Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:28]1[CH:33]=[CH:32][C:31]([C:34]([O:36][CH3:37])=[O:35])=[CH:30][CH:29]=1)[CH:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=1)[C:4]([O:6]CC1C=CC=CC=1)=[O:5]>C(O)C.[Pd]>[OH:1][CH:2]([C:28]1[CH:33]=[CH:32][C:31]([C:34]([O:36][CH3:37])=[O:35])=[CH:30][CH:29]=1)[CH:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=1)[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C(O)C(Cc2cccc(OC(F)(F)C(F)F)c2)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(C(O)C(Cc2cccc(OC(F)(F)C(F)F)c2)C(=O)O)cc1

Procedure:
A solution of benzyl (2RS,3RS)-3-hydroxy-3-[4-(methoxycarbonyl)phenyl]-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate (69.90 g, 134.3 mmol) in ethanol (200 ml) was hydrogenated overnight using 10% palladium/carbon (containing water by 50%). (5 g) as a catalyst under normal pressure. The catalyst was removed by filtration, washed with ethanol, and the solvent of the recovered filtrate was evaporated under reduced pressure to give crude (2RS,3RS)-3-hydroxy-3-[4-(methoxycarbonyl)phenyl]-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionic acid as a colorless foam.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]3[C:16]([C:19]([O-:21])=O)=[CH:17][N:18]=[C:12]3[CH:11]=2)[CH2:3][CH2:2]1.[Li+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:47][C:48]1[C:56]2[C:55]([NH2:57])=[CH:54][CH:53]=[CH:52][C:51]=2[N:50]([CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([CH3:65])[N:60]=2)[N:49]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:47][C:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][C:55]=2[NH:57][C:19]([C:16]2[N:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:11][C:12]3=[N:18][CH:17]=2)=[O:21])[N:50]([CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([CH3:65])[N:60]=2)[N:49]=1
Reactant: O=C([O-])c1cnc2cc(OCCN3CCOCC3)ccn12
Reactant: Cc1cccc(Cn2nc(C)c3c(N)cccc32)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(OCCN6CCOCC6)ccn45)cccc32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.8 %

Procedure:
Lithium 7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxylate (0.055 g, 0.186 mmol) was dissolved in dimethylformamide (0.6 mL), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (53 mL, 0.17 mmol), 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (Example 35, Steps A-D; 0.042 g, 0.167 mmol), and diisopropylethylamine (0.058 mL, 0.334 mmol) were combined in a 1 dram vial. The mixture stirred at ambient temperature overnight. The crude mixture was purified using preparative thin layer chromatography (silica, 20×20 cm, 1 mm) developed in a chamber with 10% Methanol/dichloromethane to give N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxamide (6 mg). MS m/z 526.1 (M+, APCI+).
Reaction SMILES: [C:1]([O:5][CH2:6][C@@H:7]([C:26]([NH:28][C@@H:29]([CH2:63][OH:64])[C@@H:30]([OH:62])[C@@H:31]([OH:61])[C@H:32]([OH:60])[C:33]([NH:35][C@H:36]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:37][C:38]([O:40][CH:41]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])=[O:34])=[O:27])[NH:8]C(OCC1C2CC3C(=CC=CC=3)C=2C=CC=1)=O)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>>[C:1]([O:5][CH2:6][C@@H:7]([C:26]([NH:28][C@@H:29]([CH2:63][OH:64])[C@@H:30]([OH:62])[C@@H:31]([OH:61])[C@H:32]([OH:60])[C:33]([NH:35][C@H:36]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:37][C:38]([O:40][CH:41]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39])=[O:34])=[O:27])[NH2:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1cccc2c1Cc1ccccc1-2)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Solvent: C1CCNCC1
Product: CC(C)(C)OC[C@H](N)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.7 %

Procedure:
To diphenylmethyl (S)-3-[(2S,3R,4R,5S)-5-(O-tert-butyl-N-fluorenylmethyloxycarbonyl-L-seryl)amino-2,3,4,6-tetrahydroxyhexanoyl]amino-3-phenylpropionate (874 mg) was added piperidine (5 ml) and the mixture was stirred at room temperature for 5 hours. Removal of the organic solvent gave a residue, which was subjected to flush silica gel column chromatography, followed by elution with methanol-ethyl acetate (1:2). The effective fractions were combined and concentrated under reduced pressure. The residue was recrystallized from diethylether-hexane to afford the title compound (539 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][CH:8]=1)(=[O:5])=[O:4].[NH2:18][C@@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[C:22]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[CH:23]=[CH:24][CH:25]=2)[CH2:20]1>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:35][N:32]1[CH2:33][CH2:34][N:29]([C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:21]=2[CH2:20][C@H:19]([NH:18][C:13](=[O:15])[C:10]2[CH:9]=[CH:8][C:7]([O:6][S:3]([C:2]([F:1])([F:17])[F:16])(=[O:4])=[O:5])=[CH:12][CH:11]=2)[CH2:28][CH2:27]3)[CH2:30][CH2:31]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc2)CC3)CC1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
4-Carboxyphenyl trifluoromethanesulfonate (0.40 g, 1.5 mmol; described in: Looker, J. H.; Hayes, C. H.; Thatcher, D. N. J. Am. Chem. Soc. 1957, 79, 741-4) was dissolved in thionyl chloride (10 mL) and heated at 40° C. for 45 min. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. The crude acid chloride (280 mg, 0.96 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.46 mmol) and triethylarine (96 μL, 0.69 mmol) in methylene chloride (20 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and then washed with water. The phases were separated and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 100 mg (44%) of the title compound as white crystals: mp 178-180° C.; [α]21D −31° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 497 (17, M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[Si]([O:49][CH:50]1[CH2:53][NH:52][CH2:51]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:11][C:10]1[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([N:52]3[CH2:53][CH:50]([OH:49])[CH2:51]3)[CH:31]=[CH:30][CH:29]=2)[N:7]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=1
Reactant: Cc1cc(-c2nc(-c3ccc(C4CCOCC4)cc3)no2)nn1Cc1cccc(Br)c1
Reactant: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Product: Cc1cc(-c2nc(-c3ccc(C4CCOCC4)cc3)no2)nn1Cc1cccc(N2CC(O)C2)c1

Procedure:
Analogously to the process described in Example 3, 150 mg (0.313 mmol) of the compound from Example 4A and 146 mg (0.469 mmol) of the compound from Example 8A were used to obtain 77 mg (52% of theory) of the title compound.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[N:17]=[C:18]([N:21]=[C:22]([NH2:24])[NH2:23])[S:19][CH:20]=2)[CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[C:5]([NH:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[N:17]=[C:18]([N:21]=[C:22]([NH2:24])[NH2:23])[S:19][CH:20]=2)[CH:13]=[CH:12][CH:11]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CC(=O)NCc1cccc(-c2csc(N=C(N)N)n2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride was added dropwise to a solution of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (0.44 g) in pyridine (4.4 ml). After being stirred for two hours at ambient temperature, the mixture was mixed with aqueous potassium carbonate and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo to give 4-(6-acetylaminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole. The residue was converted to the hydrochloride in a usual manner and the salt was recrystallized from a mixture of methanol and diisopropyl ether to give 4-(6-acetylaminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole dihydrochloride (0.43 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])Cl.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>C(#N)C>[CH3:1][O:2][C:3](=[O:16])[C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])[C:18]1[NH:17][CH:21]=[CH:20][N:19]=1
Reactant: COC(=O)C(Cl)(c1ccccc1)C(C)(C)C
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: COC(=O)C(c1ccccc1)(c1ncc[nH]1)C(C)(C)C

Procedure:
12.7 g (0.05 mole) phenyl-tert.-butyl-chloroacetic acid methyl ester (b.p. 96°C./0.3 mm Hg) are heated to the boil for 17 hours with 10 g imidazole and 100 ml acetonitrile. After the solvent has been distilled off in a vacuum, treatment with 70 ml of water is effected followed by extraction with methylene chloride. The methylene chloride is again extracted with 30 ml of water, dried and distilled off in a vacuum. There is so obtained the phenyl-tert.-butyl-imidazolyl-acetic acid methyl ester as oil, which solidifies after a long time.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]([S:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)([CH3:11])[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])C>CO.[OH-].[Na+]>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([S:12][C:5]([CH3:11])([CH:6]=[CH:7][CH:8]([CH3:9])[CH3:10])[C:4]([OH:21])=[O:3])=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(C)(CC=C(C)C)Sc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(SC(C)(C=CC(C)C)C(=O)O)cc1

Procedure:
2-(4-Methoxy-phenylsulfanyl)-2,5-dimethyl-hexenoic acid was prepared starting from 2-(4-methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid ethyl ester (2.0 g, 6.4 mmol) dissolved in methanol (50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in Example 1. Yield is 1.9 g, 99% of low melting solid. MS: 280 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][NH:5][CH2:4]1.Cl.P([O-])([O-])(O)=O.[K+].[K+].[F:15][C:16]1[CH:17]=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][C:21]=1F>O1CCCC1.C(O)C.[OH-].[OH-].[Pd+2].O.C(#N)C.C(Cl)(Cl)Cl>[F:15][C:16]1[CH:17]=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][C:21]=1[N:5]1[CH2:6][CH:3]([O:2][CH3:1])[CH2:4]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: COC1CNC1
Agent: [Pd+2]
Agent: Cl
Agent: O=P([O-])([O-])O
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COC1CN(c2ccc([N+](=O)[O-])cc2F)C1
Reaction time: 16 h
Yield: 83.8 %

Procedure:
A solution of 1-diphenylmethyl)-3-methoxyazetidine (2.000 g, 7.91 mmol) in 25% tetrahydrofuran/ethanol (100 mL) was treated with 5N HCl (5.0 mL) and palladium hydroxide on carbon (Pearlman's catalyst, 0.500 g). The mixture was shaken on a Parr apparatus under 45 psi of H2. After 16 h some starting material still remained by TLC analysis (silica gel, 6% acetonitrile/chloroform). An additional 0.500 g of Pearlman's catalyst was added and the hydrogenolysis continued a further 16 h, at which time the reaction appeared to be complete. The reaction mixture was filtered through Celite® and the filtrate concentrated under reduced pressure to an amber oil. This material was dissolved in dimethyl sulfoxide (30 mL) and treated with dipotassium hydrogen phosphate (6.88 g, 39.6 mmol) and 3,4-difluoronitrobenzene (1.05 mL, 9.49 mmol). The reaction mixture was stirred at ambient temperature for 16 h, at which time TLC analysis (silica gel, 6% acetonitrile/chloroform) revealed the reaction to be complete. The reaction mixture was diluted with water (150 mL) and extracted with chloroform (3×40 mL). The combined organic extracts were washed with water (3×25 mL) and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a crude product. Purification was accomplished by chromatography over silica gel (100 g), eluting with a gradient of 0-1% acetonitrile/chloroform. Concentration of appropriate fractions then afforded 1.50 g (84%) of the title compound as a bright yellow solid with mp 57.5°-58° C. and MS(EI) 226 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:14]([O:16][CH3:17])=[O:15])([CH3:13])[CH2:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>>[F:18][C:19]([F:29])([F:30])[C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27]([N:10]2[CH2:11][C:12]([C:14]([O:16][CH3:17])=[O:15])([CH3:13])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9]2)=[O:28])=[CH:24][CH:25]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C1(C)CNN=C1c1ccc(Cl)cc1
Product: COC(=O)C1(C)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Yield: 95 %

Procedure:
3-(4-chlorophenyl)-4-carbomethoxy-4-methyl-4,5-dihydro-1H-pyrazole (Example O) and 4-trifluoromethylphenyl isocyanate were reacted by substantially following the procedure given in Example D to give a 95% yield of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-carbomethoxy-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide. NMR data was consistent with the structure.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:33]1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][O:1][N:33]1[C:34](=[O:43])[C:35]2=[CH:42][CH:41]=[CH:40][CH:39]=[C:36]2[C:37]1=[O:38]
Reactant: OCc1ccc2ccccc2c1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCc1ccc2ccccc2c1
Reaction time: 8 h

Procedure:
2-(hydroxymethyl)napthalene (1.00 g, 6.33 mmol), triphenyl phosphine (1.73 g, 6.60 mmol, 1.04 equiv) and N-hydroxyphthalimide (1.08 g, 6.63 mmol, 1.05 equiv) were dissolved in 25 mL of dry THF. Diethylazodicarboxylate (1.09 mL, 6.93 mmol, 1.09 equiv) was then added dropwise and the reaction was stirred overnight. The reaction mixture was placed in a freezer for 2 h and then filtered, rinsing with Et2O, to give the proudct (1.38 g) as a white solid. MS(CI) m/e 321 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[CH:4][N:3]=1.[N:11]1([CH2:17][CH2:18][NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=O)=[CH:22][CH:21]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>O=P(Cl)(Cl)Cl>[Cl:10][C:5]1[C:6]([Cl:9])=[C:7]2[N:8]=[C:24]([C:23]3[CH:27]=[CH:28][C:20]([NH:19][CH2:18][CH2:17][N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[CH:21][CH:22]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)c(Cl)c1N
Reactant: O=C(O)c1ccc(NCCN2CCOCC2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cnc2[nH]c(-c3ccc(NCCN4CCOCC4)cc3)nc2c1Cl
Temperature: 105 °C
Yield: 2 %

Procedure:
2,3-Diamino-4,5-dichloropyridine (Example 206a) (0.10 g, 0.56 mmol) and 4-[(2-morpholin-4-ylethyl)amino]benzoic acid (prepared in a manner analogous to Example 206c) (0.14 g, 0.56 mmol) were dissolved in POCl3 (5 ml) and heated to 105° C. for 5 h. The excess of POCl3 was evaporated off and the residue was dissolved in EtOAc and aqueous K2CO3. The aqueous phase was extracted three times with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), evaporated in vacuo and the residue was purified by HPLC-C18, giving the title product (0.006 g, 2%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].CN(C1C=CC=CN=1)C.[S:39](Cl)([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40].C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[N:10]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(OCc4ccccc4)c3c2c1COC
Agent: CN(C)c1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncc2c(c1COC)c1c(OCc3ccccc3)cccc1n2S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
3.9 g of 5-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester is dissolved in 70 ml of dichloromethane with 1.84 ml of triethylamine and 0.54 g of dimethylaminopyridine. The solution is cooled to 0° C. and then mixed by portions with 2.54 g of tosyl chloride. After stirring for 2 hours at room temperature and standing overnight, it is shaken out three times with sodium hydrogen carbonate solution, the organic phase is concentrated and recrystallized from acetic acid. 4 g of 5-benzyloxy-4-methoxymethyl-9-tosyl-beta-carboline-3-carboxylic acid ethyl ester with a melting point of 149°-150° C. is obtained. This 4 g is dissolved in 40 ml of tetrahydrofuran under argon and mixed at room temperature with 17 ml of a 1.7 molar solution of calcium diisopropoxy aluminum hydride in tetrahydrofuran (Capal); after refluxing for one hour, 17 ml of Capal is added once more and refluxing is continued for 2 hours. After cooling, it is mixed with 2N sodium hydroxide solution and shaken out with acetic acid. The organic phase is concentrated and 3.1 g of 5-benzyloxy-4-methoxymethyl-9-tosyl-3-hydroxymethyl-beta-carboline is obtained, which is suspended in 57 ml of toluene and mixed with 1 ml of azodicarboxylic acid ester. After refluxing for 12 hours, it is concentrated and chromatographed over silica gel with cyclohexane:acetic acid=1:1 as eluant, 1.8 g of 5-benzyloxy-4-methoxymethyl-9-tosyl-beta-carboline-3-carbaldehyde with a melting point of 125°-127° C. is obtained.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][O:28][C:29]3[S:30][C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:30]1[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=[C:29]1[O:28][CH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:19]=[CH:20][C:15]([S:12]([NH:11][CH:7]([CH:8]([CH3:10])[CH3:9])[C:6]([OH:38])=[O:5])(=[O:14])=[O:13])=[CH:16][CH:17]=2)=[CH:22][CH:23]=1
Reactant: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(COc3nc4ccccc4s3)cc2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(COc3nc4ccccc4s3)cc2)cc1)C(=O)O
Reaction time: 6 h

Procedure:
Step 4B 2-[4′-(Benzothiazol-2-yloxymethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester (140 mg, 0.25 mml) was dissolved in 6 mL of methylene chloride followed by the addition of TFA (3 mL) The reaction was complete in 6 hrs as determined by TLC. Solvent was removed and the residue was dissolved in EtOAc. n-Hexane was added into the solution and solid precipitated from the mixture. The precipitate was collected and dried to afford 86 mg of in 68% yield.
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH:27]=[CH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:15][N:16]2COCC[Si](C)(C)C)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.C(N)CN>>[CH3:1][N:2]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH:27]=[CH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:15][NH:16]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1
Reactant: CN(c1cccc(N)c1)c1ccc2c(C=Cc3ccccc3)nn(COCC[Si](C)(C)C)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: C1CCOC1
Product: CN(c1cccc(N)c1)c1ccc2c(C=Cc3ccccc3)n[nH]c2c1
Temperature: 70 °C
Yield: 70.5 %

Procedure:
To N-methyl-N-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-benzene-1,3-diamine (237 mg, 0.5 mmol) was added 1M TBAF in THF (10.1 mL, 10.1 mmol), followed by ethylenediamine (0.34 mL, 5.04 mmol, 10 equiv). The resulting mixture was heated to 70° C. for 5 h. The reaction was then quenched with saturated NaHCO3 (10 mL) and extracted 3×35 mL EtOAc. The pooled EtOAc phase was washed 5×20 mL H2O, then brine (20 mL), dried with Na2SO4, decanted and concentrated under reduced pressure to a foam. The crude material was purified by silica gel chromatography (9:1 dichloromethane/ethyl acetate) to give N-methyl-N-(3-styryl-1H-indazol-6-yl)-benzene-1,3-diamine as a foam (120 mg, 70% yield). Rf sm 0.73, Rf p 0.27 (dichloromethane:ethylacetate 7:3); 13C NMR (75 MHz, CDCl3) δ 150.3, 148.8, 147.5, 147.5, 143.9, 143.4, 137.5, 131.1, 130.3, 129.3, 128.9, 128.2, 127.9, 126.7, 121.0, 120.5, 117.0, 116.0, 112.6, 109.8, 109.0, 98.3, 40.7; LCMS (ESI) [M+H]/z Calc'd 341. Found 341. Anal. Calc'd: C, 77.62; H, 5.92; N, 16.46. Found: C, 76.16; H, 5.88; N, 15.95.
Reaction SMILES: CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:19]1([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[N:28]2[CH2:32][CH2:31][NH:30][C:29]2=[O:33])[CH2:21][CH2:20]1.[Cl:34][C:35]1[CH:40]=[C:39](I)[CH:38]=[CH:37][N:36]=1>C(Cl)(Cl)Cl.[Cu](I)I.CO.O1CCOCC1>[Cl:34][C:35]1[CH:40]=[C:39]([N:30]2[CH2:31][CH2:32][N:28]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][C:22]=3[CH:19]3[CH2:21][CH2:20]3)[C:29]2=[O:33])[CH:38]=[CH:37][N:36]=1
Reactant: Clc1cc(I)ccn1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: O=C1N(c2ccnc(Cl)c2)CCN1c1cnccc1C1CC1
Temperature: 120 °C
Yield: 38.8 %

Procedure:
Copper iodide (6.5 mg, 0.034 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (4.8 mg, 0.034 mmol) and potassium phosphate (219.3 mg, 1.034 mmol) were added to a solution of 1,4-dioxane (5 mL) previously purged with nitrogen (10 minutes). The reaction mixture was purged with argon for 10 minutes, followed by the addition of 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 70 mg, 0.344 mmol) and 2-chloro-4-iodopyridine (99.09 mg, 0.413 mmol). The reaction mixture was heated to reflux at 120° C. overnight. The reaction was monitored by TLC (10% MeOH in chloroform). The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was concentrated to yield the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 42 mg of the product (41% yield).
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[C:27](O)(=[O:36])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:27](=[O:36])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(O)CCc1ccccc1
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: CC(C)CN([C@@H](CCCCNC(=O)CCc1ccccc1)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 81 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with dihydrocinnamic acid under the conditions described in example 86 to yield 81% of the desired product.