Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[S:8][C:9]([C:13]3[N:17]4[N:18]=[C:19]([CH3:27])[CH:20]=[C:21]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:16]4=[N:15][C:14]=3[CH3:28])=[C:10]([CH3:12])[N:11]=2)[CH2:3][CH2:2]1>[Pd].C(O)C>[CH2:23]([CH:22]([C:21]1[C:16]2[N:17]([C:13]([C:9]3[S:8][C:7]([CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[N:11][C:10]=3[CH3:12])=[C:14]([CH3:28])[N:15]=2)[N:18]=[C:19]([CH3:27])[CH:20]=1)[CH2:25][CH3:26])[CH3:24]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(C4=CCOCC4)nc3C)c(C)nc12
Agent: [Pd]
Solvent: CCO
Product: CCC(CC)c1cc(C)nn2c(-c3sc(C4CCOCC4)nc3C)c(C)nc12
Temperature: 40 °C
Yield: 22.9 %

Procedure:
Add 3-[2-(3,6-dihydro-2H-pyran-4-yl)-4-methyl-thiazol-5-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (55 mg, 0.14 mmol), 5% palladium on carbon (55 mg) and absolute ethanol (50 ml) to a pressure vessel. Purge the reaction vessel with nitrogen, purge the reaction vessel with hydrogen, pressurize the reaction mixture with hydrogen (415 KPa), seal the vessel, agitate the reaction and heat to 40° C. Continue the reaction for 18 hours then turn off the heat and allow the reaction mixture to cool to ambient temperature. Vent the excess hydrogen from the vessel and purge the vessel with nitrogen. Filter the reaction mixture to remove the 5% palladium on carbon. The filtrate is concentrated and applied onto a silica-gel chromatography column (Hexane:AcOEt:2 M NH3 in MeOH=10:3:1) to give 12.8 mg of the title compound. Yield 23%. mass spectrum (m/e): 399 (M+1). 1H NMR (CDCl3): δ 6.73 (s, 1H), 4.14 (m, 2H), 3.60 (m, 2H), 3.34 (m, 2H), 2.56 (s, 3H), 2.48 (s, 3H), 2.36 (s, 3H), 2.16 (m, 2H), 2.02 (m, 2H), 1.87 (m, 4H), 0.91 (t, J=7.6 Hz, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:23])[C:18]([O:20]CC)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:23])[C:18]([OH:20])=[O:19])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)O)CC1
Yield: 50.8 %

Procedure:
To a stirred solution of ethyl 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoacetate (0.067 g, 0.21 mmol) in THF (3.0 mL) was added a solution of lithium hydroxide (0.025 g, 1.04 mmol) in water (2.0 mL) at room temperature. After 1 h the reaction mixture was extracted with ethyl acetate (1×5.0 mL) and the aqueous solution acidified with 1 M hydrochloric acid to pH 6. The aqueous layer was extracted with 3:1 chloroform/2-propanol (2×10.0 mL). The combined organics were dried (Na2SO4), filtered, and concentrated under reduced pressure providing 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoacetic acid (0.031 g, 51%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[Cl:8][C:5]1[CH:4]=[C:3]([CH3:9])[C:2]([Cl:1])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: Cc1cc(Cl)ccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cc(Cl)c([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Prepared by a modification of the method of H. D. Dakin and J. B. Cohen, J. Chem. Soc., 79, 1130 (1901). 2,5-Dichlorotoluene (18.7 g, 0.116 mol) was added in one portion to a 10° C. mixture of concentrated sulfuric acid (24 ml) and glacial acetic acid (10 ml). This was stirred at about 10° C. while a cold mixture of 70% nitric acid (8.2 ml) and concentrated sulfuric acid (8.2 ml) was added dropwise over 10 min. The reaction mixture was warmed slowly to room temperature and stirred for 2 hours. The reaction mixture was then recooled to 10° C. with an ice bath and quenched with ice and methylene chloride. The layers were separated and the aqueous layer extracted with methylene chloride. The combined organic layers were washed two times with water, two times with saturated sodium bicarbonate solution and one time with brine. After drying over magnesium sulfate, the solvent was evaporated in vacuo and the crude product crystallized from isopropanol (30 ml). The yield of light yellow solid was 13.4 g, 56%; NMR (CDCl3) δ 7.91 (s, 1), 7.42 (s, 1), 2.43 (s, 3).
Reaction SMILES: C([O:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH3:14])[CH2:7]1)C=C.[OH-].[Na+]>Cl.O>[OH:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH3:14])[CH2:7]1
Reactant: C=CCOCC1CN(CCC)CCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCN1CCOC(CO)C1
Yield: 35 %

Procedure:
2-Allyloxymethyl-4-n-propylmorpholine (59.7 g.) is heated under reflux in hydrochloric acid (240 ml.; 20% ) for 18 hours. The solution is cooled, diluted with ice and water, basified with sodium hydroxide and extracted with ether (3× 200 ml.). The ethereal solution is dried (MgSO4), filtered and the ether evaporated to give recovered starting material. The aqueous layer is concentrated to a small volume and precipitated salt is removed by filtration and washed with ether. The filtrate is extracted with ether (3× 100 ml.) and the combined extracts and ethereal wash are dried (MgSO4), filtered and the ether evaporated. 2-Hydroxymethyl-4-n-propylmorpholine (16.7 g.) is obtained as a viscous oil which forms a hydrogen oxalate, m.p. 133°-135° C. after crystallisation from a methanol/ether mixture.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].Cl>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:7]=[CH:2][C:3]([NH2:8])=[N:9]1
Reactant: NNc1ccccc1F
Agent: Cl
Product: Nc1ccn(-c2ccccc2F)n1
Yield: 24 %

Procedure:
According to the method described in step 1 of example 2, the amine was obtained starting from 2-fluorophenylhydrazine×HCl as brown solid in 24% yield.
Reaction SMILES: Cl.N1C2C(=CC=CC=2)C=C1.C([NH:14][C@@H:15]1[C@@H:21]([OH:22])[C@H:20]([OH:23])[C@@H:19]([CH2:24][OH:25])[O:18][CH:16]1[OH:17])(=O)C>>[OH:17][CH:16]1[O:18][C@H:19]([CH2:24][OH:25])[C@@H:20]([OH:23])[C@H:21]([OH:22])[C@H:15]1[NH2:14]
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Agent: c1ccc2[nH]ccc2c1
Product: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
An enzyme solution (0.1 ml) is added to 0.3 ml of 100 mM phosphate buffer (pH 7.8) containing 0.1 ml of 1% N-acetyl-D-glucosamine as a substrate, and the resultant mixture is incubated at 37° C. for 30 minutes. The amount of D-glucosamine formed is determined colorimetrically using indole-HCl according to the method of Z. Dische and E. Borenfreund [J. Biol. Chem., 184:517 (1950)]. One unit of the enzyme is defined as the amount of the enzyme which is capable of producing 1 μmol D-glucosamine from N-acetyl-D-glucosamine per minute at 37° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:6]=[CH:7][C:8]=1[CH:9]1[C:14](=[O:15])[CH:13]([CH3:16])[O:12][C:11]([CH3:18])([CH3:17])[C:10]1=[O:19])[CH3:2].C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>ClCCl.O>[CH2:1]([C:3]1[CH:4]=[C:5]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[C:14](=[O:15])[CH:13]([CH3:16])[O:12][C:11]([CH3:18])([CH3:17])[C:10]=1[O:19][C:34](=[O:36])[CH3:35])[CH3:2]
Reactant: CCc1cc(-c2ccc(F)cc2)ccc1C1C(=O)C(C)OC(C)(C)C1=O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCc1cc(-c2ccc(F)cc2)ccc1C1=C(OC(C)=O)C(C)(C)OC(C)C1=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 61.3 %

Procedure:
To a solution of 4-(3-ethyl-4′-fluorobiphenyl-4-yl)-2,2,6-trimethylpyran-3,5-dione (0.125 g, 0.35 mmol) in dichloromethane (5 ml) is added triethylamine (0.2 ml, 1.38 mmol) and the reaction mixture is cooled to 0° C. Acetyl chloride (0.22 g, 2.8 mmol) is added slowly at 0° C. and the mixture is stirred at 0° C. for 5 hours. The reaction mixture is diluted with water and extracted with dichloromethane (3×25 ml). The organic extracts are combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to afford acetic acid 4-(3-ethyl-4′-fluorobiphenyl-4-yl)-2,2,6-trimethyl-5-oxo-5,6-dihydro-2H-pyran-3yl ester (0.085 g) as a white solid.
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:38]([C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:67])[O:48][CH2:49][C:50]2([C:56](=[O:66])[NH:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[Cl:65])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=[CH:42][CH:41]=1)[CH3:39].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:38]([C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:67])[O:48][CH2:49][C:50]2([C:56](=[O:66])[NH:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[Cl:65])[CH2:55][CH2:54][N:53]([C:3](=[O:5])[CH2:2][NH:1][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:52][CH2:51]2)=[CH:42][CH:41]=1)[CH3:39]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCc1ccc(NC(=O)OCC2(C(=O)NCc3ccccc3Cl)CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1ccc(NC(=O)OCC2(C(=O)NCc3ccccc3Cl)CCN(C(=O)CNC(=O)OC(C)(C)C)CC2)cc1
Reaction time: 3 h
Yield: 83.2 %

Procedure:
To a solution of Boc-Gly-OH (54 mg, 0.31 mmol, 1.2 equiv.) in DMF (1 mL) were added HATU (120 mg, 0.31 mmol, 1.2 equiv.), followed by addition of (4-(2-chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-ethylphenylcarbamate hydrochloride (120 mg, 0.26 mmol, 1 equiv.) and DIEA (89 μL, 0.51 mmol, 2 equiv.) at rt The reaction mixture was stirred for 3 h and purified on RP-HPLC using a mixture of acetonitrile and H2O to give (1-(2-(tert-butoxycarbonyl)aminoacetyl)-4-(2-chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-ethylphenylcarbamate (127 mg, 84%). LRMS (M-Boc+H+) m/z 487.1.
Reaction SMILES: C(OC([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[C:16](Br)=[CH:15][S:14][C:11]=32)[CH2:7]1)=O)C.[CH3:18][O-:19].[Na+]>CO.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:18][O:19][C:16]1[C:10]2[CH2:9][CH:8]3[CH:12]([C:11]=2[S:14][CH:15]=1)[CH2:13][NH:6][CH2:7]3
Reactant: C[O-]
Reactant: CCOC(=O)N1CC2Cc3c(Br)csc3C2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: COc1csc2c1CC1CNCC21

Procedure:
The product of step b) (57.8 mg, 0.183 mmol) in MeOH (51 μl) was treated with CuO (7 mg, 0.09 mmol), a 25% solution of sodium methoxide in MeOH (129 μl) and tetra-butylammonium iodide (TBAI) (10 mg) at 100° C. for 12 hours. The reaction mixture was cooled and purified by preparative LC/MS to give the title compound. 1H NMR (300 MHz, CDCl3, ppm) 2.40-2.60 (m, 1H); 2.82-3.01 (m, 2H); 3.05-3.63 (br m, 4H); 3.77 (s, 3H); 3.81-3.98 (br s, 1H); 6.17 (s, 1H); MS calculated for C10H13NOS+H 196, observed 196.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]1[C:33]2[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH:25]1[C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>O.CO>[CH2:7]([S:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]1[C:33]2[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH:25]1[C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)=[O:2])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCSCCCCCCCCCC1c2ccc(O)cc2CCC1c1ccc(O)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCS(=O)CCCCCCCCCC1c2ccc(O)cc2CCC1c1ccc(O)cc1
Reaction time: 16 h

Procedure:
A solution of sodium metaperiodate (0.026 g.) in water (2 ml.) was added to a stirred solution of (1RS, 2RS)-1-(9-n-heptylthiononyl)-2-p-hydroxyphenyl-1,2,3,4-tetrahydronaphth-6-ol (Example 7; 0.052 g.) in methanol (20 ml.) and the mixture was stirred for 16 hours. The methanol was removed by evaporation, the residue was extracted three times with ethyl acetate (10 ml. each time) and the combined extracts were washed with water, dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 2:1 v/v mixture of toluene and ethyl acetate as eluant, and there was thus obtained as an oil (1RS, 2RS)-1-(9-n-heptylsulphinylnonyl)-2-p-hydroxyphenyl-1,2,3,4-tetrahydronaphth-6-ol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4].C([Sn](CCCC)(CCCC)[C:31]#[C:32][CH:33]1[CH2:37][CH2:36][CH2:35][N:34]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])CCC.[Cl-].[Li+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:2]([CH3:25])([CH3:24])[C:3]([NH:5][C:6]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:12]([C:31]#[C:32][CH:33]2[CH2:37][CH2:36][CH2:35][N:34]2[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:13]=[CH:14][CH:15]=1)=[O:4]
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)cccc1OS(=O)(=O)C(F)(F)F
Reactant: CCCC[Sn](C#CC1CCCN1C(=O)OC(C)(C)C)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C#CC2CCCN2C(=O)OC(C)(C)C)cccc1NC(=O)C(C)(C)C
Temperature: 95 °C
Yield: 86.7 %

Procedure:
A mixture of methyl 2-(2,2-dimethylpropionylamino)-6-trifluoromethanesulfonyloxybenzoate (Intermediate 39, 3.83 g), tert-butyl 2-tributylstannanylethynyl-pyrrolidine-1-carboxylate (Intermediate 41, 5.81 g), bis(triphenylphosphine)palladium(II) dichloride (0.702 g) and lithium chloride (1.28 g) in dimethylformamide (50 mL) was stirred and heated at 95° C. under nitrogen for 1 hour. After cooling, the mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-25% to give tert-butyl 2-[3-(2,2-dimethylpropionylamino)-2-methoxycarbonyl-phenylethynyl]-pyrrolidine-1-carboxylate (3.71 g) as a viscous gum.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH:9]([CH:15]=[N:16][O:17][CH2:18][CH3:19])[C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[C:4]([CH2:21][S:22][CH3:23])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH:9]([CH:15]=[N:16][O:17][CH2:18][CH3:19])[C:10]([CH:12]2[CH2:13][CH2:14]2)=[O:11])=[C:4]([CH2:21][S:22]([CH3:23])=[O:32])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCON=CC(C(=O)c1ccc(Br)cc1CSC)C(=O)C1CC1
Solvent: ClCCl
Product: CCON=CC(C(=O)c1ccc(Br)cc1CS(C)=O)C(=O)C1CC1
Yield: 78.9 %

Procedure:
To a stirred solution of 1-[4-bromo-2-(methylsulphenylmethyl)phenyl]-3-cyclopropyl-2-(ethoxyiminomethyl)propan-1,3-dione (0.95 g) in dichloromethane cooled to -25° C. was slowly added m-chloroperbenzoic acid (50 to 60%, 0.55 g). The mixture was filtered in the cold and the filtrate diluted with ether and washed with 1M sodium metabisulphite, 25% sodium acetate and brine, dried (anhydrous sodium sulphate) and evaporated. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate and hexane, giving as a yellow gum 1-[4-bromo-2-(methylsulphinylmethyl)phenyl]-3-cyclopropyl-2-(ethoxyiminomethyl)propan-1,3-dione (compound 8, 0.78 g), NMR (CDCl3) δ 1.0-1.4(7H, m), 2.55(3H, s), 2.8(1H, m), 4.0-4.2(4H, m), 7.2(1H, d), 7.5(1H, dd), 7.65(1H, d), 7.7(1H, bs).
Reaction SMILES: NC1C=CC(C2C=NN(CCCO)C=2)=CC=1C(N(CC)CC)=O.[NH2:24][C:25]1[C:26]([C:40]([NH:42][CH3:43])=[O:41])=[N:27][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:30]=1.Br[C:45]1[CH:46]=[N:47][N:48]([C:50]([CH3:55])([CH3:54])[CH2:51][CH2:52][OH:53])[CH:49]=1>>[NH2:24][C:25]1[C:26]([C:40]([NH:42][CH3:43])=[O:41])=[N:27][C:28]([C:45]2[CH:46]=[N:47][N:48]([C:50]([CH3:55])([CH2:51][CH2:52][OH:53])[CH3:54])[CH:49]=2)=[CH:29][CH:30]=1
Reactant: CC(C)(CCO)n1cc(Br)cn1
Reactant: CNC(=O)c1nc(B2OC(C)(C)C(C)(C)O2)ccc1N
Agent: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Product: CNC(=O)c1nc(-c2cnn(C(C)(C)CCO)c2)ccc1N
Yield: 42.8 %

Procedure:
Prepared analogously to Compound 3C using 3-amino-N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (Compound 48D, 649 mg, 2.34 mmol) and 3-(4-bromo-pyrazol-1-yl)-3-methyl-butan-1-ol (Compound 50D, 600 mg, 2.57 mmol) to afford 304 mg of the title compound (43%). 1H NMR (400 MHz, CD3OD) δ 8.34 (d, J=0.5 Hz, 1H), 8.01 (s, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 3.40 (t, J=7.2 Hz, 2H), 2.94 (s, 3H), 2.17 (t, J=7.3 Hz, 2H), 1.66 (s, 6H). MS (ESI): m/z=304.26 [M+H]+. UPLC: tR=0.77 min (UPLC-TOF: polar—2 min).
Reaction SMILES: N1C=CC=CC=1.[C:7]([C:11]1[C:12](=[O:22])[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:15](=O)[CH:16]=1)([CH3:10])([CH3:9])[CH3:8].[NH2:23][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[C:7]([C:11]1[C:12](=[O:22])[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:15](=[N:23][C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)[CH:16]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: Nc1cnccn1
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C1=CC(=Nc2cnccn2)C=C(C(C)(C)C)C1=O
Temperature: 25 °C
Yield: 46.4 %

Procedure:
A 97.1 ml quantity of pyridine was dissolved in 944 ml of dichloroethane, and 32.9 ml of titanium tetrachloride was added thereto. The resulting mixture was refluxed with heating for 15 minutes. To the mixture were then added 132.2 g of 2,6-di-tert-butyl-1,4-benzoquinone and 57.1 g of aminopyrazine, and the mixture was refluxed with heating for 42 hours. The reaction mixture was cooled to room temperature and filtered through a Celite pad and the insoluble materials were washed there with dichloromethane. The filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent: diethyl ether-hexane=3:7), giving 82.8 g of Compound 1a.
Reaction SMILES: Cl.[C:2]([CH2:4][C:5](=[NH:10])[O:6][CH:7]([CH3:9])[CH3:8])#[N:3].[N:11]#[C:12]N>>[C:12]([N:10]=[C:5]([O:6][CH:7]([CH3:9])[CH3:8])[CH2:4][C:2]#[N:3])#[N:11]
Reactant: N#CN
Reactant: CC(C)OC(=N)CC#N
Agent: Cl
Product: CC(C)OC(CC#N)=NC#N
Yield: 68.5 %

Procedure:
3.25 g of isopropyl cyanoacetimidate hydrochloride and 1.26 g of cyanamide were treated with the same manner as in Example 1 and 2.07 g of isopropyl N-cyanocyanoacetimidate was obtained (yield 68.5%) mp 66.5°C. Analysis calculated for C7H9N3O (%) C 55.62, H 6.00, N 27.80, found C 55.41, H 5.91, N 27.66.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@:11]1([C:33]#[C:34][Si](C)(C)C)[O:15][C@@H:14]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:13][C@H:12]1[O:25][Si](C(C)(C)C)(C)C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.CC([Si](Cl)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C>CN(C=O)C>[C:1]([O:9][CH2:10][C@@:11]1([C:33]#[CH:34])[O:15][C@@H:14]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:13][C@H:12]1[OH:25])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn([C@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@](C#C[Si](C)(C)C)(COC(=O)c3ccccc3)O2)c(=O)[nH]c1=O
Agent: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#C[C@]1(COC(=O)c2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
A mixture of 3 (10.35 g, 60.1 mmol), imidazole (8.18 g, 120.2 mmol), and TBDPSCl (15.6 ml, 60.1 mmol) in DMF (40 ml) was stirred for 16 h at room temperature under positive pressure of dry Ar. The mixture was partitioned between EtOAc and sat. aqueous NaHCO3. The organic layer was dried (Na2SO4) and evaporated. The resulting syrupy residue was treated with MeOH (ca. 40 ml) to give the precipitated 4. This procedure was repeated further 3 times to give 4 (18.97 g, 77%) as a white solid.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[NH2:31]>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[NH:31][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:8]=1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Nc1cc(F)ccc1F
Product: Cc1nc(NCc2ccccn2)nc(Nc2cc(F)ccc2F)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (2,5-difluorophenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-yellow solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.09 (s, 3H), 2.35 (s, 3H), 4.75 (d, J=4.8 Hz, 2H), 5.96 (bs, 1H), 6.656-6.62 (m, 1H), 6.67 (bs, 1H), 7.01 (m, 1H), 7.16 (t, J=5.4 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.62 (t, J=7.8 Hz, 1H), 8.29 (bs, 1H), 8.59 (d, J=3.4 Hz, 1H); MS (ESI) m/z 342.7 (M+1)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>C(OCC)(=O)C.CO>[CH3:18][N:19]([CH3:21])[CH:20]=[CH:2][C:1]([C:4]1[CH:5]=[C:6]([NH:10][S:11]([CH2:14][CH3:15])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CCS(=O)(=O)Nc1cccc(C(C)=O)c1
Reactant: COC(OC)N(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Temperature: 150 °C
Yield: 56 %

Procedure:
2 g (8.8 mmol) of N-(3-acetyl-phenyl)-ethanesulfonamide were dissolved in 15 ml of N,N-dimethylformamide dimethyl acetal and heated at 150° C. for 12 h. The solvent was removed by reduced pressure distillation to yield a crude which was chromatographied (silica gel) using ethyl acetate/methanol as eluent. 1.4 g (yield=56%) of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-ethanesulfonamide were obtained.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:22][CH2:21][CH:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:19][CH:18]=2)=[CH:13][C:12]=1[F:31])C1C=CC=CC=1.C(Cl)Cl>CO>[C:27]([Si:24]([CH3:26])([CH3:25])[O:23][CH:20]1[CH2:21][CH2:22][CH:17]([C:14]2[CH:15]=[CH:16][C:11]([NH2:10])=[C:12]([F:31])[CH:13]=2)[CH2:18][CH2:19]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OC1CC=C(c2ccc(NC(=O)OCc3ccccc3)c(F)c2)CC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1CCC(c2ccc(N)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 110.9 %

Procedure:
{4-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohex-1-enyl]-2-fluoro-phenyl}-carbamic acid benzyl ester (1.08 g, 2.37 mmol) was dissolved in MeOH (120 mL) and DCM (5 mL) to form a clear solution. The flask was flushed with nitrogen and Pd—C (10%) (108 mg) was added. The solution was stirred under hydrogen atmosphere at rt for 4 h. TLC (30% and 50% EtOAc in Heptane) indicated that the reaction was complete. The solution was filtered through a Celite pad, rinsed with MeOH. The filtrate was concentrated in vacuo to obtain 0.85 g (100% yield) of the title compound as an oil. This material was used immediately in the following reaction.