Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.S(O)(O)(=O)=O.[CH3:45][N:46]1[C:50]([NH2:51])=[C:49]([NH2:52])[CH:48]=[N:47]1>O1CCCC1.O.C(Cl)(Cl)Cl>[NH2:51][C:50]1[N:46]([CH3:45])[N:47]=[CH:48][C:49]=1[NH:52][C:13]([C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:22])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:15]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Cn1ncc(N)c1N
Agent: COC(=O)Cl
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1ncc(NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)c1N

Procedure:
To a solution of (2S)-2-[(benzyloxycarbonyl)amino]-6-[(tert-butoxycarbonyl)amino]hexanoic acid (19.02 g) and triethylamine (5.56 g) in tetrahydrofuran (200 ml) was added methyl chloroformate (4.21 ml), followed by stirring under ice-cooling for 30 minutes. To the reaction mixture was added a solution of 1-methyl-1H-pyrazole-4,5-diamine sulfate (15.75 g) and triethylamine (15.2 g) in water (50 ml) at the same temperature. The mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added chloroform (300 ml), and the layers were separated. The organic layer was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a crude product of 1-benzyl 5-tert-butyl (1S)-{1-[(5-amino-1-methyl-1H-pyrazol-4-yl)carbamoyl]pentamethylene}biscarbamate as an oil. The crude product was used directly in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][CH2:19][S:20][CH2:21][CH2:22][CH3:23])(=[O:4])[CH2:2][CH3:3].[NH2:24][C:25]1[C:26]([CH3:31])=[CH:27][CH:28]=[CH:29][CH:30]=1>C(#N)C>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][CH2:19][S:20][CH2:21][CH2:22][CH3:23])(=[O:4])[CH2:2][CH3:3]
Reactant: Cc1ccccc1N
Reactant: CCCSCCCOc1cccc2c(Cl)c(C(=O)CC)cnc12
Solvent: CC#N
Product: CCCSCCCOc1cccc2c(Nc3ccccc3C)c(C(=O)CC)cnc12
Yield: 54 %

Procedure:
3-Propanoyl-4-chloro-8-(3-propylthiopropoxy)quinoline (2.0 g, 5.7 mmol) and o-toluidine (0.7 g, 6.5 mmol) was refluxed in acetonitrile (10 ml) for 2 h. The solvent was evaporated and the residue was partitioned between methylene chloride and 10% Na2CO3 solution. The organic layer was dried over Na2SO4 and evaporated. The residue was purified by column chromatography (methylene chloride:ethyl acetate 70:30). 1.3 g (54%) of the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:41][C:42]1[CH:55]=[CH:54][C:45]([O:46][C:47]2[CH:53]=[CH:52][C:50]([NH2:51])=[CH:49][CH:48]=2)=[CH:44][CH:43]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:41][C:42]1[CH:55]=[CH:54][C:45]([O:46][C:47]2[CH:53]=[CH:52][C:50]([NH:51][C:14]([C@@H:9]3[CH2:10][C@@H:11]([OH:13])[CH2:12][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])=[CH:49][CH:48]=2)=[CH:44][CH:43]=1
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
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: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Step (a) A flask was charged with (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (2.1 g, 9.1 mmol), HATU (3.80 g, 10.0 mmol), 4-(4-fluorophenoxy)aniline (1.85 g, 9.09 mmol), DIEA (4.8 mL, 27 mmol) and DMF (20 mL). The reaction mixture was stirred at ambient temperature for 30 minutes and then quenched with saturated sodium bicarbonate (aq., 20 mL). The mixture was extracted with ethyl acetate (60 mL) and the extract was washed with deionized water (30 mL) and then brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give crude (2S,4R)-tert-butyl 2-(4-(4-fluorophenoxy)phenylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate, which was carried forward without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([CH2:19]O)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[N+:21]([C:24]1[CH:25]=[C:26]([SH:30])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(P(CCCC)CCCC)CCC>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([CH2:19][S:30][C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=3)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1CO
Reactant: O=[N+]([O-])c1cccc(S)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1CSc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
To a solution of (2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)methanol (E13, 20 mg) and 3-nitrothiophenol (17 mg) in tetrahydrofuran (1 mL), tributylphosphine (36 μL) and 1,1′-(azodicarbonyl)dipiperidine (28 mg) were added under ice cooling, and the mixture was stirred at room temperature for 6 hours and 30 minutes. To the reaction mixture, tributylphosphine (36 μL) and 1,1′-(azodicarbonyl)dipiperidine (28 mg) were added at room temperature, and the mixture was stirred at the same temperature for 8 hours and 30 minutes. The solvent was evaporated under reduced pressure, and then the obtained residue was purified by basic silica gel column chromatography (eluent, 88 to 40% hexane in ethyl acetate) to obtain N2-(3-fluorophenyl)-5-(((3-nitrophenyl)thio)methyl)-N4-propylpyrimidine-2,4-diamine (E19, 19 mg) as yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:4][CH:3]=1
Reactant: OCCCCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCCCOc1ccc(Br)cc1
Temperature: 52.5 °C
Reaction time: 5 h
Yield: 76.4 %

Procedure:
In a flask equipped with a stirrer and a thermometer, 4.29 g (24.8 mmol) of 4-bromophenol was dissolved in 40 ml of dry dimethylformamide (abbreviated as DMF hereinbelow) under a nitrogen atmosphere, and 5.0 g (29.9 mmol) of 5-bromopentanol and 4.14 g (29.9 mmol) of potassium carbonate were added at room temperature, followed by stirring at 50 to 55° C. for 5 hours under incubation. After the completion of the reaction, water was added, and the mixture was subjected to extraction with ethyl acetate. The resulting organic phase was washed with NaCl saturated water, dried over anhydrous sodium sulfate, filtered, and concentrated, to thereby obtain 7.8 g of a crude product in the form of a yellow oil. The crude product was then purified by silica gel column chromatography using hexane/ethyl acetate as an eluting solvent to obtain 4.91 g of 5-(4-bromophenoxy)pentanol in the form of a light yellow oil in a 76% yield.
Reaction SMILES: [Si:1]([O:8][CH:9]([CH:11]1[CH:14]([S:15][CH3:16])[N:13]([CH:17](O)[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[C:12]1=[O:32])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.S(Cl)([Cl:43])=O>>[Si:1]([O:8][CH:9]([CH:11]1[CH:14]([S:15][CH3:16])[N:13]([CH:17]([Cl:43])[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[C:12]1=[O:32])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CSC1C(C(C)O[Si](C)(C)C(C)(C)C)C(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: Cc1cccc(C)n1
Product: CSC1C(C(C)O[Si](C)(C)C(C)(C)C)C(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
Following the procedure of Preparation 2, but using p-nitrobenzyl 2-[3-(1-t-butyldimethylsilyloxyethyl)-4-methylthio-2-azetidinon-1-yl]-2-hydroxyacetate (470 mg), 2,6-lutidine (168 μl) and thionyl chloride (85 μl) and purifying the product by silica gel column chromatography eluted with methylene chloride, there were obtained 450 mg of the desired compound as an oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:12]C(OC(C)(C)C)=O)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@H:10]([NH2:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88.8 %

Procedure:
Dissolve (R)-3-benzyloxy-2-(tert-butoxycarbonylamino)-propane (800 mg, 3 mmol) in DCM (10 mL), add trifluoroacetic acid (5 mL), and stir at 0° C. for 20 min. Evaporate and purify by SCX chromatography to give the title compound as a colorless oil (440 mg, 89%). MS (ES+) m/z: 166 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:10]([O:18][CH3:19])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:20](OC(=O)C)(=[O:22])[CH3:21].O1CCOCC1>O>[C:20]([NH:1][C:2]1[C:11]([O:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)=[C:10]([O:18][CH3:19])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(OC)c(OC2CCCC2)c1N
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(OC)c(OC2CCCC2)c1NC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of methyl 2-amino-3-(cyclopentyloxy)-4-methoxybenzoate (5.54 g, 20.9 mmol), acetic anhydride (21.0 mL, 222 mmol), and dioxane (35 mL) was heated at 40° C. under N2 for 17 h and then allowed to cool to rt. Water (10 mL) was added, and after 15 min of stirring, the reaction was concentrated to give methyl 2-acetamido-3-(cyclopentyloxy)-4-methoxybenzoate: MS (ESI): 307.9.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:6]([CH3:12])[C:7](=[O:11])[C:8]=1OC)=[O:5])#[N:2].[NH3:13]>>[NH2:13][C:8]1[C:7](=[O:11])[N:6]([CH3:12])[C:4](=[O:5])[C:3]=1[C:1]#[N:2]
Reactant: N
Reactant: COC1=C(C#N)C(=O)N(C)C1=O
Product: CN1C(=O)C(N)=C(C#N)C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
120 parts of 2-cyano-3-methoxy-N-methylmaleimide are dissolved in 600 parts of methylglycol and 13.5 parts of ammonia are then passed into the ice-cooled solution. Stirring is then continued for 3 hours at room temperature, and the resulting precipitate is filtered off under suction, washed with methanol and then with water, and dried to give 90 parts (83% of theory) of 3-amino-2-cyano-N-methylmaleimide.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33]2[N:36]([CH2:49][CH2:50][CH2:51][OH:52])[N:37]=[C:38]([C:39]3[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=3)[C:32]=2[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl.CCOCC.C([O-])(O)=O.[Na+]>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33]2[N:36]([CH2:49][CH2:50][CH:51]=[O:52])[N:37]=[C:38]([C:39]3[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:46])[F:47])=[CH:41][CH:40]=3)[C:32]=2[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCO)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCC=O)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
Dess-Martin periodinane (1.43 g, 3.36 mmol) was added portion wise to a stirred solution of 1-(3-hydroxy-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.30 g, 3.05 mmol) in CH2Cl2 (15 mL) at 0° C. under N2. Then the reaction was stirred at 0° C. for 15 min and allowed to warm to room temperature. After stirring at room temperature for 1.5 h the reaction was diluted with Et2O (50 mL) and saturated NaHCO3 (15 mL) was added slowly (caution! gas evolution). Then Na2S2O3.5H2O (5.31 g, 21.4 mmol) was added and stirred for 30 min. The layers were separated and the aqueous layer was extracted with Et2O (2×30 mL). The combined extracts were washed with brine, dried (Na2SO4) and concentrated. MPLC (1-10% MeOH/CH2Cl2) afforded the aldehyde in 79% yield (1.02 g). TLC (silica, 10% MeOH/CH2Cl2): Rf=0.67. MS (electrospray) calculated for C21H24F3N3O3, 424.2 ([M+H]+), m/z found, 424.2. 1H NMR (400 MHz, CDCl3): 9.82 (s, 1H), 7.65 (br d, J=8.0 Hz, 2H), 7.54 (br s, 2H), 4.53 (s, 2H), 4.21 (t, J=6.2 Hz, 2H), 3.68 (br s, 2H), 3.04 (t, J=6.2 Hz, 2H), 2.70 (t, J=5.6 Hz, 2H), 1.39 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].N1C=CC=CC=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].Cl>>[CH3:7][C:4]1[CH2:5][CH:6]=[C:2]([CH3:1])[C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][S:22]([CH3:21])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC1=CCC(C)=C1c1ccccc1N
Agent: Cl
Solvent: c1ccncc1
Product: CC1=CCC(C)=C1c1ccccc1NS(C)(=O)=O
Yield: 67.8 %

Procedure:
2-(2,5-dimethylcyclopenta-1,4-dienyl)phenylamine (0.500 g, 2.699 mmol) was melted in 5 mL of M.C, and then 0.235 g (2.969 mmol) of pyridine and 0.340 g (2.969 mmol) of methanesulfonyl chloride were added thereto. The reactants were reacted at room temperature for 7 hours. Then, 4 mL of 2 N HCl and 10 mL of M.C were added to the reaction product. The organic layer was collected and dried over MgSO4 to remove water contained therein. The solvent contained in the resultant organic layer was removed using a rotary vacuum evaporator. The product was filtered using 10 mL of diethyl ether, thereby obtaining white solid (0.482 g, 68%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][CH2:10][OH:11])=[CH:4][C:3]=1[F:12].Cl.[O:14]=[CH:15][CH2:16][C:17](S)=[NH:18]>>[C:10]([O:11][CH2:10][CH2:9][C:5]1[CH:4]=[C:3]([F:12])[C:2]([NH:1][C:17](=[NH:18])[CH2:16][C:15]([C:6]2[CH:5]=[CH:4][C:3]([F:12])=[CH:2][C:7]=2[F:8])=[O:14])=[C:7]([F:8])[CH:6]=1)(=[O:11])[CH3:9]
Reactant: Nc1c(F)cc(CCO)cc1F
Reactant: N=C(S)CC=O
Agent: Cl
Product: CC(=O)OCCc1cc(F)c(NC(=N)CC(=O)c2ccc(F)cc2F)c(F)c1

Procedure:
In stage 1, the 2-(4-Amino-3,5-difluorophenyl)ethanol and 4-Chlorophenyl difluorophenyl)-3-oxopropanimidothioate hydro-chloride are reacted together to form 2-(4-{[3-(2,4-Difluorophenyl)-3-oxopropanimidoyl]amino}-3,5-difluorophenyl)ethyl acetate. In stage 2, propiolic acid is added to form 2-{4-[6-Amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenyl}ethyl acetate. In stage 3, the acetate group is hydrolysed to leave an alcohol and in stage 4 the resulting alcohol group is oxidised to an aldehyde. The compound of the invention is then formed in stage 5, by the addition of tert-butyl L-alaninate hydrochloride. Tert-butyl L-alaninate hydrochloride is commercially available.
Reaction SMILES: [C:1]1(=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C>[Pd].C(O)C>[CH:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccccc1C=C1CCCCC1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccccc1CC1CCCCC1

Procedure:
1-(Cyclohexylidenemethyl)-2-nitrobenzene (3.45 g), prepared as above, glacial acetic acid (30 mL), ethanol (50 mL), and a catalytic amount of 10%Pd/C were shaken on a Parr Hydrogenator under a atmosphere of hydrogen at 23° C. for 24 h. The mixture was filtered through clay and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 10% EtOAc/hexanes to give 2-(cyclohexylmethyl)aniline.
Reaction SMILES: CO[C:3](=[O:18])[C@@H:4]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:5]([OH:9])[CH2:6][CH2:7][CH3:8].[CH2:19]([NH2:23])[CH:20]([CH3:22])[CH3:21]>>[C:14]([O:13][C:11](=[O:12])[NH:10][C@H:4]([C:3](=[O:18])[NH:23][CH2:19][CH:20]([CH3:22])[CH3:21])[C@H:5]([OH:9])[CH2:6][CH2:7][CH3:8])([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)CN
Reactant: CCC[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Product: CCC[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(C)C
Yield: 84 %

Procedure:
(2S,3R)-2-tert-Butoxycarbonylamino-3-hydroxy-hexanoic acid methyl ester (D94) (1.57 g, 6.02 mmol, 1 equiv) was refluxed in iso-butylamine (10 ml) for 2 h. The solution was concentrated in vacuo and the residue purified by flash chromatography on silica gel to give ((1S,2R)-2-hydroxy-1-isobutylcarbamoyl-pentyl)-carbamic acid tert-butyl ester (G33) (1.52 g, 84%) as a white solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH:18]([F:20])[F:19])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:21][C:22]1[N:27]=[C:26](Cl)[N:25]=[C:24]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[N:23]=1>CC(C)=O>[Si:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH:18]([F:19])[F:20])[N:14]([C:26]3[N:27]=[C:22]([Cl:21])[N:23]=[C:24]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)[N:25]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2[nH]c(C(F)F)nc12
Solvent: CC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1

Procedure:
Reaction of 4-(tert-butyldimethylsilyloxy)-2-(difluoromethyl)-1H-benzimidazole with 2,4-dichloro-6-(4-morpholinyl)-1,3,5-triazine as in Example 2, but using acetone as solvent, followed by chromatography on silica gel eluting with CH2Cl2/hexanes 3:1 gave 4-(tert-butyldimethylsilyloxy)-1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole: mp (hexanes) 143-145° C.; 1H NMR (CDCl3) δ 7.99 (d, J=8.4 Hz, 1H), 7.46 (t, JHF=53.5 Hz, 1H), 7.32 (t, J=8.2 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H), 3.96 (m, 3.5H), 3.88 (m, 0.5H), 3.81 (m, 3.5H), 3.75 (m, 0.5H), 1.05 (s, 9H), 0.29 (s, 6H); MS (APCI+) 497.9/499.9 MH+. Anal. Calcd. for C21H27ClF2N6O2Si: C, 50.75; H, 5.5; N, 16.9. Found: C, 50.7; H, 5.6; N, 17.0%.
Reaction SMILES: C[N:2]([C:24](OCC1C=CC=CC=1)=O)[N:3]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)C(OCC1C=CC=CC=1)=O.[CH2:34]([NH2:40])[C:35]1[O:39][CH:38]=[CH:37][CH:36]=1.N1C=CC=CC=1.C1C=CC=CC=1>CO.[C].[Pd]>[CH2:34]([NH:40][C:19](=[O:20])[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:3][NH:2][CH3:24])=[CH:23][CH:22]=1)[C:35]1[O:39][CH:38]=[CH:37][CH:36]=1
Reactant: CN(C(=O)OCc1ccccc1)N(Cc1ccc(C(=O)Cl)cc1)C(=O)OCc1ccccc1
Reactant: NCc1ccco1
Agent: [Pd]
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: CO
Product: CNNCc1ccc(C(=O)NCc2ccco2)cc1

Procedure:
By reaction of 23.4 g. of 4-[(2-methyl-1,2-dicarbobenzoxyhydrazino)-methyl]-benzoyl chloride with 4.85 g. of furfurylamine in a mixture of 8 ml. pyridine and 50 ml. of benzene according to the procedure of Example 4 above, followed by hydrogenolysis of the condensation product with palladium-carbon in methanol, there was obtained 4-[(2-methyl-hydrazino)-methyl]-benzoic acid furfurylamide, the oxalate of which melted at 170°-171° (dec.).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].Cl.[CH3:13][NH:14][O:15][CH3:16].Cl.CN(C)CCCN=C=NCC.N1C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:14]([O:15][CH3:16])[CH3:13])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1cccc(Br)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cccc(Br)c1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
500 mg of 3-bromo-2-chlorobenzoic acid are placed in 12.5 ml of tetrahydrofuran in a round-bottomed flask. The reaction mixture is cooled to 0° C. with an ice bath and then 228 mg of N,O-dimethylhydroxylamine hydrochloride, 814 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.21 ml of pyridine are added thereto. The reaction mixture is subsequently stirred at ambient temperature for 16 h and the solvent is evaporated under reduced pressure. The residue is taken up between water and dichloromethane. The separated organic phase is subsequently washed once with a saturated ammonium chloride solution and once with a saturated sodium hydrogencarbonate solution, then dried over magnesium sulphate and concentrated under reduced pressure. 500 mg of compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:18]([OH:20])=O)[C:10](=[O:14])[C:11]=1[CH2:12][CH3:13].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:45][C@H:46]([CH3:49])[CH2:47][OH:48]>CC(N(C)C)=O.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:18]([NH:45][C@H:46]([CH3:49])[CH2:47][OH:48])=[O:20])[C:10](=[O:14])[C:11]=1[CH2:12][CH3:13]
Reactant: CCc1c(OCc2ccc(F)cc2F)ncn(-c2cc(C(=O)O)ccc2C)c1=O
Reactant: C[C@@H](N)CO
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Product: CCc1c(OCc2ccc(F)cc2F)ncn(-c2cc(C(=O)N[C@H](C)CO)ccc2C)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
To a cooled solution (0° C.) of 3-[4-[(2,4-difluorobenzyl)oxy]-5-ethyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (from Step 4) (0.25 g, 0.62 mmol) and 4-methylmorpholine (0.10 mL, 0.94 mmol) in DMA (2 mL) was added isobutyl chloroformate (0.12 mL, 0.94 mmol). Stirred 5 min at 0° C., 30 min at ambient temperature. Added (R)-(−)-2-amino-1-propanol (0.07 mL, 0.94 mmol) and DMAP (0.02 g, 0.12 mmol) to the cooled (0° C.) reaction mixture. Stirred at ambient temperature for 3 h. Purified crude product by preparatory HPLC using a 10–90% CH3CN/H2O (30 min) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z=458) were combined and concentrated to approximately 20 mL under reduced pressure. Added 5% NaHCO3 (20 mL) and extracted with DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and dried in vacuo to give the desired product as an off-white foam (0.20 g, 70%). 1H NMR (CD3OD/400 MHz) δ8.18 (s, 1H), 7.90 (m, 1H), 7.73 (m, 1H), 7.57 (q, 1H, J=8.4 Hz), 7.50 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.52 (q, 2H, J=12.4 Hz), 4.16 (m, 1H), 3.57 (m, 2H), 2.21 (q, 2H, J=7.6 Hz), 2.17 (s, 3H), 1.22 (m, 3H), 1.05 (t, 3H, J=7.2 Hz). ESHRMS m/z 458.1855 (M+H calculated for C24H26F2N3O4 requires 458.1886).