Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[C:3]1[CH3:10].ClC(N(C)C)=C(C)C.[CH2:19]([O:26][C:27]1[CH:34]=[CH:33][C:30]([NH:31][CH3:32])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)C(C)C)C>ClCCCl.ClCCl>[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]([N:31]([CH3:32])[C:7]([C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[C:3]=2[CH3:10])=[O:9])=[CH:33][CH:34]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1c(C(=O)O)ccn1C
Reactant: CNc1ccc(OCc2ccccc2)cc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(C(=O)N(C)c2ccc(OCc3ccccc3)cc2)ccn1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 1,2-dimethylpyrrole-3-carboxylic acid (2.085 g; 15 mmol) in 1,2-dichloroethane (40 mL) there is added 1-chloro-N,N,2-trimethyl-prop-1-en-1-amine (2.37 mL; 17.9 mmol), and the solution formed is stirred for 1 hour. To the resulting solution there is added, dropwise, an ice-cold solution of 4-benzyloxy-N-methyl-aniline (3.73 g; 15 mmol) and N-ethyl-N-isopropyl-propan-2-amine (7.75 mL; 45 mmol) in 1,2-dichloroethane (40 mL). The reaction mixture is stirred at ambient temperature for 1 hour; it is then diluted with dichloromethane (250 mL) and washed with water (2×30 mL), dried over Na2SO4 and evaporated. The crude product is triturated with diethyl ether and the solid formed is filtered off to yield the title compound.
Reaction SMILES: [C:1]([O-])(=O)[CH:2]=[CH2:3].C1CC=CC=1.[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:2]1[CH:1]2[CH:14]3[CH:13]=[CH:12][CH:16]([CH:11]2[CH:17]=[CH:3]1)[CH2:15]3
Reactant: C=CC(=O)[O-]
Reactant: Cc1ccccc1
Agent: C1=CCC=C1
Product: C1=CC2C3C=CC(C3)C2C1

Procedure:
The derivative was synthesized as follows. 20 grams of the derivative of acrylate obtained as the third example was dissolved in 20 milliliters of toluene. 7 grams of cyclopentadiene was dropped into the solution cooled with ice, and was agitated through all night. Dicyclopentadiene was produced as byproduct, and was eliminated in vacuum. Then, 24.9 grams of the derivative of norbornene was obtained. The derivative of norbornene was viscous liquid, and the yield was 95%.
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[C:10]([Cl:16])=[N:11][CH:12]=[CH:13][C:14]=1[I:15])C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:16][C:10]1[C:9]([NH:7][CH3:6])=[C:14]([I:15])[CH:13]=[CH:12][N:11]=1
Reactant: CN(C(=O)OC(C)(C)C)c1c(I)ccnc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1c(I)ccnc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice-cold solution of (2-chloro-4-iodo-pyridin-3-yl)-methyl-carbamic acid tert-butyl ester (0.97 g, 2.63 mmol) in CH2Cl2 (5 mL) was added TFA (6.00 g, 4.05 mL, 52.6 mmol) and the solution was stirred at room temperature for 1.5 hours before another TFA (6.00 g, 4.05 mL, 52.6 mmol) was added. After stirring at room temperature for 3 hours the clear solution was evaporated. The residue was taken up in saturated aqueous NaHCO3 solution (50 mL) and CH2Cl2 (30 mL) and the layers were separated. The aqueous layer was extracted twice with CH2Cl2 (30 mL each) and the organic layers were washed with brine, dried over MgSO4, filtered and evaporated. Colorless oil (0.61 g; 86%). MS (ESI): m/z=268.93 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:6]([Cl:22])=[N:7][C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[N:9][C:10]=1[N:11]([CH3:13])[CH3:12].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH:57]1[C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH:60]=[CH:59][C:58]=1[C:67](O)=[O:68].O>CN(C=O)C>[Cl:22][C:6]1[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:23])=[C:10]([N:11]([CH3:12])[CH3:13])[N:9]=[C:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:67]([C:58]3[CH:59]=[CH:60][C:61]4[C:66](=[CH:65][CH:64]=[CH:63][CH:62]=4)[CH:57]=3)=[O:68])=[CH:19][CH:20]=2)[N:7]=1
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(N)cc2)nc1N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N(C)C

Procedure:
To a mixture of methyl[2-(4-aminobenzyl)-4-chloro-6-(dimethylamino)pyrimidin-5-yl]acetate (0.090 g, 0.30 mmol) and PyBOP (0.187 g, 0.36 mmol) in anhydrous DMF (1 mL) at room temperature was added 2-naphthoic acid (0.062 g, 0.36 mmol). The resulting reaction mixture was stirred at room temperature for 3 hours at which time water was added and the resulting aqueous phase was extracted with EtOAc. The combined organic extracts was sequentially washed with 0.5N HCl, saturated NaHCO3, and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give methyl {4-chloro-6-(dimethylamino)-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate as a colorless oil.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15]([F:27])=[CH:16][C:17]=2[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:12]=1.CS(O[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-:43])=[O:42])[CH:36]=1)(=O)=O>CN(C)C=O>[F:27][C:15]1[CH:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([CH3:10])=[N:12]2)=[C:17]([N:21]2[CH2:26][CH2:25][N:24]([CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-:43])=[O:42])[CH:36]=3)[CH2:23][CH2:22]2)[CH:16]=1
Reactant: CS(=O)(=O)OCCc1cccc([N+](=O)[O-])c1
Reactant: Cc1ccc2c(N3CCNCC3)cc(F)cc2n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(N3CCN(CCc4cccc([N+](=O)[O-])c4)CC3)cc(F)cc2n1
Temperature: 90 °C
Yield: 88 %

Procedure:
N,N-Diisopropylethylamine (0.07 mL; 3 eq) was added to a solution of 2-methyl-5-(1-piperazinyl)-7-fluoro quinoline (0.03 g; 1 eq) and 2-(3-nitrophenyl)ethyl methanesulfonate (D4) (0.033 g; 1.1 eq) in dimethylformamide (1.0 mL). The reaction mixture was heated to 90° C. for 10 hours. The dark solution was cooled to room temperature and concentrated under reduced pressure, diluted with water (3 mL) and brine (1 mL) and extracted into ethyl acetate (3×3 mL). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by flash chromatography on silica, eluting with a gradient from dichloromethane to dichloromethane-MeOH (98:2) affording the title compound in 88% yield (0.04 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[CH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]3)[CH2:10][CH2:9]1.Cl.[H][H]>O.[C].[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]3)[CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: O=C1CCc2cc(C=CCCN3CCN(c4ccccc4Cl)CC3)ccc2N1
Agent: [Pd]
Agent: Cl
Solvent: O
Product: O=C1CCc2cc(CCCCN3CCN(c4ccccc4Cl)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.37 Gram of 6-{4-[4-(2-chlorophenyl)-1-piperazinyl]-1-butenyl}-3,4-dihydrocarbostyril and 0.1 g of 10%-palladium carbon were suspended in 40 ml of water, then 0.2 ml of concentrated hydrochloric acid was added to the suspension and the mixture was catalytically hydrogenated under 5 atmospheric pressure of hydrogen gas at an ordinary temperature. The catalyst was removed by filtration and to the filtrate were added 10N-NaOH and ether and stirred at a room temperature for 30 minutes. The crystals thus precipitated were collected by filtration and recrystallized from ispropanol to obtain 6-{4-[4-(2-chlorophenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyril in colorless prism-like crystals. Yield: 0.27 g. Melting point: 129°-130° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH2:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].C1COCC1.II.[Mg]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]3[N:15]=[C:16]([NH2:18])[N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1nc2c(-c3ccc(F)c(F)c3)cccn2n1
Agent: II
Agent: [Mg]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc2n(n1)CCCC2c1ccc(F)c(F)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 8-(3,4-difluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (prepared in analogy to example 66a-c, 500 mg, 2.03 mmol) in methanol (60 mL) and THF (30 mL) magnesium (395 mg, 16.2 mmol) and iodine (3 mg) were added. After 1.5 hours at room temperature further magnesium (395 mg, 16.2 mmol) was added and the reaction mixture was stirred at 50° C. for 1 hour. Further magnesium (148 mg, 6.09 mmol) was added again and stirred at room temperature for 4 hours. The solvent was evaporated, the residue was dissolved in THF and dried over Na2SO4. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, 100 g, 0% to 15% MeOH/NH3 (9:1) in dichloromethane, 45 minutes). The title compound was obtained as white solid (226 mg, 45%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:10][CH2:9][C:8]2([CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[O:11]2)[CH2:7][CH2:6]1)=[O:4].[C:22](Cl)(=[O:25])[CH2:23][CH3:24].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[F:21][C:2]([F:1])([F:20])[C:3]([N:5]1[CH2:10][CH2:9][C:8]2([CH2:15][CH2:14][C:13]3[CH:16]=[C:17]([C:22](=[O:25])[CH2:23][CH3:24])[CH:18]=[CH:19][C:12]=3[O:11]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(N1CCC2(CCc3ccccc3O2)CC1)C(F)(F)F
Reactant: CCC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCC(=O)c1ccc2c(c1)CCC1(CCN(C(=O)C(F)(F)F)CC1)O2
Temperature: 10 °C
Reaction time: 0.33 h
Yield: 80.2 %

Procedure:
A mixture of 1′-trifluoroacetyl-spiro[3,4-dihydrobenzopyran-2,4′-piperidine] (1.49 g, 4.98 mmol) and propanoyl chloride (0.4 mL, 5 mmol) in methylene chloride (13 mL) was cooled at 10° C. Tin tetrachloride (1M solution in methylene chloride) (0.76 mL, 6.5 mmol) was added at 10° C. and stirred at 10° C. for 20 min then quenched with aqueous 2N HCl at 0° C. The aqueous layer was extracted twice with methylene chloride and the combined organics was washed with brine, dried (Na2SO4), filtered, and concentrated to provide a crude product. The crude product was purified by ISCO (80 g column) chromatography using 17 to 35% EtOAc in hexane to produce 1′-trifluoroacetyl-6-(propanoyl)-spiro[3,4-dihydrobenzopyran-2,4′-piperidine] (1.42 g, 81%),
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[S:12]([NH:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([CH3:32])=[C:21]([CH2:27][C:28]([O:30]C)=[O:29])[C:22](=[O:26])[O:23]2)=[CH:18][CH:17]=1)(=[O:14])=[O:13])#[N:2].Cl>C1COCC1.O>[C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[S:12]([NH:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([CH3:32])=[C:21]([CH2:27][C:28]([OH:30])=[O:29])[C:22](=[O:26])[O:23]2)=[CH:18][CH:17]=1)(=[O:14])=[O:13])#[N:2]
Reactant: COC(=O)Cc1c(C)c2ccc(NS(=O)(=O)c3ccc([N+](=O)[O-])cc3C#N)cc2oc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)c(=O)oc2cc(NS(=O)(=O)c3ccc([N+](=O)[O-])cc3C#N)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 2a was dissolved in THF (3.5 ml), lithium hydroxide•monohydrate (22.2 mg, 0.53 mmol, 7.6 equivalents) dissolved in H2O (3.5 ml) was added under cooling on ice, and the mixture was stirred. After 30 min, the reaction mixture was warmed to room temperature and further stirred. After 3 hr, the disappearance of the starting materials was confirmed by TLC and the reaction mixture was acidified with 5% HCl and extracted with CHCl3. The organic layer was washed with saturated brine, and dried over Na2SO4. The solvent was evaporated, and the residue was purified by silica gel column chromatography (eluate: 1% acetic acid-containing CHCl3:MeOH=20:1) (compound 3a: 29.6 mg, 0.07 mmol, 95%).
Reaction SMILES: O=[C:2]([CH:12]([CH3:14])[CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][CH:2]([CH:12]([CH3:14])[CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:18][CH:17]=1
Reactant: CC(C)C(=O)CCCCCCC(=O)O
Reactant: NCc1ccc(F)cc1
Product: CC(C)C(CCCCCCC(=O)O)NCc1ccc(F)cc1

Procedure:
Using the procedure exemplified in example I step D and starting from 8-oxo 9-methyl decanoic acid and para-fluorobenzylamine, dl 8-(para fluorobenzylamino) 9-methyl decanoic acid is obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])[CH:2]=[CH2:3].[NH2:14][C:15]1[C:16]([CH2:24][CH2:25][CH3:26])=[N:17][N:18]([CH3:23])[C:19]=1[C:20]([NH2:22])=[O:21]>ClCCl.N1C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:14][C:15]1[C:16]([CH2:24][CH2:25][CH3:26])=[N:17][N:18]([CH3:23])[C:19]=1[C:20]([NH2:22])=[O:21])=[O:8])[CH:2]=[CH2:3]
Reactant: CCCc1nn(C)c(C(N)=O)c1N
Reactant: C=CCOc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCOc1ccccc1C(=O)Nc1c(CCC)nn(C)c1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
A solution of 2-allyloxybenzoyl chloride (3.93 g, 0.02 mol) in dichloromethane (20 ml) was added dropwise to a stirred, partial solution of 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide (3.64 g, 0.02 mol) in pyridine (50 ml), and the resulting mixture stirred at room temperature overnight in a dry atmosphere. The solvent was evaporated under vacuum and the residue partitioned between dichloromethane (50 ml) and saturated aqueous sodium carbonate solution (50 ml). The organic layer was separated and the aqueous layer exhaustively extracted with further dichloromethane. The combined organic solutions were washed with 2M Hcl (3×30 ml), then brine (1×30 ml), and dried (Na2SO4). After filtration and evaporation under vacuum of the filtrate, the crude product was crystallised from ethyl acetate to give the title compound (4.525 g, 66%), m.p. 132-134° C. Found: C, 63.49; H, 6.42; N, 16.33. C18H22N4O3 requires C, 63.14; H, 6.48; N, 16.36%.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[CH2:4][C:5]1[S:6][C:7]2[N:8]=[C:9]([S:17][CH3:18])[N:10]=[C:11]([O:14]CC)[C:12]=2[N:13]=1.O1CCOCC1.Cl>O>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[CH2:4][C:5]1[S:6][C:7]2[N:8]=[C:9]([S:17][CH3:18])[N:10]=[C:11]([OH:14])[C:12]=2[N:13]=1
Reactant: CCOc1nc(SC)nc2sc(Cc3c(Cl)cccc3Cl)nc12
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CSc1nc(O)c2nc(Cc3c(Cl)cccc3Cl)sc2n1
Temperature: 90 °C
Reaction time: 12 h
Yield: 62.2 %

Procedure:
To a mixture of 2-(2,6-dichloro-benzyl)-7-ethoxy-5-methylsulfanyl-thiazolo[5,4-d]pyrimidine (1.7 g, 4.4 mmol), 1,4-dioxane (20 mL), and H2O (4 mL) was added 4 N HCl in dioxane (13 mmol, 3.3 mL) and the resulting solution was heated to 90° C. After 12 h, the solution was cooled and concentrated. The resulting residue was purified by FCC to afford the title compound (980 mg, 62%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:5]2[C:10]([CH3:11])=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:18][N:19]([CH3:29])[C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>ClCCl.C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:13][CH2:14][N:15]([C:27]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([N:19]([CH3:29])[CH3:18])=[CH:21][CH:22]=3)=[O:28])[CH2:16][CH2:17]2)[C:5]2[C:10]([CH3:11])=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: CN(C)c1ccc(N=C=O)cc1
Reactant: Cc1csc2nc(N)nc(N3CCNCC3)c12
Solvent: CC#N
Solvent: ClCCl
Product: Cc1csc2nc(N)nc(N3CCN(C(=O)Nc4ccc(N(C)C)cc4)CC3)c12
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of Example 22 (70 mg, 0.28 mmol) in dichloromethane (2 mL) and acetonitrile (2 mL) was added 4-(dimethylamino)phenyl isocyanate (48 mg, 0.29 mmol). The reaction mixture was stirred overnight. The solvents were evaporated in vacuo and the crude residue was purified by flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually increasing from 1% to 4% methanol in dichloromethane), yielding the title compound (75 mg) as a white powder. 13C NMR δ (75 MHz, CDCl3) 171.76, 164.09, 158.58, 155.98, 147.34, 129.12, 128.44, 122.79 (2C), 114.11 (2C), 113.95, 113.07, 49.96 (2C), 43.42 (2C), 40.79 (2C), 16.75. MS (m/z) 412 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.O.[CH:26](/B(O)O)=[CH:27]/[CH3:28].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[CH:4][C:3]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[C:2](/[CH:26]=[CH:27]\[CH3:28])[CH:7]=1)=[O:9]
Reactant: C/C=C\B(O)O
Reactant: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(I)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C/C=C\c1cc(C(=O)OC)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
tert-Butyl 4-(2-iodo-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (127 mg, 0.285 mmol) was dissolved in N,N-dimethylformamide:water=3:1 (2.8 mL). At room temperature, (Z)-propenylboronic acid (59 mg, 0.684 mmol), tetrakistriphenylphosphine palladium (16 mg, 0.0143 mmol) and sodium carbonate (121 mg, 1.14 mmol) were added sequentially, and the mixture was stirred at 80° C. for 1 hour, under microwave irradiation. The reaction solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (96 mg (yield 94%)) was obtained as a yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:25][CH2:26][S:27](Cl)(=[O:29])=[O:28].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:13][CH:14]=2)[C:5]2[N:6]([CH:7]=1)[CH2:25][CH2:26][S:27](=[O:29])(=[O:28])[N:8]=2
Reactant: Nc1ncc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=C(Cl)C=C(c3ccc(OC4CCCCC4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
A mixture of 5-chloro-3-[4-(cyclohexyloxy)phenyl]pyridin-2-amine (210 mg) in THF (dry) (10 mL) was added to a mixture of NaH (60%, 139 mg) and 2-chloroethanesulfonyl chloride (339 mg) in THF (dry) (10.0 mL) at room temperature. The mixture was stirred at room temperature overnight. Water was added and the mixture was concentrated in vacuo. The residue was washed with water and IPE to give the title compound (232 mg) as a pale yellow solid. The solid was crystallized from EtOAc-hexane to give a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:7]=1.[C:19](OC(=O)CC)(=O)[CH2:20][CH3:21].Cl>C(N(CC)CC)C>[CH2:20]([C:21]1[O:18][C:5]2[C:6]([C:8](=[O:17])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH3:19]
Reactant: O=C(Cc1ccccc1F)c1cc(F)ccc1O
Reactant: CCC(=O)OC(=O)CC
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1oc2ccc(F)cc2c(=O)c1-c1ccccc1F
Temperature: 25 °C
Yield: 63.1 %

Procedure:
Intermediate 66 (1.1 g, 4.43 mmoles) was taken in a RB flask and to this triethylamine (10 ml) and propionic anhydride (1.80 g, 13.86 mmoles) were added and the mixture was refluxed for 24 h. After cooling to RT, the reaction mixture was acidified by the addition of 1N HCl solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried with sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-white solid (0.800 g, 63% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 7.82(dd, J=9.0,4.4Hz, 1H), 7.75(m,2H), 7.50(m,1H), 7.37-7.28(m, 3H), 2.56(m,2H), 1.19(t, J=7.6Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][NH:6][CH3:7].[C:12](Cl)(=[O:14])[CH3:13]>O1CCCC1.C([O-])(=O)C.[Na+].C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][N:6]([CH3:7])[C:12](=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: CNCc1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 83.5 %

Procedure:
A solution of (3,4-dichlorobenzyl)-methylamine (0.50 g, 2.63 mmol) (Shapiro et al. J. Amer. Chem. Soc., (1959) 81, 3725) in a mixture of tetrahydrofuran (20 ml) and 40% aqueous sodium acetate (10 ml) was cooled to 0–5° C. (ice bath) and treated with a solution of acetyl chloride (0.3 g in tetrahydrofuran) added dropwise over 5 min. After 1 h at 0–5° C., the reaction mixture was diluted with ethyl acetate, washed successively with 1 N hydrochloric acid, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and distillation of the residue in vacuo gave 0.51 g (83% yield) of the title amide as a clear oil: bp 110–120° C./0.2 torr, (bulb to bulb distillation, air bath temperature). 1HNMR 400 MHz (CDCl3) δ (ppm), mixture of rotamers: 2.36 and 2.39 (3H, 2 s, COCH3), 3.16 (3H, s, NCH3), 4.70 and 4.75 (2H, 2 s, NCH2), 7.2–7.7 (3H, m, aromatics). Anal. calcd for C10H11Cl2NO: C, 51.74; H, 4.78; N, 6.03. Found: C, 51.70; H, 4.77; N, 6.04.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:32])=[C:4]([CH:25]2[CH2:28][N:27]([CH:29]([CH3:31])[CH3:30])[CH2:26]2)[C:5]([O:23][CH3:24])=[C:6]([CH:8]([N:10]2[C:14]3=[N:15][CH:16]=[N:17][C:18]([NH2:19])=[C:13]3[C:12]([CH:20]([F:22])[F:21])=[N:11]2)[CH3:9])[CH:7]=1.[CH3:33][N:34](C)C(=O)C>NC1N=CN=C2N(C(C3C(OC)=C(C4C=CN=C(C(N(CCO)C)=O)C=4)C(C)=C(C#N)C=3)C)N=C(C)C=12.[Zn].[C-]#N.[Zn+2].[C-]#N>[NH2:19][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:10]([CH:8]([C:6]3[C:5]([O:23][CH3:24])=[C:4]([CH:25]4[CH2:26][N:27]([CH:29]([CH3:31])[CH3:30])[CH2:28]4)[C:3]([CH3:32])=[C:2]([CH:7]=3)[C:33]#[N:34])[CH3:9])[N:11]=[C:12]([CH:20]([F:21])[F:22])[C:13]=12
Reactant: CC(=O)N(C)C
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(C)C)C1
Agent: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(C#N)c(C)c1-c1ccnc(C(=O)N(C)CCO)c1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CN(C(C)C)C1
Temperature: 120 °C

Procedure:
0.5 mL of the preformed catalyst (from Example 40) was added to a mixture of 1-{1-[5-chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (22 mg, 0.047 mmol), zinc (1.3 mg, 0.021 mmol) and zinc cyanide (5.6 mg, 0.047 mmol) in N,N-dimethylacetamide (0.7 mL). The mixture was flushed with N2 and heated at 120° C. overnight. The reaction was about 50% complete and was stopped there so that both compounds could be isolated. The reaction mixture was filtered, washing with dichloromethane, and concentrated. The crude was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give both title compounds. The products were isolated as a racemic mixture. Example 126: Yield=6.6 mg (30%); LCMS calculated for C22H28ClF2N6O (M+H)+: m/z=465.2; Found: 465.2; Example 127: Yield=3.0 mg (14%); LCMS calculated for C23H28F2N7O (M+H)+: m/z=456.2; Found: 456.2.