water (200 mL). The organic phase was separated, washed with water (3×100 mL), dried (MgSO4) and concentrated to give the title compound of Step A (40.5 g).
Reaction SMILES: C([O:5][C:6](=[O:26])[CH2:7][CH:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[C:17]([CH3:19])[CH:18]=1)[NH:15][N:14]=[CH:13]2)(C)(C)C.Cl>O1CCOCC1>[CH3:19][C:17]1[CH:18]=[C:10]([CH2:9][CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:7][C:6]([OH:26])=[O:5])[CH:11]=[C:12]2[C:16]=1[NH:15][N:14]=[CH:13]2
Reactant: Cc1cc(CC(CC(=O)OC(C)(C)C)c2ccccn2)cc2cn[nH]c12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(CC(CC(=O)O)c2ccccn2)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a flask containing 4-(7-Methyl-1H-indazol-5-yl)-3-pyridin-2-yl-butyric acid tert-butyl ester (10 mg, 0.028 mmol) was added hydrogen chloride in dioxane (4 M, 0.8 mL). The suspension was stirred at room temperature overnight (LCMS indicated 2/3 conversion after 2 h). The reaction mixture was concentrated in vacuo to dryness. Dioxane (1 mL) was added and the mixture again concentrated to dryness. The residue was carried on without further characterization. MS (ESI) 296 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:12][CH3:13])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([C:39]2[CH:43]=[CH:42][NH:41][N:40]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]>C1COCC1.CCOC(C)=O>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([C:39]2[CH:43]=[CH:42][N:41]([C:9](=[O:11])[CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:12][CH3:13])[N:40]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]
Reactant: COC(C(=O)O)c1ccc(F)cc1
Reactant: COc1ccc(-c2cc[nH]n2)cc1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccn(C(=O)C(OC)c3ccc(F)cc3)n2)cc1OC
Reaction time: 0.17 h
Yield: 53.1 %

Procedure:
To a solution of 2-(4-fluorophenyl)-2-methoxyacetic acid (0.11 g, 0.61 mmol) in anhydrous THF (2 mL) at room temperature was added DCC (0.14 g, 0.67 mmol) in one portion. After stirring for 10 min, 3-(3,4-dimethoxyphenyl)-1H-pyrazole (0.14 g, 0.67 mmol) was added in one portion. After 48 hrs, the reaction mixture was diluted with EtOAc and the solids removed via filtration. The filtrate was concentrated in vacuo. Purification by chromatography (0-30% EtOAc-hexanes) gave the product as an oil (0.12 g, 46% yield). MS: m/z 371.1 [M+H]+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:7]([O-])([OH:9])=[O:8].S(=O)(=O)(O)O>O>[N+:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1ccccc1

Procedure:
The starting substances, benzene and nitric acid, are reacted in a large excess of sulfuric acid, which takes up the heat of reaction liberated and the water formed during the reaction. For the process of carrying out the reaction, nitric acid and sulfuric acid are mixed to give so-called mixed acid, and benzene is metered into this. The benzene reacts with the nitric acid to give water and substantially nitrobenzene. The temperature of the reaction mixture and the concentrations of benzene, nitric acid and sulfuric acid are preferably chosen such that after a reaction zone, conventionally in the nitrating reactor, a mixture of benzene, nitrobenzene, sulfuric acid and water is obtained. This mixture is substantially free from nitric acid. The temperatures required for this are conventionally between 70° and 145° C. To establish the mixed acid, nitric acid having a concentration of from 60 to 98 wt. %, and sulfuric acid having a concentration of from 60 to 96 wt. % are conventionally employed. Benzene is preferably employed at least in the stoichiometric amount, based on the amount of nitric acid. It is more preferred, however, that benzene is employed in an excess of 2 to 10%, compared with the amount of benzene required stoichiometrically.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:15]([OH:17])=O)[N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12.CN1CCOCC1.C(Cl)(=O)C(Cl)=O.[N:35]1([C:40]2[CH:41]=[C:42]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=2)[NH2:43])[CH:39]=[CH:38][N:37]=[CH:36]1.NC1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:35]1([C:40]2[CH:41]=[C:42]([NH:43][C:15](=[O:17])[C:14]3[CH:18]=[CH:19][C:20]([CH3:21])=[C:12]([C:11]#[C:10][C:3]4[N:4]5[CH:9]=[CH:8][N:7]=[CH:6][C:5]5=[N:1][CH:2]=4)[CH:13]=3)[CH:44]=[C:45]([C:47]([F:49])([F:50])[F:48])[CH:46]=2)[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: Nc1cc(-n2ccnc2)cc(C(F)(F)F)c1
Reactant: Cc1ccc(C(=O)O)cc1C#Cc1cnc2cnccn12
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Nc1ccccc1
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1C#Cc1cnc2cnccn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-4-methylbenzoic acid (18 mmol) is dissolved in methylene chloride (100 mL). To this solution is added 3 equivalents of 4-methylmorpholine (NMM) followed by 1.05 equivalents of oxalyl chloride. After stirring at ambient temperature for 30 minutes, 0.8 equivalents of 3-(1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (prepared as above) is added along with 5 mole % of DMAP. After initially stirring at ambient temperature, the mixture is brought to reflux and stirred overnight. After 16 h an additional 0.2 equivalents of the aniline is added, bringing the total charge to 1 equivalent. The mixture can then be stirred for an additional 2 h, quenched with water, and the layers separated. The aqueous layer can be extracted with methylene chloride (2×50 mL) and the combined extracts can be washed with water. The combined methylene chloride layers can then be evaporated and the residue dissolved in 100 mL of ethyl acetate (20 mL). After standing for 1 h, the product is allowed to crystallize. The mixture is cooled, e.g. to 0° C., filtered, and the solid product is washed with cold ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][NH2:10].[Br:11][C:12]1[S:16][C:15]2=[N:17][C:18]([C:20](O)=[O:21])=[CH:19][N:14]2[CH:13]=1>>[Br:11][C:12]1[S:16][C:15]2=[N:17][C:18]([C:20]([NH:10][CH2:9][C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])=[O:21])=[CH:19][N:14]2[CH:13]=1
Reactant: NCc1c(F)cccc1F
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Product: O=C(NCc1c(F)cccc1F)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using (2,6-difluorophenyl)methanamine and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10](C(NC(C)(C)C)=O)[CH2:9]1)=O)(C)(C)C.C(OC([NH:31][C@@H](CC1C=CC=CC=1)[C@@H]1OC1)=O)C1C=CC=CC=1>C(O)(C)C>[N:8]1([C:6]([NH2:31])=[O:5])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)NC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Solvent: CC(C)O
Product: NC(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
0.395 g of 4-(tert.butoxycarbonyl)-N-tert.butyl-2-piperazinecarboxamide was dissolved in 50 ml of dry isopropanol and treated with 0.413 g of 3(S)-(benzyloxyformamido)-1,2(S)-epoxy-4-phenylbutane. The mixture was stirred at room temperature for 72 hours. The solvent was removed by evaporation to give a brown semi-solid material which was purified by flash chromatography on silica gel using 5% methanol in dichloromethane for the elution. There was obtained 0.234 g of 1-[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-4-(tert.butoxycarbonyl)-N-tert.butyl-2(R or S)-piperazinecarboxamide as a mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.Br[C:13]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([C:13]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Product: COc1ccc(C(=O)c2ccc(C)cc2C(=O)O)cc1

Procedure:
This compound is obtained according to the procedure described in 1.1. by reacting 4-methoxybenzoyl chloride and 2-bromo-5-methylbenzoic acid after halogen-lithium exchange. It is used in crude form in the following reaction.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4](Cl)[N:3]=1.[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=CC=1.C(N(CC)CC)C>C(O)CC>[NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([C:14]2[S:17][CH:11]=[CH:16][CH:15]=2)[N:3]=1
Reactant: Nc1cc(Cl)nc(N)[n+]1[O-]
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCCO
Product: Nc1cc(-c2cccs2)nc(N)[n+]1[O-]
Yield: 51.7 %

Procedure:
5 g of 2,4-diamino-6-chloropyrimidine 3-oxide, 6.85 g of thiophenol and 11.5 g of triethylamine are placed in 110 ml of n-propanol. The reaction mixture is heated at reflux for 24 hours. It is evaporated to dryness. The residue is taken up in 25 ml of ethyl ether, stirred for 1/2 an hour, filtered on sintered glass and rinsed with 2×25 ml of ethyl ether. The precipitate is taken up in 75 ml of water. The pH is adjusted to 1 with concentrated hydrochloric acid. After stirring for 1/2 an hour, the pH is returned to 8 by addition of concentrated sodium hydroxide solution. The precipitate is filtered, rinsed with 10 ml of water and then recrystallized twice from a 75/25 ethanol/water mixture. 3.35 g of 2,4-diamino-6-thiophenylpyrimidine 3-oxide are obtained.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=[N:6][C:5]=1[F:22].[AlH4-].[Li+].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[F:22][C:5]1[C:4]([CH2:3][OH:2])=[CH:9][CH:8]=[C:7]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=2)[N:6]=1
Reactant: COC(=O)c1ccc(NCc2ccc(C(F)(F)F)nc2)nc1F
Agent: O=S(=O)([O-])[O-]
Agent: [AlH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(NCc2ccc(C(F)(F)F)nc2)nc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To 2-fluoro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-nicotinic acid methyl ester (562, 1.40 g, 4.25 mmol) in tetrahydrofuran (100.0 mL) under an atmosphere of nitrogen at room temperature, a solution of lithium tetrahydroaluminate (1.00 M in tetrahydrofuran, 10.0 mL) was added slowly. The reaction was stirred at room temperature overnight, followed by addition of an appropriate amount of sodium sulfate decahydrate. After 1 hour, the reaction mixture was filtered and concentrated to give crude compound (563, 1.2 g, 93.7%) that was used in the next step without further purification.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:18]([CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[CH3:14])[CH2:11]2
Reactant: Cc1ccccc1CN
Reactant: COC(=O)c1c(I)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccccc1CN1Cc2cccc(I)c2C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.107 g, 0.3 mmol), 2-methyl-benzylamine (0.063 mL, 0.5 mmol), and K2CO3 (0.138 g, 1.0 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-(2-methyl-benzyl)-2,3-dihydro-isoindol-1-one (0.056 g, 51%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.35 (s, 3H), 4.14 (s, 2H), 4.82 (s, 2H), 7.11-7.38 (m, 6H), 7.91 (d, 1H). GC-MS: m/z 363 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][N:16]([C:18]([N:20]3[CH2:25][CH2:24][S:23][CH2:22][CH2:21]3)=[O:19])[CH2:15][CH:14]([C:26]([OH:28])=O)[CH2:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].O[N:30]=[C:31]([O:33][CH2:34][CH3:35])[NH2:32]>>[CH2:34]([O:33][C:31]1[N:32]=[C:26]([CH:14]2[CH2:13][CH:12]([C:4]3[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:11])[F:10])=[C:2]([F:1])[CH:3]=3)[CH2:17][N:16]([C:18]([N:20]3[CH2:21][CH2:22][S:23][CH2:24][CH2:25]3)=[O:19])[CH2:15]2)[O:28][N:30]=1)[CH3:35]
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)c(F)c2)CN(C(=O)N2CCSCC2)C1
Reactant: CCOC(N)=NO
Product: CCOc1noc(C2CC(c3ccc(C(F)(F)F)c(F)c3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 4, 151 mg (0.280 mmol) of the compound from Example 85A and 43 mg (0.420 mmol) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] were reacted. Yield: 38 mg (25% of theory).