Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([NH:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:23][NH:22][CH2:21]3)[CH2:16][CH2:15]2)=[O:13])=[C:5]([OH:24])[CH:4]=1.CCN(CC)CC.[C:32](Cl)(=[O:35])[CH:33]=[CH2:34].O>C(Cl)Cl.CN(C=O)C>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([NH:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:23][N:22]([C:32](=[O:35])[CH:33]=[CH2:34])[CH2:21]3)[CH2:16][CH2:15]2)=[O:13])=[C:5]([OH:24])[CH:4]=1
Reactant: O=C(CNc1cc(Cl)c(Cl)cc1O)N1CCN(C2CNC2)CC1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CC(=O)N1CC(N2CCN(C(=O)CNc3cc(Cl)c(Cl)cc3O)CC2)C1
Reaction time: 0.08 h
Yield: 24.2 %

Procedure:
2-(4,5-dichloro-2-hydroxyphenylamino)-1-(4-(azetidin-3-yl)piperazin-1-yl)ethanone hydrochloride (120 mg, 0.30 mmol) was added to the mixture of Et3N (0.2 mL, 1.44 mmol) in DCM (10 mL) followed by addition of DMF (1 drop). The mixture was stirred for 5 min and then acryloyl chloride (27 mg, 0.30 mmol) was added. The resulting mixture was stirred at room temperature for 1 h, poured into water and then extracted with MeOH/DCM. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/MeOH/NH3.H2O=50:1:0.1 to 20:1:0.2) to afford the desired product (30 mg, 24% yield). 1H NMR (400 MHz, DMSO-d6) δ: 10.17 (s, 1H), 6.78 (s, 1H), 6.71 (s, 1H), 6.30 (dd, J=10.4, 17.2 Hz, 1H), 6.09 (dd, J=2.0, 17.2 Hz, 1H), 5.67 (dd, J=2.4, 10.4 Hz, 1H), 5.32 (t, J=4.4 Hz, 1H), 4.26-4.22 (m, 1H), 4.11-4.04 (m, 1H), 3.93-3.91 (m, 3H), 3.79-3.75 (m, 3H), 3.52-3.51 (m, 4H), 3.19-3.16 (m, 1H), 2.36-2.30 (m, 4H). ESI-MS m/z: 411.2 [M−H]−.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:14]([CH:15]=[O:16])=[C:13]([NH:17]C(=O)OC(C)(C)C)[CH:12]=[CH:11][N:10]=1.ClCCl>CC(OC)(C)C>[NH2:17][C:13]1[C:14]([CH:15]=[O:16])=[C:9]([Cl:8])[N:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1C=O
Solvent: COC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccnc(Cl)c1C=O
Temperature: 35 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (17.4 mL, 234 mmol) was added carefully to a stirred mixture of Boc aldehyde 1-4 (20 g, 78.1 mmol) and dichloromethane (60 mL) keeping the temperature below 25° C. The solution was warmed to 35° C., aged overnight (vigorous off-gassing) and then cooled to room temperature. 25 mL of MTBE was added and the resulting white slurry was aged for one hour, filtered, and the filter cake rinsed with MTBE (10 mL×2). Solid 1-5c TFA salt was dried under vacuum.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[CH:2].[Cl:9][C:10]1[C:15]([NH2:16])=[C:14](Cl)[N:13]=[CH:12][N:11]=1.CCN(C(C)C)C(C)C>COCCOC.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:9][C:10]1[C:15]([NH2:16])=[C:14]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:13]=[CH:12][N:11]=1
Reactant: C#Cc1ccccc1
Reactant: Nc1c(Cl)ncnc1Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: Nc1c(Cl)ncnc1C#Cc1ccccc1
Temperature: 25 °C
Yield: 22 %

Procedure:
Ethynylbenzene (0.092 mL, 0.92 mmol) was added to a solution of 4,6-dichloropyrimidin-5-amine (100 mg, 0.61 mmol), Pd(PPh3)4 (140 mg, 0.12 mmol), CuI (116 mg, 0.61 mmol) and DIPEA (0.5 mL, 3.05 mmol) in DME (6.1 mL). The reaction mixture was stirred in the dark over night at room temperature, diluted with DCM, washed sequentially with dilute aqueous citric acid and water, dried over anhydrous Na2SO4 and concentrated under reduce pressure. The residue was purified by flash chromatography, eluent EtOAc/hexane (1:3), to afford title compound 251 (30.8 mg, 22% yield) as a yellow solid. MS (m/z): 230.1 (100.0%), 232.1 (33%) (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[N:13]([CH3:15])[C:12]1[CH2:11][CH2:10][C:9](=[CH:16][C:17]3[N:18]=[CH:19][NH:20][C:21]=3[CH3:22])[C:8](=[O:23])[C:7]2=1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[N:13]([CH3:15])[C:12]1[CH2:11][CH2:10][CH:9]([CH2:16][C:17]3[N:18]=[CH:19][NH:20][C:21]=3[CH3:22])[C:8](=[O:23])[C:7]2=1
Reactant: [H][H]
Reactant: Cc1[nH]cnc1C=C1CCc2c(c3cccc(F)c3n2C)C1=O
Agent: [Pd]
Solvent: CCO
Product: Cc1[nH]cnc1CC1CCc2c(c3cccc(F)c3n2C)C1=O
Yield: 99.4 %

Procedure:
8-Fluoro-1,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4-yl) methylene]-4H-carbazol-4-one (1.5 g) was dissolved in ethanol (50 ml) and added to a suspension of 5% palladium on charcoal (200 mg) in ethanol (ca. 50 ml), and the resulting mixture was hydrogenerated at room temperature and atmospheric pressure until hydrogen uptake had ceased. The mixture was filtered, and the filtrate was evaporated in vacuo to give the title compound (1.5 g), m.p. 189°-191° (decomp.), t.l.c. (System A 100:8:1), Rf 0.43.
Reaction SMILES: [CH:1]([Br:17])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CS(C)=O.C([O-])(O)=O.[Na+]>>[CH2:1]([Br:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCC=CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCC=CCCCCCCCCCCBr
Temperature: 60 °C

Procedure:
Hexadecenyl bromide (360 g; 1.2 mol) and 1800 mL (2660 g; 34 mol) of DMSO were mixed and heated to 60° C. for 30 minutes. Then, NaHCO3 and a co-solvent were added, pressure reduced and temperature raised for the period of time specified in Table I. Reaction mixture was then cooled and concentrated on a rotary evaporator. GLC analysis was then carried out to determine aldehyde/alcohol ratios in the reaction product. Results from reactions employing several different co-solvents are summarized in Table I as runs 5-9.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](=O)([O-])[O-].[Cs+].[Cs+].IC>CC(C)=O.C(OCC)C>[CH3:13][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:12])[C:9]([F:11])=[CH:10][C:2]=1[Cl:1]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: CI
Product: COC(=O)c1cc(F)c(F)cc1Cl
Temperature: 25 °C

Procedure:
2-Chloro-4,5-difluorobenzoic acid (1.93 g, 10 mmol) was dissolved in 20 mL of acetone. Cesium carbonate (5.29 g, 15 mmol) was added followed by iodomethane (1.0 mL, 15 mmol). This reaction mixture was heated under reflux for 1 h and then cooled to room temperature. This suspension was then diluted with 40 mL of ethyl ether. The solid was removed by filtration and washed with ethyl ether. The filtrate was evaporated in vacuo to give the title compound in quantitative yield as a clear oil.
Reaction SMILES: [CH2:1]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[F:22][B-:23]([F:26])([F:25])[F:24].[N:27]#[O+].[K+].[Br-]>C(#N)C.C(Cl)Cl>[F:22][B-:23]([F:26])([F:25])[F:24].[CH2:1]([C:15]1[CH:16]=[CH:17][C:18]([N+:19]#[N:27])=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: N#[O+]
Reactant: CCCCCCCCCCCCCCc1ccc(N)cc1
Agent: F[B-](F)(F)F
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CCCCCCCCCCCCCCc1ccc([N+]#N)cc1
Yield: 69 %

Procedure:
The 4-tetradecylaniline was dissolved in a 1:1 mixture of acetonitrile and dry methylene chloride prior to addition to the nitrosonium tetrafluoroborate. Yield: 69%. MP, 82° C. IR (KBr) 3103.8, 2919.5, 2289.6, 1577.8, 1473.7, 1070.8, 1024.8, 844.5, 813.8, 716.9, 541.0, 510.2 cm−1. IR (KBr) 3103.8, 2919.5, 2289.6, 1577.8, 1473.7, 1070.8, 1024.8, 844.5, 813.8, 716.9, 541.0, 510.2 cm−1. 1H NMR (400 MHz, CDCl3) δ 8.02 (ABq, J=8.8 Hz, Δv=370.6 Hz, 4H), 2.76 (t, J=7.7 Hz, 2H), 1.61 (quin, J=7.8 Hz, 2H), 1.23 (s, 22H), 0.85 (t, J=7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 159.92, 133.26, 131.94, 110.96, 37.49, 32.34, 30.87, 30.12, 30.10, 30.07, 30.04, 29.91, 29.78, 29.75, 29.72, 23.11, 14.55.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CC(C)([O-])C.[K+].Cl[CH2:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30])=[O:21].O>CN(C)C=O.[O-]CC.[Na+]>[NH2:5][C:4]1[C:3]2[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:2]=2[O:1][C:19]=1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30])=[O:21]
Reactant: O=C(CCl)Nc1ccc(Cl)cc1Cl
Reactant: COc1ccc(C#N)c(O)c1
Agent: CC(C)(C)[O-]
Agent: CC[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(N)c(C(=O)Nc3ccc(Cl)cc3Cl)oc2c1
Reaction time: 0.5 h

Procedure:
2-Hydroxy-4-methoxybenzonitrile (3 g) synthesized according to the method described in JP-A-8-253466 was dissolved in dimethylformamide (20 ml) and potassium tert-butoxide (5 g) was added under ice-cooling. After stirring for 30 min, 2-chloro-N-(2,4-dichlorophenyl)acetamide was added and the mixture was further stirred for 1 hr. Then water (20 ml) was added and the crystals were precipitated. The crystals were added to ethanol (20 ml) to give a solution, to which sodium ethoxide (0.6 mg) was added. The mixture was stirred at 78° C. for 1 hr and cooled to give the title compound (1.36 g). melting point: 187-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[CH:10]=[C:11]([C:20]([OH:22])=[O:21])[C:12](=[O:19])[N:13]3[C:18]=2[CH:17]=[CH:16][CH:15]=[CH:14]3)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([C:20]([OH:22])=[O:21])[C:12](=[O:19])[N:13]3[C:18]=2[CH:17]=[CH:16][CH:15]=[CH:14]3)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(C(O)c2ccc(Cl)cc2)c2ccccn2c1=O
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(Cc2ccc(Cl)cc2)c2ccccn2c1=O
Reaction time: 1.5 h

Procedure:
To a solution of 1-[(4-chlorophenyl)(hydroxy)methyl]-4-oxo-4H-quinolizine-3-carboxylic acid (0.300 mg, 0.910 mmol) in 5 mL of CH2Cl2 was added triethylsilane (0.29 mL, 1.8 mmol) and trifluoroacetic acid (0.35 mL, 4.5 mmol). After 1.5 h, 10 mL of water was added, and the reaction was extracted with CH2Cl2, dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was subjected to purification via reverse phase HPLC to yield the title compound that gave a mass ion (ES+) of 313.96 for M+H+. 1H NMR (400 MHz, CD3OD) δ 9.49 (d, J=7.1 Hz, 1H), 8.40 (s, 1H), 8.07 (d, J=9.1 Hz, 1H), 7.99-7.94 (m, 1H), 7.62-7.58 (m, 1H), 7.32 (d, J=8.5 Hz, 2H), 7.22 (d, J=8.8 Hz, 1H), 4.32 (s, 2H).
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][CH2:14][C:15]3=[O:18])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1>CO>[F:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][CH2:14][CH:15]3[OH:18])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCc2ccc(-c3cccc(F)c3)cc21
Agent: [Na]
Solvent: CO
Product: OC1CCc2ccc(-c3cccc(F)c3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
Sodium borohyride (19 mg, 0.5 mmol) was added to a solution of 6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-one (55 mg, 0.24 mmol) and methanol (12 mL) in a 100 mL round bottom flask at 0° C. After stirring for 1 hour, the resulting mixture was warmed to room temperature. The reaction was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (100 mL). The organic extract was dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (4 g column, hexanes→100% ethyl acetate/hexanes, gradient) to afford 55 mg (99%) of 6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-ol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8](OCC)=O)=[N:4][NH:5][C:6]=1C.[CH2:13]([N:17](CCCC)[C:18]1[CH:22]=[C:21]([CH3:23])NN=1)[CH2:14][CH2:15][CH3:16]>>[CH2:13]([N:17]([CH2:18][CH2:22][CH2:21][CH3:23])[C:6]1[C:2]([Cl:1])=[C:3]([CH3:8])[NH:4][N:5]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN(CCCC)c1cc(C)[nH]n1
Reactant: CCOC(=O)c1n[nH]c(C)c1Cl
Product: CCCCN(CCCC)c1n[nH]c(C)c1Cl
Yield: 61 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1A, N,N-dibutyl-5-methyl-1H-pyrazol-3-amine (419 mg, 2.00 mmol) was converted to the title compound (297 mg, 61%). 1H NMR (CDCl3) δ 3.26-3.17 (m, 4H), 2.19 (s, 3H), 1.57-1.44 (m, 4H), 1.32 (qd, J=15.0, 7.3 Hz, 4H), 0.91 (t, J=7.4 Hz, 6H); MS(ESI+) m/z 243.9 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:5]=1
Reactant: C1CCNCC1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1N1CCCCC1
Yield: 44.9 %

Procedure:
A suspension of methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.081 g; 0.25 mmol), piperidine (0.122 mL; 1.228 mmol) and potassium carbonate (0.102 mg; 0.737 mmol) in acetonitrile (1 mL) was irradiated at 130° C. for 2 h in a microwave oven. The mixture was partitioned between brine and ethyl acetate, the phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (1-10%) in heptane furnished 0.042 g (46%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:34][N:35]1[CH:40]2[CH2:41][CH2:42][CH:36]1[CH2:37][NH:38][CH2:39]2>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:38]4[CH2:37][CH:36]5[N:35]([CH3:34])[CH:40]([CH2:41][CH2:42]5)[CH2:39]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CN1C2CCC1CNC2
Product: CN1C2CCC1CN(C1=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S1)C2

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-thiazol-4-one was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 8-methyl-3,8-diaza-bicyclo[3.2.1]octane following General Procedure C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH2:46])=[CH:43][CH:42]=1.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C(O[Na])(C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6](=[O:39])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:46][CH2:45][C:44]5[CH:47]=[CH:48][C:41]([Cl:40])=[CH:42][CH:43]=5)[CH:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(Br)c4)nn(COCC[Si](C)(C)C)c3n2)CC1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(NCc5ccc(Cl)cc5)c4)nn(COCC[Si](C)(C)C)c3n2)CC1

Procedure:
To a stirred solution of {4-[3-(3-bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 39 supra) (300 mg, 0.48 mmol), 4-chlorobenzylamine (120 mg, 1.06 mmol), DavePhos (20 mg, 0.048 mmol) and t-BuONa (56 mg, 0.58 mmol) in 1,4-dioxane (10 mL), Pd2(dba)3 (28 mg, 0.48 mmol) was added in one portion under N2 atmosphere. The resultant mixture was stirred at 100° C. for 4 hours. The mixture was cooled and filtered; the filtrate was evaporated under reduced pressure to give the crude product. It was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:EtOAc, 3:1, v/v) to give {-4-[3-[3-(4-chloro-benzylamino)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester. (Yield 120 mg, 36%).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)[CH:3]=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:41](Cl)(Cl)([Cl:43])[Cl:42]>[Zn]>[CH3:1][C:2]([CH3:21])([CH:3]=[C:41]([Cl:43])[Cl:42])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1
Reactant: CC(C)(C=O)COCc1cccc(Oc2ccccc2)c1
Reactant: ClC(Cl)(Cl)Cl
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C=C(Cl)Cl)COCc1cccc(Oc2ccccc2)c1
Temperature: 25 °C

Procedure:
A mixture of 2,2-dimethyl-3-(3-phenoxybenzyloxy)propan-1-al (0.25 g), triphenylphosphine (0.47 g), zinc dust (0.12 g) and carbon tetrachloride (0.2 cm3) was heated at the relux temperature for one hour. After cooling to the ambient temperature (ca 25° C.) the mixture was diluted with petroleum ether (boiling range 40°-60° C.) and the solid component removed by filtration. The filtrate was concentrated by evaporation of the solvent under reduced pressure, and the residual oil subjected to purification by flash chromatography using a silica gel column eluted with dichloromethane to yield 2,2-dimethyl-1-(3-phenoxybenzyloxy)-4,4-dichlorobut-3-ene (0.2 g).
Reaction SMILES: [O-]CC.[Na+].[N:5]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][CH:6]=1.[Cl-].[CH:14]1([O:19][C:20]2[CH:21]=[C:22]([C:28]3C=CC=CC=3[P+](C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:23]=[CH:24][C:25]=2[O:26][CH3:27])[CH2:18][CH2:17][CH2:16][CH2:15]1>C(O)C>[CH:14]1([O:19][C:20]2[CH:21]=[C:22](/[CH:28]=[CH:11]\[C:8]3[CH:7]=[CH:6][N:5]=[CH:10][CH:9]=3)[CH:23]=[CH:24][C:25]=2[O:26][CH3:27])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COc1ccc(-c2ccccc2[P+](C)(c2ccccc2)c2ccccc2)cc1OC1CCCC1
Reactant: O=Cc1ccncc1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(/C=C\c2ccncc2)cc1OC1CCCC1
Reaction time: 2 h
Yield: 11.9 %

Procedure:
A solution of sodium ethoxide [prepared from sodium (0.10 g, 4.50 mmol)] in ethanol (50 ml) was added over 5 min to a stirred mixture of 4-pyridine carboxaldehyde (0.44 g, 4.10 mmol) and (3-cyclopentyloxy-4-methoxyphenyl)-methyltriphenylphosphonium chloride (2.00 g, 4.08 g) in ethanol (30 ml). After 2 h, the reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc (75 ml) and brine (50 ml). The organic layer was separated, then dried (MgSO4) and concentrated in vacuo. A 1H n.m.r. spectrum indicated that the mixture consisted of a 3:2 mixture of (Z):(E) title compound (and triphenyiphosphine oxide). A portion (0.6 g) of the mixture was subjected to chromatography (SiO2 ; hexane to EtOAc) to afford pure (Z)-title compound (0.14 g) as a pale yelow solid m.p. (Found: C, 77.18; H, 7.16; N, 4.63. C19H21NO2 requires C, 77.26; H, 7.17; N, 4.74%); δH (300MHz; CDCl3) 1.5-1.55 (2H, br m, cyclopentyl H's), 1.65-1.9 (6H, br m, cyclopentyl H's), 3.83 (3H, s, OMe), 4.44 (1H, br m, OCHCH2), 6.40 (1H, d, J 12.2 HZ, CH=CH), 6.65-6.80 (4H, m, ArH ortho to OMe+2×ArH meta to OMe+CH=CH), 7.15 (2H, ca. d, J 6.0 HZ, pyridine H2, H6); m/z 295 (M+, 22%), 228 (15), 227 (100), 226 (94), 198 (35), 184 (15), 166 (12), 43 (19), and 41 (29).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14].C(N(CC)CC)C>C1COCC1.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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])=[CH:6][CH:5]=1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.7 %

Procedure:
Under argon condition, 4-bromobenzoic acid methyl ester (500 mg, 2.33 mmol), bis(triphenylphosphine)palladium dichloride (Pd(PPh3)2Cl2; 86.1 mg, 0.116 mmol), triphenylphosphine (PPh3; 18.3 mg, 0.0698 mmol), trimethylsilyl acetylene (TMS acetylene; 493 μL, 3.49 mmol), and triethylamine (Et3N; 486 μL, 3.49 mmol) were dissolved in 10 mL of dry THF and the reaction mixture was stirred for 20 minutes at room temperature. To this cuprous iodide (CuI; 8.86 mg, 0.0465 mmol) was again added and the mixture was stirred for 15 hours at room temperature. Upon completion of the reaction, the solvent was removed by distillation under reduced pressure and then 20 mL of n-pentane was added to the residue. The mixture was filtered through celite pad to remove the precipitate. The resulting solution was concentrated by distillation under reduced pressure, and purified by column chromatography to obtain 503 mg (2.16 mmol, 93%) of the desired compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:5][CH:6]=[C:7]([Cl:12])[C:8]=1[C:9]([OH:11])=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:29][N:30]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][C:38]=2[CH:42]([CH3:44])[CH3:43])[S:31]1(=[O:33])=[O:32]>CO>[ClH:2].[Cl:2][C:3]1[C:4]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:5][CH:6]=[C:7]([Cl:12])[C:8]=1[C:9]([O:11][CH2:29][N:30]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][C:38]=2[CH:42]([CH3:44])[CH3:43])[S:31]1(=[O:32])=[O:33])=[O:10]
Reactant: O=C(O)c1c(Cl)cnc(OCCN2CCOCC2)c1Cl
Reactant: CC(C)c1cccc2c1C(=O)N(CCl)S2(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: CC(C)c1cccc2c1C(=O)N(COC(=O)c1c(Cl)cnc(OCCN3CCOCC3)c1Cl)S2(=O)=O
Temperature: 80 °C
Yield: 16.8 %

Procedure:
A solution of the free base of 3,5-dichloro-2-[2-(4-morpholinyl) ethoxy) pyridine-4-carboxylic acid hydrochloride (3.6 g, 0.01 mol) and cesium carbonate (4.85 g, 0.015 mol) in methanol (50 ml) was stirred for 30 minutes. The methanol was removed in vacuo and the residue was dissolved in DMF (50 ml). 2-Chloromethyl-4-(isopropyl)saccharin (3.0 g, 0.01 mol) was then added and the reaction mixture was heated at 80° C. for 3 hours. The DMF was removed in vacuo, the residue was taken up in methylene chloride and was filtered through charcoal. The solvent was removed in vacuo, the residue was taken up in tert-butyl-methylether and the solution was filtered. The solvent was removed in vacuo and the residue was treated with ethereal HCl. A gum was obtained which was triturated with CH3CN to afford 0.5 g (9%) of 4-(isopropyl]-2-saccharinylmethyl 3.5-dichloro-2-[2-(4-morpholinyl)ethoxy]pyridine-4-carboxylate hydrochloride as a white solid, m.p. 120°-140° C.