Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][C:9]1([C:12]([CH:14]2[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]2([CH3:22])[CH3:21])=[CH2:13])[CH2:11][CH2:10]1)(OC(C)(C)C)=O.O.[OH-].[K+]>FC(F)(F)C(O)=O>[NH2:8][C:9]1([C:12]([CH:14]2[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]2([CH3:22])[CH3:21])=[CH2:13])[CH2:11][CH2:10]1
Reactant: C=C(C1C(C)(C)CCC1(C)C)C1(NC(=O)OC(C)(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C=C(C1C(C)(C)CCC1(C)C)C1(N)CC1
Reaction time: 8 h

Procedure:
N-Boc-1-amino-1-(2,2,5,5-tetramethyl-1-cyclopentyl)ethenylcyclopropane is dissolved in trifluoroacetic acid and the solution is stirred overnight. Water is added and the mixture is made basic with 20% KOH. The mixture is extracted with ether, and the organic layer is dried over Na2SO4 and is evaporated to yield 1-amino-1-(2,2,5,5-tetramethyl-1-cyclopentyl)ethenylcyclopropane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15]/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C@@H:30]1[CH2:32][C@@H:31]1[C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C@@H:30]1[CH2:32][C@@H:31]1[C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]([OH:24])[CH2:15]/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:35][CH:34]=1)=[O:29])[CH3:26]
Reactant: CCOC(=O)[C@@H]1C[C@@H]1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C/C=C/c1ccccc1
Product: CCOC(=O)[C@@H]1C[C@@H]1c1ccc(-c2ccc(-c3onc(C)c3C(O)C/C=C/c3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using (E)-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-but-3-en-1-ol and (cis)-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([N:5]1[C:13]2[CH:12]=[CH:11][N:10]=[C:9]([O:14][CH3:15])[C:8]=2[C:7]([C:16]2[CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[S:19][CH:20]=2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O.C1COCC1>[C:1]([N:5]1[C:13]2[CH:12]=[CH:11][N:10]=[C:9]([O:14][CH3:15])[C:8]=2[C:7]([C:16]2[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[S:19][CH:20]=2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(-c2nn(C(C)(C)C)c3ccnc(OC)c23)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1nccc2c1c(-c1csc(C(=O)O)c1)nn2C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a mixture of methyl 4-(1-tert-butyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylate (1.88 g) in a mixed solvent of methanol (30 mL)/THF (30 mL)/water (25 mL) was added 1N aqueous sodium hydroxide solution (5.44 mL) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added 1N hydrochloric acid, and the mixture was concentrated under reduced pressure. The residue was washed with water, and dried in vacuum to give the title compound (1.50 g).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CC(C)=O.C(OCC)(=O)C>[CH2:20]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:2]([CH3:1])([CH3:3])[CH3:4])[CH:19]=[CH2:18]
Reactant: CC(C)(C)c1ccccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C=CCOc1ccccc1C(C)(C)C
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A solution of 150 g (1 mol) of 2-(1,1-dimethylethyl)phenol, 151.8 g (1.1. mol) of potassium carbonate and 115 g (1.05 mol) of allyl bromide dissolved in 500 ml of acetone was stirred at reflux temperature for 70 hours and then cooled to room temperature. Once cooled, all precipitates were removed by filtration and the resulting filtrate was concentrated to provide a residue. This residue was dissolved in ethyl acetate and the resulting solution was washed with a 1 N hydrochloric acid solution, water and then a saturated brine solution and then concentrated to dryness to provide a residue. This residue was purified by column chromatography, using hexane as eluent, to provide 167.1 g of title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][N:13]=[CH:14][C:15](=O)[C:16]([F:19])([F:18])[F:17])=[C:4]([F:21])[CH:3]=1.N1CCCCC1.[CH3:28][CH:29](C(O)=O)[C:30](O)=[O:31].C(O)(=O)C>N1C=CC=CC=1>[F:21][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]=1[N:12]1[C:30](=[O:31])[C:29]([CH3:28])=[C:15]([C:16]([F:19])([F:18])[F:17])[CH:14]=[N:13]1
Reactant: CC(C)Oc1cc(NN=CC(=O)C(F)(F)F)c(F)cc1Cl
Reactant: CC(C(=O)O)C(=O)O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: Cc1c(C(F)(F)F)cnn(-c2cc(OC(C)C)c(Cl)cc2F)c1=O
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 57.2 %

Procedure:
Under a stream of nitrogen gas, 0.399 g of 3,3,3-trifluoro-2-oxopropanal 1-(4-chloro-2-fluoro-5-isopropoxyphenylhydrazone), compound 3-3 was dissolved in 2.4 ml of pyridine at room temperature. To this solution were added 0.133 ml of piperidine and 0.159 g of methylmalonic acid. and the mixture was heated to 70° C. and stirred for 3.5 hours. Then, 2.4 ml of acetic acid was added, and stirring was further continued at 130° C. for 8 hours. The reaction solution was left cooling to room temperature and concentrated under reduced pressure. The residue was diluted with 100 ml of diethyl ether. The diluted solution was washed twice with 20 ml of 3 N hydrochloric acid and once with 30 ml of saturated sodium bicarbonate solution, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography to give 0.255 g of 2-(2-fluoro-4-chloro-5-isopropoxyphenyl)-4-methyl-5-trifluoromethylpyridazin-3-one, compound 5-2.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].N1C=CN=C1>>[Br:1][CH2:2][CH2:3][CH2:4][O:5][Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:12])[CH3:11]
Reactant: OCCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)OCCCBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
A modified procedure of Galka et al. (J. Lab. Comp. Rad. 2005, 48(11): 797-809) was used to prepare the title compound. A mixture of 3-bromopropanol (39.1 mmole; 5.43 g), tert.-butyldimethylsilylchloride (43.2 mmole; 6.47 g) and imidazole (46.7 mmole; 3.20 g) was stirred at RT for 3 hours under inert gas. The reaction was quenched with water, extracted with diethylether, the organic layer dried over MgSO4, filtered and concentrated. The purification was achieved by column chromatography (PE) to yield the title compound (36.4 mmole; 93%). 1H NMR (300 MHz, CDCl3) 3.73 (t; 3J=5.7 Hz; 2H; CH2O); 3.51 (t; 3J=6.4 Hz; 2H; CH2Br); 2.02 (q; 3J=5.7 Hz; 3J=6.4 Hz; 2H; CH2CH2CH2); 0.89 (s; 9H; C(CH3)3); 0.06 (s; 6H; 2×CH3).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:26]=[CH:25][C:17]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].[N+](C1C=CC=CC=1)([O-])=O>[C:19]1([N:18]([C:33]2([N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=3)[CH:32]=[CH:31][C:30]([C:34]3[CH:10]=[CH:9][CH:8]=[CH:13][CH:12]=3)=[CH:29][CH2:28]2)[C:17]2[CH:25]=[CH:26][C:14]([C:11]3[CH:12]=[CH:13][C:8]([NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:9][CH:10]=3)=[CH:15][CH:16]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cccc(I)c1
Reactant: c1ccc(Nc2ccc(-c3ccc(Nc4ccccc4)cc3)cc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1cccc(N(c2ccccc2)C2(N(c3ccccc3)c3ccc(-c4ccc(Nc5ccccc5)cc4)cc3)C=CC(c3ccccc3)=CC2)c1
Yield: 83.6 %

Procedure:
A 500-ml reactor was charged with 33.6 g (0.10 mol) of N,N'-diphenylbenzidine, 25.0 g (0.11 mol) of m-iodotoluene, 27.6 g (0.2 mol) of potassium carbonate, 2.6 g of copper powder, and 200 ml of nitrobenzene. In an argon stream, the contents were heated under reflux for 24 hours. At the end of reaction, the insoluble was removed by filtration and the solvent was distilled off from the filtrate. The still residue was purified twice through a silica gel column with a 1/2mixture of n-hexane and toluene, obtaining 28.10 g of N,N'-diphenyl-N-[4-(N-phenyl-N-3-methylphenylamino)-biphenyl-4-yl]benzidine (yield 42%).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[CH:12][C:13]([F:27])=[C:14]([C@:16]2([CH:24]([F:26])[F:25])[C@@H:22]3[C@@H:20]([CH2:21]3)[O:19][C:18]([NH2:23])=[N:17]2)[CH:15]=1.[C:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[N:35][CH:36]=1)#[C:29][CH3:30]>O1CCOCC1.O.O.C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[F:25][CH:24]([F:26])[C@@:16]1([C:14]2[CH:15]=[C:10]([C:33]3[CH:34]=[N:35][CH:36]=[C:31]([C:28]#[C:29][CH3:30])[CH:32]=3)[CH:11]=[CH:12][C:13]=2[F:27])[C@@H:22]2[C@@H:20]([CH2:21]2)[O:19][C:18]([NH2:23])=[N:17]1
Reactant: CC#Cc1cncc(B(O)O)c1
Reactant: NC1=N[C@@](c2cc(Br)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC#Cc1cncc(-c2ccc(F)c([C@@]3(C(F)F)N=C(N)O[C@@H]4C[C@@H]43)c2)c1
Temperature: 110 °C
Yield: 73.9 %

Procedure:
A microwave vial was charged with mixture of potassium phosphate (0.19 g, 0.90 mmol), (1R,5S,6R)-5-(5-bromo-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine (16f-B, 0.10 g, 0.30 mmol), (5-(prop-1-yn-1-yl)pyridin-3-yl)boronic acid (0.12 g, 0.75 mmol) and 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (10.56 mg, 0.015 mmol) in dioxane/water (2.0/0.5 mL). The reaction mixture was heated to 110° C. for 30 min in the microwave. The reaction mixture was then diluted with water and extracted with DCM three times. The combined organic extracts were washed with brine and dried over sodium sulfate. The filtrate was concentrated in vacuo and the crude material was purified by silica gel chromatography (0-100% EtOAc-DCM) to obtain the title compound as a white solid (82.3 mg, 74% yield). MS m/z=372 [M+H]+. Calculated for C20H16F3N3O: 371.4.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17](SC)=[CH:16][CH:15]=3)=[CH:12][CH:11]=[C:10]2[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:5]([CH3:29])[CH:4]=1)#[N:2].O[O:31][S:32]([O-:34])=O.[K+].[CH3:36]O>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:32]([CH3:36])(=[O:34])=[O:31])=[CH:16][CH:15]=3)=[CH:12][CH:11]=[C:10]2[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:5]([CH3:29])[CH:4]=1)#[N:2]
Reactant: CO
Reactant: O=S([O-])OO
Reactant: CCOC(=O)CCc1ccc(-c2ccc(SC)cc2)n1-c1ccc(C#N)cc1C
Agent: [K+]
Solvent: O
Product: CCOC(=O)CCc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(C#N)cc1C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a vigorously stirred solution of ethyl 3-(1-(4-cyano-2-methylphenyl)-5-(4-(methylthio)phenyl)-1H-pyrrol-2-yl)propanoate 28A (50 mg, 0.12 mmol) in methanol (1 mL) was added dropwise a solution of oxone (300 mg, 0.74 mmol) in water (5 mL) at 20° C. The mixture was stirred for 1 h, diluted with water (10 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by silica gel flash chromatography (PE:EA=3:1) to afford ethyl 3-(1-(4-cyano-2-methylphenyl)-5-(4-(methylsulfonyl)phenyl)-1H-pyrrol-2-yl)propanoate (28B) as a brown solid (120 mg, 37%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12](O)=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].P(Cl)(Cl)(Cl)(Cl)[Cl:17]>C(OCC)C>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([Cl:17])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Solvent: CCOCC
Product: CC(C)Cc1ccc(C(C)C(=O)Cl)cc1
Yield: 98.9 %

Procedure:
4.66 g of 2-(4-isobutylphenyl)propionic acid is agitated in 150 ml of diethyl ether with 5.04 g of phosphorus pentachloride for one hour at 20° C. The mixture is then concentrated under vacuum, thus obtaining 5.02 g of 2-(4-isobutylphenyl)propionyl chloride. This compound is reacted with trimethyl phosphite as described in Example 2, thus producing the dimethyl ester of 2-(4-isobutylphenyl)propionylphosphonic acid. The dimethyl ester is reacted with dimethyl phosphite under the conditions described in Example 2, thus obtaining the 2-(4-isobutylphenyl)-1-hydroxypropane-1,1-bis(phosphonic acid dimethyl ester).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH3:17])[CH2:12][C:11]2=[O:18])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:19]1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+].CCOC(C)=O>C(OC)(OC)OC>[N:1]1[C:2]2[C:3](=[N:4][CH:5]=[CH:6][CH:7]=2)[N:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH3:17])[CH2:12][C:11]2=[O:18])[CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCC1CC(=O)N(CNc2ncccc2N)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CCOC(C)=O
Product: CCCC1CC(=O)N(Cn2cnc3cccnc32)C1
Yield: 302.4 %

Procedure:
A solution of 1-{[(3-aminopyridin-2-yl)amino]methyl}-4-propylpyrrolidin-2-one x78 (1 eq, 1.6 mmol, 300 mg), and para-toluenesulfonic acid (0.32 mmol, 0.2 eq, 42 mg) in trimethyl orthoformate (15 ml) is allowed to react at room temperature for 3 days. After hydrolysis (20 ml of saturated NaHCO3), extraction with AcOEt (2×10 ml), drying of the cumulated organic layers over MgSO4, and filtration, the volatiles are removed under reduced pressure and the crude material is purified by preparative chromatography affording 250 mg of 1-(3H-imidazo[4,5-b]pyridin-3-ylmethyl)-4-propylpyrrolidin-2-one 268.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[N:6]=1)=[O:4].O.[OH-].[Li+]>CO.C(OCC)(=O)C>[Cl:22][C:18]1[CH:17]=[C:16]([C:7]2[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][C:8]=2[CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)[CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(C2CCCO2)c(-c2cccc(Cl)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1ccc(C2CCCO2)c(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
A mixture of 6-(3-chlorophenyl)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid methyl ester (0.3 g, 1 mmol) and lithium hydroxide monohydrate (CAN 1310-66-3, 130 mg, 3 mmol) in THF/H2O 1/1 (20 mL) was stirred at room temperature for 1 h. After removal of the organic solvent under reduced pressure the aqueous phase was washed with ethyl acetate (10 mL) and acidified with 1 N HCl to pH=3. The resulting solution was extracted with ethyl acetate (2×20 mL). The organic layer was concentrated under reduced pressure to give the title compound (0.28 g, 98%) as black oil which was used in the next step without further purification; MS (EI): m/e=304.0 [M+H]+.
Reaction SMILES: N[C@H](C(N[C@H](C(N[C@H]([C:20]([NH:22][C@H](C(O)=O)C)=[O:21])CC(C)C)=O)C)=O)CC(C)C.[CH:28]1[C:33]([C:34]([NH:36][C@H:37]([C:43]([OH:45])=[O:44])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:35])=[CH:32][CH:31]=[C:30]([NH:46][CH2:47][C:48]2[CH:49]=[N:50][C:51]3[N:57]=[C:56]([NH2:58])[N:55]=[C:54]([NH2:59])[C:52]=3[N:53]=2)[CH:29]=1.C1([N:66]=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH:32]1[C:33]([C:34]([NH:36][C@H:37]([C:43]([OH:45])=[O:44])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:35])=[CH:28][CH:29]=[C:30]([NH:46][CH2:47][C:48]2[CH:49]=[N:50][C:51]3[N:57]=[C:56]([NH2:58])[N:55]=[C:54]([NH2:59])[C:52]=3[N:53]=2)[CH:31]=1.[NH2:66][C:20]([NH2:22])=[O:21]
Reactant: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(C)C)C(=O)N[C@@H](C)C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Nc1nc(N)c2nc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2n1
Solvent: CN(C)C=O
Product: NC(N)=O

Procedure:
Conjugation Via Leu-Ala-Leu-Ala Spacer: The N-hydroxysuccinimide ester of aminopterin was prepared as above. To 10.2 ml of a 23 mM solution of the aminopterin derivative (0,236 mmol) in dimethylformamide were added 104 mg (0,236 mmol) of solid L-Leu-L-Ala-L-Leu-L-Ala (LALA). The mixture was stirred overnight at 50° C. during which time the solid LALA dissolved. To the reaction mixture was added 48.7 mg (0.236 mmol) of dicyclohexylcarbodiimide in 0.58 ml of dimethylformamide. Copious quantities of urea formed within 2 hours at room temperature and were removed by filtration. The filtrate containing the N-hydroxy succinimide ester of the LALA derivative of aminopterin was retained.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH:4]1[CH2:6][O:5]1.[NH3:9].[ClH:10]>>[Cl-:10].[F:1][C:2]([F:8])([F:7])[CH2:3][CH:4]([OH:5])[CH2:6][NH3+:9]
Reactant: N
Reactant: Cl
Reactant: FC(F)(F)CC1CO1
Product: [Cl-]
Product: [NH3+]CC(O)CC(F)(F)F
Temperature: 60 °C
Reaction time: 1.25 h
Yield: 53.3 %

Procedure:
2-(2,2,2-Trifluoroethyl)oxirane (5.27 g, 41.8 mmol) was added to a solution of ammonia (2 M in methanol; 170 mL, 340 mmol) and the solution heated to 60° C. After 1.25 h, the mixture was allowed to cool to ambient temperature and concentrated to a volume of 20 mL. HCl (4 M in dioxane; 12 mL, 48 mmol) was added slowly and the mixture concentrated to give a white solid (4.0 g) that was 85% pure and contained 15% of a dimeric byproduct. MS 144.1 (M+H). 1H NMR (500 MHz, CD3OD) δ 4.17-4.12 (m, 1H), 3.10 (dd, J=12.9, 2.9 Hz, 1H), 2.89 (dd, J=12.7, 9.8 Hz, 1H), 2.50, 2.35 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]3C(=O)CCC[C:8]3=[N:7][C:6]=2[C:5](=[O:16])[N:4]([CH3:17])[C:3]1=[O:18]>CS(C)=O>[N:4]1([C:5](=[O:16])[C:6]2[NH:7][CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:18])[CH3:17]
Reactant: Cn1c(=O)c2nc3n(c2n(C)c1=O)C(=O)CCC3
Solvent: CS(C)=O
Product: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reaction time: 8 h
Yield: 53 %

Procedure:
To a solution of 2.4 μmol flavin N6 -aminohexyl-adenine dinucleotide, prepared as described in part A of Example 1 above, in 200 μl dimethylsulfoxide under argon gas was added 0.9 mg 1,3-dimethyl-1,6,7,8-tetrahydropyrido[1,2-e]purine-2,4,9(3H)-trione (3.62 μmol), prepared according to the method of Cook et al, Res. Comm. in Chem. Pathol. and Pharm. 13:497 (1976), followed after 4 hours by addition of a further 1.8 mg (7.3 μmol) of the same. After stirring overnight, the solvent was evaporated under vacuum (0.1 mm Hg) and the residue chromatographed on a 2.5×90 cm LH-20 Sephadex (Pharmacia Fine Chemicals, Uppsala, Sweden) column and eluted with 0.3 M triethylammonium bicarbonate buffer (pH 7.8). The crude product eluted between 210 and 246 ml of the effluent, was collected, applied to a 20×20 cm×1000μ silica gel plate and eluted with an 8:2 ethanol: 1 M triethylammonium bicarbonate buffer (pH 7.8) mixture. The band containing the desired product (Rf =0.77) was scraped from the plate, extracted with 1 M triethylammonium bicarbonate buffer (pH 7.8), filtered and concentrated. Final purification by rechromatography on LH-20 Sephadex eluted with the buffer at 0.3 M gave 1.26μ moles of the labeled conjugate, as determined by absorbance measurement at 450 nm, which was a yield of 53%.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:48]=[CH:47][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)=[CH:24][C:23]=3[F:46])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:66][C:67]1[CH:72]=[CH:71][C:70]([O:73][CH2:74][CH:75]2[CH2:77][O:76]2)=[CH:69][CH:68]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:46][C:23]1[CH:24]=[C:25]([OH:28])[CH:26]=[CH:27][C:22]=1[CH2:21][NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:47]=[CH:48][C:7]([CH2:6][CH2:5][NH:4][CH2:77][CH:75]([OH:76])[CH2:74][O:73][C:70]3[CH:71]=[CH:72][C:67]([OH:66])=[CH:68][CH:69]=3)=[CH:8][CH:9]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](Oc1ccc(CNC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)c(F)c1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: O=C(NCc1ccc(O)cc1F)N1CCC(Nc2ccc(CCNCC(O)COc3ccc(O)cc3)cc2)CC1

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(4-{[tert-butyl(diphenyl)silyl]oxy}-2-fluorobenzyl)-1-piperidinecarboxamide formate (0.855 g, 1.3 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane according to Procedure G to give the title compound (0.24 g, 0.2 mmol).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:27][N:28]([CH3:35])[C@H:29]1[CH2:33][NH:32][CH2:31][C@@H:30]1[OH:34].CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Na+].[Na+]>CC(O)C>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:32]3[CH2:31][C@H:30]([OH:34])[C@@H:29]([N:28]([CH3:35])[CH3:27])[CH2:33]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: CN(C)[C@H]1CNC[C@@H]1O
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CN(C)[C@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2ccn[nH]2)C[C@@H]1O
Temperature: 110 °C

Procedure:
A mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1, 63 mg, 0.156 mmol), (3S,4S)-4-(dimethylamino) pyrrolidin-3-ol (50.8 mg, 0.250 mmol) and DIPEA (0.191 mL, 1.094 mmol) and iPrOH (1 mL) in a sealed vial was heated at 110° C. for 4 h The RM was treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with brine (10 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by preparative SFC (Column 4-EP, isocratic 25% in 15 min) followed by preparative HPLC (Condition 10). Fractions containing product were combined, treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure to give an aq. residue which was extracted with DCM. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the title product as a white foam. HPLC (Condition 7) tR=5.71 min, UPLC-MS (Condition 3) tR=0.78 min, m/z=493 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.14 (s, 6H) 2.95-3.03 (m, 1H) 3.16-3.26 (m, 2H) 3.34-3.46 (m, 2H) 4.00-4.13 (m, 1H) 4.97-5.13 (m, 1H) 6.33-6.45 (m, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.80-7.91 (m, J=9.40 Hz, 3H) 8.04 (s, 1H) 8.68-8.81 (m, 1H) 10.20 (s, 1H) 12.88-13.16 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=[O:8])=[CH:5][NH:4]N=1.[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[N:25]=[C:24](S(C)(=O)=O)[CH:23]=[CH:22][N:21]=3)=[CH:16][CH:17]=2)[CH:12]=[N:11]1.[H-].[Na+].[CH2:32]1COCC1>>[CH3:1][C:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]([C:24]2[CH:23]=[CH:22][N:21]=[C:20]([NH:19][C:15]3[CH:14]=[C:13]4[C:18](=[CH:17][CH:16]=3)[N:10]([CH3:9])[N:11]=[CH:12]4)[N:25]=2)[CH:32]=1
Reactant: Cn1ncc2cc(Nc3nccc(S(C)(=O)=O)n3)ccc21
Reactant: Cc1n[nH]cc1C=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: Cc1cn(-c2ccnc(Nc3ccc4c(cnn4C)c3)n2)cc1C=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66 %

Procedure:
To a solution of 3-methyl-1H-pyrazole-4-carbaldehyde, intermediate 12 (0.33 g, 3.0 mmol) in 10 mL of THF was added 0.12 g of 60% sodium hydride with ice bath cooling and then it was stirred for 20 minute at the same temperature. To this, was added of 10 mL solution of 1-methyl-N-(4-(methansulfonyl)pyrimidin-2-yl)-1H-indazol-5-amine (0.6 g, 2.0 mmol) in THF. The reaction was allowed to warm up to room temperature and then stirred for 2 hours at rt. The reaction was quenched with water, extracted with dichloromethane (×2) and washed with brine. The collected organic layers were dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was solidified with heptane and then collected by filtration to afford the desired intermediate 13 as a white solid (0.45 g, 66%).