Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]CC2C=CC=CC=2)=[CH:6][C:5]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:27])[C:17]2=[O:28])=[C:4]([F:29])[CH:3]=1.[H][H]>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[N:18]([CH3:27])[C:17]2=[O:28])=[C:4]([F:29])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCc3ccccc3)c(Cl)cc2F)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Yield: 58.9 %

Procedure:
A mixture of 1.12 g (2.61 mmol) of 3-[4-chloro-2-fluoro-5-(phenylmethoxy)phenyl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione and 220 mg of 10% palladium on charcoal in 40 mL of ethyl acetate was placed in a Paar bottle and was agitated under 45 psi hydrogen over a 20 hour period. It was filtered and washed with 100 mL of ethyl acetate. The filtrate was concentrated in vacuo and the resultant crude product flash chromatographed over silica gel eluting with a 1:4 v:v mixture of ethyl acetate and hexane to give 521 mg of the title compound as a white foam.: 1H-NMR (CDCl3, 200 MHz) ppm 7.15 (d, 1H) , 6.9 (d, 1H) , 6.4 (s, 1H), 5.8 (s, 1H), 3.6 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[C:8]([I:21])=[C:9]([C:18](Cl)=[O:19])[C:10]([I:17])=[C:11]([C:15]=1[I:16])[C:12]([Cl:14])=[O:13])=[O:5].C(N(CCCC)CCCC)CCC.[OH:35][CH:36]([CH2:39][OH:40])[CH2:37][NH2:38].CN(C=[O:45])C>>[Cl-:14].[OH:35][CH:36]([CH2:39][OH:40])[CH2:37][NH:38][C:18](=[O:19])[C:9]1[C:8]([I:21])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][O:2][CH3:1])[C:15]([I:16])=[C:11]([C:12]([OH:45])=[O:13])[C:10]=1[I:17]
Reactant: NCC(O)CO
Reactant: COCC(=O)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reactant: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: COCC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NCC(O)CO)c1I
Product: [Cl-]
Temperature: 60 °C
Reaction time: 2 h

Procedure:
50 g. (75 mmol) of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid dichloride is dissolved in 200 ml. of dry DMF; 18 g. (97.3 mmol) of tributylamine is added thereto, the mixture is heated to 60° C., and, at this temperature, a solution of 7.5 g. (82.4 mmol) of 2,3-dihydroxypropylamine in 50 ml. of DMF is added dropwise thereto. The mixture is stirred for 2 hours at 60° C., then concentrated to 100 ml., and stirred into 1.2 l. of methylene chloride. The precipitate thus formed is vacuum-filtered, dried, refluxed twice with respectively 500 ml. of ethyl acetate, and filtered in the hot state. The evaporated filtrate yields 40.5 g. (56 mmol)=74.5% of theory of the desired product as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:15][C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18].O>ClCCl>[CH3:15][C:16]([CH3:21])([CH3:20])[C:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:18]
Reactant: Nc1ccccn1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccccn1
Reaction time: 2 h
Yield: 103 %

Procedure:
2-Aminopyridine (3.1 g, 33 mmol) and triethylamine(6.9 mL, 49 mmol) was dissolved in dichloromethane (40 mL), 2,2-dimethylpropionyl chloride (4.5 mL, 36 mmol) was added on an ice bath, and the solution was stirred for 2 hours at the same temperature. Water was added thereto for extraction, the organic layer was sequentially washed with an aqueous solution of saturated sodium bicarbonate and brine, then, dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, and the title compound (6.0 g, 34 mmol, 102%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:31]=[C:5]2[N:6]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:7]([CH3:20])=[C:8]([C:18]#[N:19])[C@@H:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.N1C=CC=CC=1.Cl[C:39]([O:41][CH:42]([CH3:44])[CH3:43])=[O:40]>C1COCC1>[C:18]([C:8]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[N:4]2[N:3]=[C:2]([NH:1][C:39](=[O:40])[O:41][CH:42]([CH3:44])[CH3:43])[N:31]=[C:5]2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=2)[C:7]=1[CH3:20])#[N:19]
Reactant: CC(C)OC(=O)Cl
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)OC(C)C)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (25 mg, 59 μmol) was dissolved in a mixture of abs. THF (2.5 ml) and abs. pyridine (48 μl, 593 μmol, 10 eq.). At room temperature, isopropyl chloroformate (36 mg, 297 μmol, 5 eq.) was added and the mixture was heated at 80° C. for 12 h. Once HPLC analysis showed substantial conversion, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (23.2 mg, 77% of theory).
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([C:10]1[CH:11]=[C:12]([C:21]([O:23]CC)=[O:22])[C:13]([C:16]([O:18]CC)=[O:17])=[N:14][CH:15]=1)[CH3:9].[OH-].[Na+]>O>[CH2:8]([C:10]1[CH:11]=[C:12]([C:21]([OH:23])=[O:22])[C:13]([C:16]([OH:18])=[O:17])=[N:14][CH:15]=1)[CH3:9]
Reactant: CCOC(=O)c1cc(CC)cnc1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cnc(C(=O)O)c(C(=O)O)c1
Temperature: 25 °C
Yield: 73.7 %

Procedure:
Toluene 50 ml, 5-ethyl-2,3-diethoxycarbonylpyridine 10.3 g (0.041 mol), and water 29 ml were mixed in a 200 ml four neck distillation flask with a reflux condenser, and 48% aqueous sodium hydroxide solution 21.9 g was added thereto under vigorous stirring in nitrogen atmosphere and refluxed for 3.5 hours. The reaction mixture was allowed to cool to room temperature and stand still to separate into water layer and toluene layer. The water layer was acidified at 45° to 55° C. with 28.3 g of 50% sulfuric acid, and slowly cooled to 20° C. The resultant white crystals were filtered and washed with 10 ml of cold water. Dried under reduced pressure at 50° to 60° C., 5.9 g of 5-ethylpyridine-2,3-dicarboxylic acid was obtained. The melting point of the obtained crystals was 154° to 156° C. (decomposed). The 5-ethylpyridine-2,3-dicarboxylic acid obtained was recrystallized from a mixed solvent of acetone and n-hexane and gave a melting point of 156.5° C. to 157.5° C. (decomposed).
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([CH:21]([O:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][N:33]=2)[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[C:27]([Si:24]([CH3:26])([CH3:25])[O:23][CH2:22][CH:21]([CH:10]1[CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:12][NH:8][CH2:9]1)[O:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][N:33]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OCC(Oc1ccc(Cl)cn1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCC(Oc1ccc(Cl)cn1)C1CNCC1c1ccc(Cl)c(Cl)c1
Temperature: 100 °C
Yield: 51.4 %

Procedure:
To a solution of 2-[(RS)-1-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-pyridine (7A-1) 108 mg (0.182 mmol) dissolved in toluene (2 mL) was added 0.059 mL (0.547 mmol) of 1-chloroethyl chloroformate and 0.093 mL (0.547 mmol) of Hunig base subsequently, and the mixture was heated at 100° C. for 40 minutes, then concentrated in vaccuo. The residue was dissolved in methanol (5 mL) and heated at reflux temperature for 30 minutes. The mixture was concentrated in vacuo and diluted with ethyl acetate, then washed with aq. sodium bicarbonate solution twice. The combined organic layers was dried over sodium sulfate and concentrated in vaccuo after filtration. The residue was purified by silica gel column chromatography (DCM/MeOH 10:1 to 4:1) yielding 0.047 g (51%) of the title compound as a light brown oil. ES-MS m/e: 501.2 (M+H+).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([CH:15]([O:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([N:27]2[C:32](=[O:33])[C:31]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]4[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=4)=[CH:37][CH:36]=3)=[C:30]([CH2:49][CH2:50][CH3:51])[N:29]3[N:52]=[C:53]([CH3:55])[N:54]=[C:28]23)[CH2:23][CH2:22]1)[C:16]([OH:19])([CH3:18])[CH3:17])[CH3:14]>O>[CH2:13]([CH:15]([O:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([N:27]2[C:32](=[O:33])[C:31]([CH2:34][C:35]3[CH:36]=[CH:37][C:38]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:47]4[NH:3][C:4](=[O:7])[O:5][N:48]=4)=[CH:39][CH:40]=3)=[C:30]([CH2:49][CH2:50][CH3:51])[N:29]3[N:52]=[C:53]([CH3:55])[N:54]=[C:28]23)[CH2:23][CH2:22]1)[C:16]([OH:19])([CH3:17])[CH3:18])[CH3:14]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(CC)C(C)(C)O)CC2)c2nc(C)nn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OC(CC)C(C)(C)O)CC2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.21 g), sodium hydrogen carbonate (0.34 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-({4-[trans-4-(1-ethyl-2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.11 g) was added, and the mixture was stirred at 90° C. for 11 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.040 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.037 mL) were added, and the mixture was stirred at room temperature for 4 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.079 g, 60%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:20])([CH3:19])[CH2:13][S:14]([O:16]CC)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C([O-])(=O)C.[Na+].[NH2:28]OS(O)(=O)=O>C(O)C.O>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:20])([CH3:19])[CH2:13][S:14]([NH2:28])(=[O:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOS(=O)CC(C)(C)NC(=O)OCc1ccccc1
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(CS(N)(=O)=O)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 86 %

Procedure:
In ethanol (10 ml) was dissolved 0.60 g (2 mmol) of ethyl 2-(benzyloxycarbonylamino)-2-methylpropane-1-sulfinate, and 0.9 g (2.2 mmol) of 10% aqueous sodium hydroxide solution was slowly dropped thereinto under ice-cooling. The reaction was carried out at room temperature for 1 hour and then the ethanol was distilled off. Water (10 ml), 0.18 g (2.2 mmol) of sodium acetate and 0.25 g (2.2 mmol) of hydroxylamine-O-sulfonic acid were added to the residue, and the reaction was carried out at room temperature for 1 hour. The reaction mixture was poured into water, followed by three runs of extraction with ethyl acetate. The extract solution was washed with saturated aqueous sodium hydrogencarbonate solution and then saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off and 0.49 g (yield 86%) of the thus obtained crude 2-(benzyloxycarbonylamino)-2-methylpropane-1-sulfonamide was used without further purification in the subsequent reaction.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=2)[C:8](=[O:22])[CH:7]=1.P(Br)(Br)[Br:28]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:28][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][N:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[F:1])=[CH:7][C:8]2=[O:22])=[CH:15][CH:16]=1
Reactant: O=c1cc(OCc2ccccc2F)ccn1CCc1ccc(CO)cc1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1cc(OCc2ccccc2F)ccn1CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 250 mg (0.71 mmol) 4-(2-fluoro-benzyloxy)-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (example 9.1a) in 4.0 mL of DCM is added 100 μL (1.06 mmol) phosphorus tribromide. The mixture is stirred 2 h at RT and is diluted with half saturated aqueous NaHCO3-solution. The layers are separated and the aqueous phase is extracted three times with DCM. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated to afford the product.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:17][CH2:18]1)=[N:7]2
Reactant: CCOC(=O)Cl
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: CCOC(=O)N1CCN(c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)CC1

Procedure:
Prepared according to Procedure N using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50 mg, 0.11 mmol) and ethyl chloroformate to give ethyl 4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazine-1-carboxylate. 1H NMR (DMSO-d6) δ ppm 1.09 (t, J=7.2 Hz, 3H), 2.13 (s, 3H), 3.04-3.06 (m, 4H), 3.27 (s, 4H), 3.55 (s, 4H), 3.68-3.70 (m, 4H), 4.08 (q, J=6.8 Hz, 2H,), 6.49 (m, 1H), 7.14-7.20 (m, 1H), 7.29 (dd, J=9.8 Hz, J=2 Hz, 1H), 7.52 (d, J=1.6 Hz, 1H), 7.78 (d, J=2 Hz, 1H), 8.38 (s, 1H). Mass Spectrum (ESI) m/e=513.1 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:9])[CH3:8].[Cl:10][CH:11]([C:13]1[O:18][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:15]=2[N:14]=1)[CH3:12]>O1CCCC1.C([Li])CCC.CCCCCC>[Cl:10][CH:11]([CH3:12])[C:13]([NH:14][C:15]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](=[O:19])[CH2:8][C:7]([NH:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[O:9])=[O:18]
Reactant: CC(=O)Nc1nccs1
Reactant: CC(Cl)c1nc2c(F)cccc2c(=O)o1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(Cl)C(=O)Nc1c(F)cccc1C(=O)CC(=O)Nc1nccs1
Yield: 39.2 %

Procedure:
Using the procedure of Step A of Example 6, a solution of 17 g of N-(2-thiazolyl)-acetamide in 340 ml of tetrahydrofuran, 160 ml of butyllithium-hexane solution and 0.06 moles of the product of Step D in 130 ml of tetrahydrofuran were reacted to obtain 8.7 g of 2-[(2-chloro-1-oxo-propyl)-amino]-β-oxo-N-(2-thiazolyl)-3-fluoro-benzene propanamide melting towards 170° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[K+].[CH3:35][C:36]1[O:40][C:39]([C:41]([O-:43])=O)=[N:38][N:37]=1.[F:44][C:45]1[CH:50]=[CH:49][C:48]([N:51]2[C:59]3[C:54](=[CH:55][C:56]([O:60][C@@H:61]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)[C@H:62]([NH2:64])[CH3:63])=[CH:57][CH:58]=3)[CH:53]=[N:52]2)=[CH:47][CH:46]=1>CN(C=O)C.ClCCl>[F:44][C:45]1[CH:46]=[CH:47][C:48]([N:51]2[C:59]3[C:54](=[CH:55][C:56]([O:60][C@H:61]([C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)[C@@H:62]([NH:64][C:41]([C:39]4[O:40][C:36]([CH3:35])=[N:37][N:38]=4)=[O:43])[CH3:63])=[CH:57][CH:58]=3)[CH:53]=[N:52]2)=[CH:49][CH:50]=1
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: Cc1nnc(C(=O)[O-])o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nnc(C(=O)N[C@@H](C)[C@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)c2ccccc2)o1
Reaction time: 0.33 h

Procedure:
To a stirred solution of HATU (630 mg, 1.66 mmol) in DMF (1 ml) was added ethyldiisopropylamine (570 μl, 3.3 mmol), followed by 5-methyl-[1,3,4]oxadiazol carboxylic acid potassium salt (138 mg, 830 μmol) and stirred for 20 min. Then (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (300 mg, 830 mmol) in DMF (1 ml) was added to the brown/red solution and the stirring was continued for 24 h at r.t. The mixture was diluted by dichloromethane and filtrated through a path of silica gel. Solvent was removed under reduced pressure, and the residue was purified by preparative TLC on silica gel (hexane/acetone 50%). Yield 82 mg (21%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[NH:11][C:10](=[S:20])[NH:9]1.[CH3:21][I:22]>CCO>[IH:22].[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C@H:12]1[C@@H:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[NH:9][C:10]([S:20][CH3:21])=[N:11]1
Reactant: Fc1ccccc1[C@H]1NC(=S)N[C@H]1c1ccccc1F
Reactant: CI
Solvent: CCO
Product: CSC1=N[C@@H](c2ccccc2F)[C@@H](c2ccccc2F)N1
Product: I
Temperature: 25 °C
Yield: 94.2 %

Procedure:
A mixture of cis-4,5-bis-(2-fluorophenyl)imidazolidine-2-thione (26) (2.45 g, 0.0084 mol) and methyl iodide (0.79 mL, 0.012 mol) in abs. EtOH (30 mL) is heated at 90° C. overnight. The reaction mixture is cooled to rt, concentrated in vacuo, and the residue crystallized from abs EtOH/Et2O to give 3.42 g of the product 43. 1H NMR (DMSO-d6) δ 10.85 (s, 2H), 7.30-7.10 (m, 4H), 7.10-6.90 (m, 4H), 6.04 (s, 2H), 2.80 (s, 3H); MS: m/z 305 (M++1).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[N:9]=[N:10][NH:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20].[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.ClOC(C)(C)C.[F:36][P-:37]([F:42])([F:41])([F:40])([F:39])[F:38].[K+]>ClCCl>[F:36][P-:37]([F:42])([F:41])([F:40])([F:39])[F:38].[CH3:21][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH+:9]1[CH:29]=[C:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:11]([C:12]2[C:13]([CH3:20])=[CH:14][C:15]([CH3:19])=[CH:16][C:17]=2[CH3:18])[NH:10]1
Reactant: C#Cc1ccccc1
Reactant: Cc1cc(C)c(N=NNc2c(C)cc(C)cc2C)c(C)c1
Agent: CC(C)(C)OCl
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(C)c(N2N[NH+](c3c(C)cc(C)cc3C)C=C2c2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of triazene 8b (845 mg, 3 mmol) and phenylacetylene 9a (660 μL, 6 mmol) in dry dichloromethane (20 mL) in the dark at −78° C. is added tert-butyl hypochlorite (500 μL, 4.4 mmol), upon which the mixture instantly darkens. The mixture is stirred overnight as it is slowly allowed to warm to room temperature. The contents are then filtered, and the solid residue is washed with dichloromethane. The filtrate is collected, and volatiles are evaporated under reduced pressure. The crude solid is redissolved in acetone (20 mL), to which is then added potassium hexafluorophosphate (750 mg, 4 mmol). The mixture is stirred at room temperature for ca. 1 hour, filtered, and the solid residue is washed with dichloromethane. The collected filtrate is evaporated under reduced pressure. Diethyl ether is then added, and the mixture is vigorously triturated for ca. 1 hour, with occasional scratching of the glass surfaces to ensure efficient mixing. Filtration and washing with copious quantities of diethyl ether afford, after drying under vacuum, triazolium salt 10ba as an off-white solid (1.42 g, 89%). Analytical samples were obtained after recrystallization by vapor diffusion of diethyl ether in an acetonitrile solution of 10ba. 1H-NMR (CD3CN, 300 MHz): δ=9.03 (s, 1H), 7.61 (tt, J=7.2, 1.5 Hz, 1H), 7.53-7.43 (m, 4H), 7.24 (s, 2H), 7.20 (s, 2H), 2.42 (s, 3H), 2.39 (s, 3H), 2.21 (s, 6H), 2.04 (s, 6H). 13C-NMR (CD3CN, 75 MHz): δ=145.9, 144.7, 144.4, 136.0, 135.6, 133.5, 132.5, 131.3, 131.0, 130.8, 129.5, 122.9, 21.4, 17.7, 17.6. HR-MS (ESI): Calcd. for C26H28N3 [M+]: 382.2278. found 382.2288.
Reaction SMILES: [CH:1]1([NH2+:7][CH:8]2[CH2:13]CCCC2)CCCCC1.[C:14]([NH:24][C@H:25]([C:35]([O-:37])=[O:36])[CH2:26][CH:27]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O-:30])=[O:29])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[CH:38]1([NH2+:44][CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.CC(C)(N)C[Cl:54]>>[CH3:38][N:7]([CH2:8][CH2:13][O:36][C:35](=[O:37])[C@H:25]([CH2:26][CH:27]([C:31]([CH3:32])([CH3:33])[CH3:34])[C:28]([OH:30])=[O:29])[NH:24][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH3:1].[Cl-:54].[CH:45]1([NH2+:44][CH:38]2[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]2)[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]1
Reactant: CC(C)(C)C(C[C@H](NC(=O)OCc1ccccc1)C(=O)[O-])C(=O)[O-]
Reactant: CC(C)(N)CCl
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Product: CN(C)CCOC(=O)[C@H](CC(C(=O)O)C(C)(C)C)NC(=O)OCc1ccccc1
Product: [Cl-]

Procedure:
In said first step, N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-dicyclohexyl ammonium salt suspended in the organic solvent is reacted with dimethyl-aminoethylchloride in the solution to form N-carbobenzyloxi-γ-tert.butyl-L-glutamic acid-dimethylaminoethyl ester (Intemediate I) and dicyclohexyl-ammonium chloride to be precipitated.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[CH3:26].C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:17]=[C:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][C:21]=3[CH3:26])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[N:3]=1
Reactant: Cc1cccc(-c2nc3nccnc3c(=O)[nH]2)n1
Reactant: Cc1cnccc1N
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: Cc1cccc(-c2nc(Nc3ccncc3C)c3nccnc3n2)n1

Procedure:
The title product was synthesized by reaction of the 2-(2-methyl-6-pyridyl)pteridin-4-one with 4-amino-3-methylpyridine following the procedure described for 4-[(butyl)-(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]1([OH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[N:17]=1>C1(C)C(C)=CC=CC=1.C(Cl)Cl>[C:8]1([O:14][S:2](=[O:4])(=[O:3])[NH:5][C:6]([NH:15][C:16]2[N:17]=[C:18]([O:24][CH3:25])[CH:19]=[C:20]([O:22][CH3:23])[N:21]=2)=[O:7])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Oc2ccccc2)n1
Temperature: 0 °C
Yield: 76.7 %

Procedure:
To a well stirred solution of 1.6 g of chlorosulfonyl isocyanate in 7 ml of dry xylene at ambient temperature and pressure was added 0.9 g of phenol. The resulting mixture was heated to reflux temperature for 1.5 hours. The solvent was removed under reduced pressure to give a clear oil. The oil was diluted with 5 ml of methylene chloride and added to a cooled (ice-water bath) suspension of 1.5 g of 2-amino-4.6-dimethoxypyrimidine in 10 ml of methylene chloride. The solvent was removed under vacuum. The resultant oil was triturated with 1-chlorobutane and filtered to yield 2.6 g of white solid, m.p. 136°-139° C. The infrared spectrum showed characteristic absorption bands at 3150 cm-1, 1720 cm-1, 1625 cm-1, 1580 cm-1.