Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])([O-])([O-])=O.C1C[O:9]CC1.C(#N)C.[N+](C1C=CC(COC(C2N3[C@H](SC=2)C([CH:33]([O:43][C:44](=O)[CH3:45])[C:34]2[CH:42]=[C:41]4[N:36]([CH2:37][S:38][CH2:39][CH2:40]4)[N:35]=2)(Br)C3=O)=O)=CC=1)([O-])=O>[Zn].C(OCC)(=O)C>[CH2:44]([O:43][C:33]([C:34]1[CH:42]=[C:41]2[N:36]([CH2:37][S:38][CH2:39][CH2:40]2)[N:35]=1)=[O:9])[CH3:45]
Reactant: C1CCOC1
Reactant: CC(=O)OC(c1cc2n(n1)CSCC2)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Agent: O=P([O-])([O-])[O-]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cc2n(n1)CSCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40.5 %

Procedure:
Freshly activated Zn dust (21.4 g) was added rapidly with 0.5 mol/L phosphate buffer (pH 6.5, 112 mL) to the THF (76 mL) and acetonitrile (36 mL) solution of crude (5R)-6-[acetoxy-(4,5-dihydro-6-thia-1,7a-diazainden-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid p-nitrobenzyl ester. The reaction vessel was covered with foil to exclude light. The reaction mixture was vigorously stirred for 1.5 h at room temperature. The reaction solution was cooled at 0° C., and then the pH was adjusted to 8.0. ethyl acetate (56 mL) was added to the mixture and filtered through a pad of Celite. The pad was washed with water (150 mL). The aqueous layer was separated and then the organic layer was extracted with 0.5 mol/L phosphate buffer (pH 6.5, 2×30 mL). The combined aqueous layers were cooled at 0° C., and then the pH was adjusted to 8.0. The mixture was concentrated to 236 g, and then applied to Diaion HP-21 resin (480 mL, Mitsubishi Kasei Co. Ltd.) column chromatography. After adsorbing, the column was eluted with water (960 mL) and then acetonitrile aqueous solution (5%; 960 mL, 10%; 960 mL, 20%; 960 mL). The combined active fractions were concentrated under high vacuum at 35° C. and lyophilized to give the titled compound as a yellow amorphous solid (1.28 g, 40.5%, pH 7.45).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])=[N:9][CH:10]=1)=[N+]=[N-].C(OCC)(=O)C.C(O)C.[H][H]>[Pd].CO.ClCCl>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[C:8]2[N:9]=[CH:10][C:5]([CH2:4][NH2:1])=[CH:6][CH:7]=2)(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCO
Product: NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Yield: 38.7 %

Procedure:
Under argon atmosphere, 5-azidomethyl-2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridine (77 mg, 0.177 mmol), palladium on carbon (14 mg), and ethyl acetate (2 ml) were added to ethanol (10 ml). The resulting mixture was stirred for 50 minutes under 1 atom hydrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to chromatography on a silica gel column. A fraction obtained from the elution portion with dichloromethane:methanol=10:1 was concentrated under reduced pressure, whereby the title compound (28 mg, 0.0685 mmol, 39%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH2:18][OH:19])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[CH2:1]([O:3][C:4]([CH2:6][N:7]([CH:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH2:18][OH:19])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNc1cc(CO)cc(C(=O)OC)c1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(c1cc(CO)cc(C(=O)OC)c1)C(c1ccccc1)c1ccccc1
Temperature: 50 °C

Procedure:
A mixture of the product from step (iv) (3 g), potassium carbonate (15.48 g) and bromodiphenylmethane (2.77 g) in dimethylformamide (100 ml) was heated at 50° C. for 24 hours. The mixture was partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4) and evaporated. Purified by chromatography eluting with 30% ethyl acetate in isohexane. Yield 0.51 g.
Reaction SMILES: [Si]([O:8][C@H:9]1[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[N:11]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Cl:25])[CH:18]=2)[C@H:10]1[CH3:26])(C(C)(C)C)(C)C.C1COCC1.Cl.C(=O)([O-])O.[Na+]>CO>[Cl:25][C:19]1[CH:18]=[C:17]([N:11]2[C@@H:10]([CH3:26])[C@@H:9]([OH:8])[C:13]3([CH2:15][CH2:14]3)[C:12]2=[O:16])[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: C[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C2(CC2)C(=O)N1c1ccc(C#N)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H]1[C@@H](O)C2(CC2)C(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.3 %

Procedure:
To a solution of 4-[(6S,7S)-7-(tert-butyldimethylsilyloxy)-6-methyl-4-oxo-5-azaspiro[2.4]hept-5-yl]-2-chlorobenzonitrile (89.0 mg) in a mixed solvent of THF (6 mL) and methanol (6 mL) was added 6 mol/L hydrochloric acid (4.0 mL), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and recrystallized from hexane-ethyl acetate to give the title compound as a colorless solid (yield: 48.7 mg, 66%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:17])[C:9](=[O:16])[N:10]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[C:24]([Sn](CCCC)(CCCC)CCCC)=[CH:23][CH:22]=[CH:21][N:20]=1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:13][C:12]([CH3:15])([CH3:14])[CH2:11][N:10]1[C:5]2[C:6](=[N:7][C:2]([C:24]3[C:19]([F:18])=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:3][CH:4]=2)[N:8]([CH3:17])[C:9]1=[O:16]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(Cl)nc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1F
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccnc3F)nc21
Temperature: 90 °C

Procedure:
To a microwave vial was added 5-chloro-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (14-1) (25 mg, 0.1 mmol), 2-fluoro-3-(tributylstannanyl)pyridine (55 mg, 0.15 mmol), and bis(tri-t-butylphosphine)palladium(0) (10 mg, 0.02 mmol). The reagents were purged with nitrogen, dissolved in DMF (0.5 ml), and heated at 90° C. overnight. The reaction was cooled to room temperature, diluted with methanol, and passed through a syringe filter. The solution was purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile) and the desired fractions were collected and concentrated to produce 1-(2,2-dimethylpropyl)-5-(2-fluoropyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (22-1). HRMS (M+H)+: observed=315.1618, calculated=315.1616.
Reaction SMILES: [CH3:1][S:2][CH3:3].[F:4][C:5]([F:14])([F:13])[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].ClN1C(=O)CCC1=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2][CH2:3][C:9]1[CH:10]=[CH:11][CH:12]=[C:6]([C:5]([F:4])([F:14])[F:13])[C:7]=1[NH2:8]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: CSC
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSCc1cccc(C(F)(F)F)c1N
Temperature: 15 °C
Reaction time: 0.25 h

Procedure:
Dimethylsulfide, 16 ml, was syringed all at once into a solution of 25.0 grams (g) of 2-(trifluoromethyl)aniline in 400 milliliters (ml) of methylene chloride. The reaction solution was cooled to 15° C. and 29.0 g of N-chlorosuccinimide was added in small portions over a 20 minute period at such a rate that the reaction temperature did not exceed 20° C. The reaction mixture was stirred at 15° C. for 15 minutes, then 30.4 ml of triethylamine was added dropwise over 15 minutes at such a rate that the temperature did not exceed 15° C. After an additional five minutes of stirring, the reaction was refluxed overnight, allowed to cool to room temperature, washed with two 200 ml portions of 10% sodium hydroxide, the organic phase separated, dried with magnesium sulfate and filtered. The remainder of the solvent was distilled off to yield 35.8 g of the crude desired product which was used without any additional purification in subsequent reactions.
Reaction SMILES: [C:1]([N:4]=[C:5](OCC)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[Cl:13])(=O)[CH3:2].Cl.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][NH2:27].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:13][C:7]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=1[C:5]1[N:4]=[C:1]([CH3:2])[N:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([F:18])([F:29])[F:28])[N:27]=1
Reactant: CCOC(=NC(C)=O)c1ccc(F)cc1Cl
Reactant: NNc1ccccc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccc(F)cc2Cl)nn1-c1ccccc1C(F)(F)F

Procedure:
A mixture of 6.1 g (22 mmol) of ethyl N-acetyl-2-chloro-4-fluorobenzimidate and 6.7 g (25 mmol) of o-trifluoromethylphenylhydrazine hydrochloride in 100 ml of toluene is treated with 3.9 ml (28 mmol) of triethylamine and the whole is heated at reflux temperature for 18 hours. Thereafter, the reaction mixture is washed once with water and extracted twice with 50 ml of concentrated hydrochloric acid. The acidic aqueous phases are neutralized with ice-cold sodium hydroxide solution and extracted twice with diethyl ether, and the combined extracts are dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue is subjected to a bulb-tube distillation, the fractions with b.p. 200° C./0.01 mmHg (9.33 Pa) being collected and finally crystallized from diisopropyl ether/n-hexane. In this manner there is obtained 3-(2-chloro-4-fluorophenyl)-5-methyl-1-(α,α,α-trifluoro-o-tolyl)-1H-1,2,4-triazole, m.p. 116° C.; 1H--NMR (CDCl3, 60 MHz): 2.37 (s,CH3); mass spectrum: 335 (48), 314(43), 159(100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5](=[O:8])[CH2:6]Br.[C-]#N.[Na+].ClC1C=C(Cl)C=CC=1C(C[C:22]#[N:23])=O.C(C1C=CC=CC=1C(CC#N)=O)C.C(C1C=CC(C(CC#N)=O)=CC=1)(C)C.C(C1C=C(C=CC=1)C(CC#N)=O)C(C)C.CC1C=C(C=CC=1C)C(CC#N)=O.C(OC1C=C(C=CC=1)C(CC#N)=O)C.C(OC1C=CC(C(CC#N)=O)=CC=1)(C)C.C(OC1C=C(C=CC=1OCC)C(CC#N)=O)C.FC1C=CC(F)=CC=1C(CC#N)=O>O.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([CH2:6][C:22]#[N:23])=[O:8]
Reactant: N#CCC(=O)c1ccc(Cl)cc1Cl
Reactant: O=C(CBr)c1ccc(F)c(F)c1
Agent: CC(C)Cc1cccc(C(=O)CC#N)c1
Agent: CC(C)Oc1ccc(C(=O)CC#N)cc1
Agent: CC(C)c1ccc(C(=O)CC#N)cc1
Solvent: O
Solvent: CCO
Product: N#CCC(=O)c1ccc(F)c(F)c1
Reaction time: 1 h

Procedure:
A solution of 13.2 g. (0.056 mole) of 3,4-difluorophenacyl bromide was dissolved in 100 ml. of ethanol and cooled to 5° C. in ice. A solution of 7.6 g. (0.16 mole) of sodium cyanide in 40 ml. of water was added dropwise over 0.5 hr. and the reaction is stirred for an additional one hour. At that time, the mixture was diluted with 100 ml. of water and filtered through Celite®. Acidification of the filtrate gave a cloudy mixture which was extracted with methylene chloride. The organic phase was dried, filtered through Magnesol® and evaporated. Recrystallization of the residue from carbon tetrachloride provides 5.3 g. (52%) of colorless solid, m.p. 74°-75° C. Similarly prepared were 2,4-dichlorobenzoylacetonitrile, o-ethylbenzoylacetonitrile, p-isopropylbenzoylacetonitrile, m-isobutylbenzoylacetonitrile, 3,4-dimethylbenzoylacetonitrile, m-ethoxybenzoylacetonitrile, p-isopropoxybenzoylacetonitrile, 3,4-diethoxybenzoylacetonitrile, and 2,5-difluorobenzoylacetonitrile.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([S:19][CH3:20])=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([S:19][CH3:20])=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1
Reactant: CSc1ncnc2cc(OCc3ccccc3)ccc12
Solvent: O=C(O)C(F)(F)F
Product: CSc1ncnc2cc(O)ccc12
Yield: 98.1 %

Procedure:
A solution of 7-benzyloxy4-methylsulphanylquinazoline (3 g, 10.6 mmol) in TFA (30 ml) was heated at reflux for 5 hours. After cooling, the volatiles were removed by evaporation. The residue was suspended in water and solid sodium hydrogen carbonate was added until complete dissolution. After extraction with ether, the aqueous layer was acidified to pH2 with 2M hydrochloric acid. The precipitate was collected by filtration, washed with water, followed by ether and dried under vacuum to give 7-hydroxy4-methylsulphanylquinazoline (2 g, quant.).
Reaction SMILES: C([N:9]1[CH2:17][C@@H:16]2[C@@H:11]([N:12]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][CH2:14][O:15]2)[CH2:10]1)(=O)C1C=CC=CC=1.Cl.C(O)(=O)C1C=CC=CC=1>O>[CH2:18]([N:12]1[C@@H:11]2[C@@H:16]([CH2:17][NH:9][CH2:10]2)[O:15][CH2:14][CH2:13]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(c1ccccc1)N1C[C@H]2OCCN(Cc3ccccc3)[C@H]2C1
Agent: Cl
Agent: O=C(O)c1ccccc1
Solvent: O
Product: c1ccc(CN2CCO[C@@H]3CNC[C@@H]32)cc1

Procedure:
91 g (0.265 mol) of cis-8-benzoyl-5-benzyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane are refluxed overnight with 200 ml of concentrated hydrochloric acid and 140 ml of water. The batch is cooled and the benzoic acid suctioned off. The batch is concentrated to half its original volume, adjusted to alkalinity with potassium carbonate, extracted with chloroform, dried over potassium carbonate, concentrated, and distilled.
Reaction SMILES: [OH:1][CH:2]([CH2:24][O:25][C:26]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].N1C=CN=C1.[Si:50](Cl)([C:63]([CH3:66])([CH3:65])[CH3:64])([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C=O)C>[Si:50]([O:1][CH:2]([CH2:24][O:25][C:26]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([C:63]([CH3:66])([CH3:65])[CH3:64])([C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
To a solution of 3 (5 mmol) in 30 ml of DMF is added imidazole (20 mmol) at 0° C. tert-Butyldiphenylsilyl chloride then is added dropwise to this mixture. The mixture is slowly warmed to room temperature. After 6 hours at room temperature, this is poured into ice water and extracted with ethyl acetate. The combined organic phases are washed with saturated NaCl solution, dried over MgSO4, filtrated and concentrated. The residue is purified by silica gel chromatography using isohexane/ethyl acetate (9:1). Yield: 95% of a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[C:4]([CH2:12][O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[C:28]1[CH:33]=[C:32]([CH3:34])[N:31]=[N:30][CH:29]=1)[NH2:24].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:9]([NH:8][C:6]1[CH:5]=[C:4]([CH2:12][O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[N:3]=[C:2]([NH:24][C:23]2[CH:25]=[CH:26][C:27]([C:28]3[CH:33]=[C:32]([CH3:34])[N:31]=[N:30][CH:29]=3)=[C:21]([O:20][CH3:19])[CH:22]=2)[N:7]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Nc1cc(COCC(F)(F)F)nc(Cl)n1
Reactant: COc1cc(N)ccc1-c1cnnc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(NC(C)C)n2)ccc1-c1cnnc(C)c1
Temperature: 120 °C
Yield: 49.4 %

Procedure:
A mixture of 2-chloro-N-isopropyl-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-amine (41 mg, 0.14 mmol), 3-methoxy-4-(6-methylpyridazin-4-yl)aniline (31 mg, 0.14 mmol), cesium carbonate (94 mg, 0.29 mmol), palladium(II) acetate (5 mg, 0.02 mmol) and 2-(dicyclohexyl-phosphino)biphenyl (8 mg, 0.02 mmol) in dioxane (2 mL) was heated under argon at 120° C. for 90 minutes in a microwave reactor. The mixture was filtered through a short silica gel plug which was washed with 10% solution of methanol in ethyl acetate. The eluate was concentrated in vacuum and the residue was purified by preparative HPLC to give the title compound 32 mg (48%).
Reaction SMILES: I[C:2]1[C:3]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]2)=[N:4][C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:6][C:7]=1[O:8][CH3:9].[N:30]1([C:35]2[S:36][CH:37]=[C:38](B3OC(C)(C)C(C)(C)O3)[N:39]=2)[CH:34]=[CH:33][CH:32]=[CH:31]1.C([O-])([O-])=O.[Cs+].[Cs+]>[Pd+2].Cl[Cu].CN(C=O)C>[N:30]1([C:35]2[S:36][CH:37]=[C:38]([C:2]3[C:3]([NH:16][C@@H:17]4[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:18]4)=[N:4][C:5]([N:10]4[CH2:11][CH2:12][O:13][CH2:14][CH2:15]4)=[N:6][C:7]=3[O:8][CH3:9])[N:39]=2)[CH:34]=[CH:33][CH:32]=[CH:31]1
Reactant: CC1(C)OB(c2csc(-n3cccc3)n2)OC1(C)C
Reactant: COc1nc(N2CCOCC2)nc(NC2CCCN(C(=O)OC(C)(C)C)C2)c1I
Agent: Cl[Cu]
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1csc(-n2cccc2)n1
Temperature: 100 °C

Procedure:
In a 40 mL vial chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]-palladium(II) (0.023 g, 0.029 mmol), tert-butyl 3-((5-iodo-6-methoxy-2-morpholinopyrimidin-4-yl)amino)piperidine-1-carboxylate (Compound (21) (0.15 g, 0.289 mmol), 2-(1H-pyrrol-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (0.088 g, 0.318 mmol) and CuCl (0.031 g, 0.318 mmol) were combined. This mixture was then evacuated and backfilled with argon. Then DMF (2.89 ml) and Cs2CO3 (0.376 g, 1.16 mmol) were added to this flask all under argon. This mixture was then heated at 100° C. for 18 h. The mixture was cooled, filtered, diluted with ethyl acetate (mL), washed with water, then dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified via column chromatography. (0-50% EtOAc/hexane) to give the title compound as a white solid. MS (m/z)=542 (M+H).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[CH:17]=[CH:16][C:8]([CH:9]=[N:10][N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)=[CH:7][CH:6]=1)#[N:4]>CO>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][N:11]2[CH:12]=[N:13][N:14]=[CH:15]2)=[CH:16][CH:17]=1)#[N:4]
Reactant: N#Cc1ccc(C=Nn2cnnc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(CNn2cnnc2)cc1
Reaction time: 1 h
Yield: 42.2 %

Procedure:
2.28 Grams of sodium borohydride was added gradually to a suspension of 9.85 g of 4-[(4-cyanobenzylidene)amino]-4H-1,2,4-triazole obtained in Referential Example 1 in 100 ml methanol under ice-cooling. The reaction mixture was stirred at the same temperature for 1 hour, and the solvent was removed by distillation under reduced pressure. Water and sodium chloride were added to the residue successively for salting-out, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was subjected to silica gel column chromatography, and crude crystals from the chloroform/methanol (15:1) eluate were washed with chloroform to give 4.2 g of 4-[(4-cyanobenzyl)amino]-4H-1,2,4-triazole.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][SiH:12]([CH3:14])[CH3:13].[C:15]([Mg]Br)#[CH:16]>>[CH2:11]([Si:12]([CH3:14])([CH3:13])[C:15]#[CH:16])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2]
Reactant: C#C[Mg]Br
Reactant: C[SiH](C)CCCCCCCCCCCl
Product: C#C[Si](C)(C)CCCCCCCCCC
Temperature: 0 °C

Procedure:
A round bottom flask was charged with chlorodecyldimethylsilane (12.362 g; 50.00 mmol) and the flask was cooled with an ice-water bath to 0° C. Ethynylmagnesium bromide (0.5M in THF, 125.0 cm3, 62.50 mmol) was added into the flask over 30 min. The cooling bath was removed and the mixture was stirred at 50° C. for an additional hour.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:34]2[CH:35]=[N:36][N:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=23)=[N:9][C:10]([NH:13][C:14]2[CH:15]=[C:16]([NH2:33])[C:17]([N:22]([CH3:32])[CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[CH:18][C:19]=2[O:20][CH3:21])=[N:11][CH:12]=1>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:34]2[CH:35]=[N:36][N:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=23)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]([CH3:32])[CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[C:16]([NH:33][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: COc1cc(N(C)CCN2CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3cnn4ccccc34)n2)c(OC)cc1N(C)CCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
A solution of acryloyl chloride (0.028 mL, 0.35 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred mixture of N4-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-5-methoxy-N1-methyl-N1-[2-(4-methylpiperazin-1-yl)ethyl]benzene-1,2,4-triamine (Intermediate 107, 0.174 g, 0.33 mmol) in CH2Cl2 (2.5 mL) under N2. The mixture was then stirred at r.t. for 1 h and was then diluted with CH2Cl2 (25 mL). This solution was washed with sat. NaHCO3 (25 mL) and the aqueous wash solution was extracted with CH2Cl2 (20 mL). The combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-8% CH3OH in CH2Cl2 gave the title compound (0.12 g, 63%) as a beige foam; 1H NMR: (CDCl3) 2.31 (3H, s), 2.35-2.6 (10H, m), 2.67 (3H, s), 3.00 (2H, t), 3.88 (3H, s), 5.64-5.82 (1H, m), 6.31-6.50 (2H, m), 6.79 (1H, s), 6.91 (1H, t), 7.29 (1H, t), 7.48 (1H, s), 8.47 (1H, s), 8.54 (2H, t), 8.94 (1H, s), 9.15 (1H, s), 9.38 (1H, s); m/z: ES+ MH+ 576.59.