Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([F:33])=[C:12]([N:16]2[CH2:19][CH:18]([CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH2:17]2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[C:11]([F:33])=[C:12]([N:16]2[CH2:19][CH:18]([CH:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)[CH2:17]2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2CN(c3cccc(CO[Si](C)(C)C(C)(C)C)c3F)C2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)OCc1cccc(N2CC(C3CCNCC3)C2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.5 %

Procedure:
tert-Butyl 4-{1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine-1-carboxylate (2 g) was mixed with CH2Cl2 (20 ml), and TFA (5 ml) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was mixed with CH2Cl2 (30 ml), and TEA (6 ml) and TBSCl (2.5 g) were added thereto, followed by stirring at 60° C. overnight. Water was added to the reaction mixture, and the organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was mixed with MeOH (20 ml), and a 1 M aqueous NaOH solution (5 ml), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, CHCl3 and water were added to the obtained residue, and the organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/EtOAc) to obtain 4-{1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine (673 mg).
Reaction SMILES: [CH2:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10](=[N:12]O)[CH3:11])[CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>CN(C)C(=O)C>[CH3:11][C:10]1[NH:9][C:6]2[N:7]([N:8]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:5]=2)[N:12]=1
Reactant: CCCc1cc(NC(C)=NO)n[nH]1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: CCCc1cc2[nH]c(C)nn2n1
Reaction time: 0.5 h

Procedure:
A 5.38 g portion of N-(5-propyl-1H-pyrazol-3-yl)acetamidoxime was dissolved in 45 ml of N,N-dimethylacetamide. With cooling on an ice bath, to this were added 2.39 ml of pyridine and 5.63 g of p-toluenesulfonic acid chloride, followed by 30 minutes of stirring at the same temperature and additional 3 hours of stirring at room temperature. The resulting reaction mixture was added to 350 ml of water and extracted with chloroform. After distilling off chloroform from the organic layer under a reduced pressure, the thus obtained residue was dissolved in 135 ml of methanol, mixed with 2.39 ml of pyridine and then heated under reflux for 2 hours.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=2)=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2].[BH4-].[Na+]>ClCCl.C(O)C>[OH:11][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1)[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=1
Reactant: CCOC(=O)CCc1ccc(C(=O)c2ccc([N+](=O)[O-])cn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCc1ccc(C(O)c2ccc([N+](=O)[O-])cn2)cc1
Reaction time: 1 h

Procedure:
To a solution of ethyl 3-[4-(5-nitropyridine-2-carbonyl)phenyl]propionate (1.52 g, 4.63 mmol) in dichloromethane (15 mL) and ethanol (15 mL) was added sodium borohydride (0.175 g, 4.63 mmol) under ice cooling, and the resulting solution was stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was dissolved in water and ethyl acetate. To the solution was added acetic acid and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby yield 0.264 g of the title compound.
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[C:25]([CH2:37][CH2:38][CH3:39])[N:24]=1.C(O)(C)C>CO>[CH3:34][O:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][C:29]=1[O:35][CH3:36])[N:26]=[C:25]([CH2:37][CH2:38][CH3:39])[N:24]=[C:23]2[N:18]1[CH2:19][CH2:20][CH:15]([N:5]2[C:6](=[O:14])[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=3)[N:3]([CH3:2])[C:4]2=[O:21])[CH2:16][CH2:17]1
Reactant: CCCc1nc(Cl)c2cc(OC)c(OC)cc2n1
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Agent: Br
Solvent: CO
Solvent: CC(C)O
Product: CCCc1nc(N2CCC(n3c(=O)c4cc(C)ccc4n(C)c3=O)CC2)c2cc(OC)c(OC)cc2n1
Yield: 35 %

Procedure:
The procedure similar to that described in Example 40 was repeated, except that 354.0 mg (1.0 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide (Compound v) obtained in Example 41 was used, 4-chloro-6,7-dimethoxy-2-propylquinazoline was used in place of 4-chloro-6,7-dimethoxyquinazoline, and isopropyl alcohol was used as a reaction solvent in place of methanol. As a result, 174.3 mg (yield: 35%) of Compound 82 was obtained as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6](=[O:12])[N:5]3[CH2:13][CH:14]([CH2:15][N:16]4[CH2:21][CH2:20][CH:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18][CH2:17]4)[C:3]=1[C:4]=23.Cl>ClCCl.CO.O.O1CCOCC1>[NH2:22][CH:19]1[CH2:18][CH2:17][N:16]([CH2:15][CH:14]2[C:3]3[C:4]4[N:5]([C:6](=[O:12])[CH:7]=[N:8][C:9]=4[CH:10]=[CH:11][C:2]=3[F:1])[CH2:13]2)[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2Cn3c(=O)cnc4ccc(F)c2c43)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: NC1CCN(CC2Cn3c(=O)cnc4ccc(F)c2c43)CC1
Reaction time: 1.5 h
Yield: 97.6 %

Procedure:
A solution of 1,1-dimethylethyl {1-[(7-fluoro-3-oxo-5,6-dihydro-3H-pyrrolo[1,2,3-de]quinoxalin-6-yl)methyl]-4-piperidinyl}carbamate (8.13 g, 20.2 mmol) in dichloromethane (150 ml) and methanol (100 ml) was cooled in iced water. Hydrogen chloride in 1,4-dioxane (4M, 160 ml) was added gradually, then the mixture was stirred for 1.5 h. The mixture was evaporated and the residue was triturated with ether and filtered off. The solid was partially dissolved in 25% methanol/dichloromethane (200 ml) and stirred with MP-carbonate (3.03 mmol/g, 27 g) for 1 h. The resin was filtered off, washed a few times with 10% methanol/dichloromethane and methanol alternately, and the filtrate was evaporated to give the product (5.96 g, 98%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:34][C:35]1[N:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1>>[O:31]1[CH2:32][CH2:33][N:28]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([S:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=5[F:27])(=[O:19])=[O:20])[CH2:16][CH2:17]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:38]3[CH:37]=[N:36][C:35]([NH2:34])=[N:40][CH:39]=3)[N:3]=2)[CH2:29][CH2:30]1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: O=S(=O)(c1ccccc1F)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(=O)(=O)c5ccccc5F)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-[4-(2-fluoro-benzenesulfonyl)-piperazin-1-ylmethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica and recrystallization from hot DCM/hexane gave 282. NMR (CDCl3/MeOD): 2.53-2.56 (4H, m), 3.15-3.20 (4H, m), 3.75 (2H, s), 3.75-3.81 (4H, m), 3.89-3.93 (4H, m), 7.15 (1H, s), 7.14-7.25 (2H, m), 7.51-7.58 (1H, m), 7.71-7.77 (1H, m), 9.08 (2H, s). MS (ESI+): MH+ 571.22 (80%)
Reaction SMILES: [H-].[Na+].[C:3](OCC)(=[O:5])[CH3:4].[C:9]1([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCCCCC>O1CCCC1>[C:3]([CH:22]([C:19]1[CH:20]=[CH:21][C:16]([S:15][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:17][CH:18]=1)[C:23]#[N:24])(=[O:5])[CH3:4]
Reactant: N#CCc1ccc(Sc2ccccc2)cc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)C(C#N)c1ccc(Sc2ccccc2)cc1
Yield: 73.3 %

Procedure:
To a stirred suspension of 144 mg of 60% sodium hydride, in 10 ml of tetrahydrofuran at 0° C. under nitrogen atmosphere was added a mixture of 396 mg of ethyl acetate, 675 mg of 4-phenylthiophenylacetonitrile and 5 ml of tetrahydrofuran. Thirty minutes later, the ice bath was removed. Seventeen hours later, the tetrahydrofuran was distilled off in vacuo, and 10 ml of 2N hydrochloric acid and 20 ml of dichloromethane were added and separated, and the water layer was further extracted twice in 20 ml of dichloromethane. The organic layer and extract were combined, and dried by anhydrous magnesium sulfate, and concentrated in vacuo, and the residue was isolated and refined by silica gel chromatography (the eluent was a mixed solvent of hexane:ethyl acetate at a (v/v) rate of 4:1), and 587 mg of the title compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][N:10]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:9]2[CH:18]=[CH:19][CH:20]=[C:21](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:26][CH:25]=3)[C:8]=2[O:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:47](I)[CH3:48].O>CN(C)C=O>[CH2:47]([O:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][N:10]1[C:9]2[CH:18]=[CH:19][CH:20]=[C:21](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:26][CH:25]=3)[C:8]=2[O:7][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11]1)[CH3:48]
Reactant: CCI
Reactant: CCOC(=O)C1CN(CCCC(=O)O)c2cccc(/C=C/c3ccc(OCCCCc4ccccc4)cc3)c2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCN1CC(C(=O)OCC)Oc2c(/C=C/c3ccc(OCCCCc4ccccc4)cc3)cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
To a solution of the compound prepared in Example 46 (330 mg) in dimethylformamide (5 mL) were added potassium carbonate (252 mg) and ethyl iodide (142 mg), and the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine sequentially, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=8:2) to give the title compound (210 mg) having the following physical data.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][S:9](N1C=CC(=[N+](C)C)C=C1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][CH:24]=1>ClCCl.O>[C:1]([O:5][C:6]([NH:8][S:9]([NH:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:27][CH:28]=1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[N+](C)=c1ccn(S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Reactant: CCOC(=O)C(C)c1ccc(CN)cc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C)c1ccc(CNS(=O)(=O)NC(=O)OC(C)(C)C)cc1
Reaction time: 16 h
Yield: 50.9 %

Procedure:
N-(1-(tert-butoxycarbonyl)sulfamoyl)pyridine-4(1H)-ylidene)-N-methylmethanaminium (A) (5.81 g, 19.32 mmol) was added to a suspension of ethyl 2-(4-(aminomethyl)phenyl)propanoate (4.0 g, 19.32 mmol) in dichloromethane (40 mL) at room temperature and stirred for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×75 mL). Combined organic layer was washed with water (50 mL), brine (50 mL), dried over sodium sulfate and concentrated to get crude compound, which was purified by column chromatography (silica gel; 100-200 mesh). The product eluted with 20% ethyl acetate in pet ether to yielded ethyl 2-(4-((N-(tert-butoxycarbonyl)sulfamoylamino)methyl)phenyl)propanoate (3.8 g, 51%) as pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=3)[CH:17]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C-]#N.[K+].[N:34]12CCN(CC1)C[CH2:35]2.CC(O)=O>O.CS(C)=O>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([C:35]#[N:34])[N:24]=3)[CH:17]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2cccc(Oc3ccnc(Cl)n3)c2)cc1
Reactant: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCCc1ccc(-c2cccc(Oc3ccnc(C#N)n3)c2)cc1
Reaction time: 4 h

Procedure:
A mixture of {2-[3′-(2-chloro-pyrimidin-4-yloxy)-biphenyl-4-yl]-ethyl}carbamic acid tert-butyl ester (150 mg), potassium cyanide (76 mg) and 1,4-diazabicyclo[2,2,2]octane (13 mg) in water (0.4 ml) and DMSO (2 ml) is left at 5° C. for 4 h. This mixture is acidified with AcOH to pH 4-5, quenched with brine and extracted twice with diethyl ether. The combined organic phases are dried over sodium sulfate, the solvent is evaporated and the crude product is purified on silica (15 g) with cyclohexane/EtOAc=5/1 to afford pure {2-[3′-(2-cyano-pyrimidin-4-yloxy)-biphenyl-4-yl]-ethyl}carbamic acid tert-butyl ester.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C:11]1[CH:12]=[N:13][C:14]([N:17]2[CH2:22][CH:21]3[CH:19]([CH:20]3[N:23]([CH3:37])[S:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)(=[O:26])=[O:25])[CH2:18]2)=[N:15][CH:16]=1)=[O:10].C(O)(C(F)(F)F)=O.C(Cl)Cl.CO>>[OH:7][NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([N:17]2[CH2:22][CH:21]3[CH:19]([CH:20]3[N:23]([CH3:37])[S:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)(=[O:26])=[O:25])[CH2:18]2)=[N:13][CH:12]=1)=[O:10]
Reactant: CN(C1C2CN(c3ncc(C(=O)NOC4CCCCO4)cn3)CC21)S(=O)(=O)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CN(C1C2CN(c3ncc(C(=O)NO)cn3)CC21)S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3 %

Procedure:
To N-(tetrahydro-2H-pyran-2-yloxy) 2-{6-[methyl(naphthalene-2-sulfonyl)amino]-3-azabicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide was added TFA/DCM/MeOH (5 ml, 1:1:1 mixture). The solution was stirred at r.t. for 2 h. The mixture was then concentrated under reduced pressure, and purified by reverse phase HPLC to yield the title compound (34 mg, 3% yield over 2 steps). LCMS purity >98%, m/z 440 [M−+H]+, 1H NMR (300 MHz, d6-DMSO) δ: 1.55 (1H, m), 2.25 (2H, m), 2.77 (3H, s), 3.58 (2H, m), 3.78 (2H, d, J=11.8 Hz), 7.66-7.84 (2H, m), 7.82 (1H, dd, J=1.8, 8.6 Hz), 8.06 (1H, m), 8.18 (1H, d, J=8.7 Hz), 8.22-8.28 (1H, m), 8.49-8.52 (1H, m), 8.61 (2H, s), 9.01 (1H, br s), 11.05 (1H, br s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:25]([C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1)#[N:26]>CN(C=O)C.O>[C:25]([C:27]1[CH:28]=[C:29]([NH:33][C:34]([N:4]([CH2:3][CH2:2][OH:1])[CH:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:9][CH2:10]2)=[O:35])[CH:30]=[CH:31][CH:32]=1)#[N:26]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: OCCNC1CCN(Cc2ccccc2)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1cccc(NC(=O)N(CCO)C2CCN(Cc3ccccc3)CC2)c1
Temperature: 60 °C
Yield: 68.2 %

Procedure:
To a stirred solution of 4-(2-hydroxyethyl)amino-1-benzylpiperidine (1.82 g), and triethylamine (0.789 g, 7.8 mmol) in DMF (50 mL) was added 3-cyanophenylisocyanate (1.12 g, 7.8 mmol). This mixture was heated at 60° C. for 18 under a N2 atmosphere. The reaction was diluted with water and extracted with ethyl acetate, dried with MgSO4, filtered and concentrated to give the desired product, N-(3-cyanophenyl)-N'-(2-hydroxyethyl)-N'-(1-benzylpiperidin-4-yl)urea (2.04 g, 5.3 mmol). LRMS (M+H)+ m/z 379.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:9]2[CH2:10][CH2:11][C:6]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]#[C:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:27][CH:28]=3)(=[O:22])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1
Reactant: CCCCCC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(Br)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(Br)cc3)CC2)cc1

Procedure:
1-(4-Bromobenzyl)-4-(4-oct-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid was prepared starting from 1-(4-bromobenzyl)-4-(4-oct-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid ethyl ester (1.36 g, 2.3 mmol) dissolved in THF:methanol (50:50 ml) and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 660 mg (51%); off white solid; mp 199° C.; MS: 562 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:22])[C:10]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)=[C:6]2[N:5]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:3]=1.[NH:29]1[CH:33]=[CH:32][C:31](B(O)O)=[N:30]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:22][C:9]1[C:10]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[C:6]2[N:5]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:3]=[C:2]([C:33]3[CH:32]=[CH:31][NH:30][N:29]=3)[N:7]2[N:8]=1
Reactant: Cc1nn2c(Cl)cc(N3CCOCC3)nc2c1Cc1cccc2ccccc12
Reactant: OB(O)c1cc[nH]n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: Cc1nn2c(-c3cc[nH]n3)cc(N3CCOCC3)nc2c1Cc1cccc2ccccc12
Temperature: 140 °C
Yield: 21.2 %

Procedure:
In 5 mL MW vial was added in 7-chloro-2-methyl-5-(4-morpholinyl)-3-(1-naphthalenylmethyl)pyrazolo[1,5-a]pyrimidine (70 mg, 0.178 mmol), 1H-pyrazol-3-ylboronic acid (59.8 mg, 0.535 mmol), PdCl2(dppf)-CH2Cl2 adduct (17.46 mg, 0.021 mmol) and potassium carbonate (98 mg, 0.713 mmol) in 1,2-Dimethoxyethane (DME) (1.6 mL) and Water (0.400 mL). The reaction vessel was heated with microwave irradiation at 140° C. for 15 min. LC-MS showed 15% conversion. 1H-pyrazol-3-ylboronic acid (59.8 mg, 0.535 mmol) and PdCl2(dppf)-CH2Cl2 adduct (17.46 mg, 0.021 mmol) was added in. The reaction vessel was heated with microwave irradiation at 140° C. for 35 min. LC-MS showed 50% conversion. 1H-pyrazol-3-ylboronic acid (59.8 mg, 0.535 mmol), potassium carbonate (98 mg, 0.713 mmol) and PdCl2(dppf)-CH2Cl2 adduct (17.46 mg, 0.021 mmol) was added in. The reaction vessel was heated with microwave irradiation at 140° C. for 50 min. The reaction mixture was filtered through celite and washed with EtOAc (50 mL). The organic phase was washed with brine (10 mL). The aqueous phase was extracted with DCM (20 mL). The organic phases were combined, dried (MgSO4) and concentrated. The crude was purified on silica column (EtOAc/Hexane: 20˜40%) to give the product (16 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.26 (s, 3H) 3.61-3.79 (m, 8H) 4.38 (s, 2H) 7.12 (br. s., 1H) 7.33-7.46 (m, 2H) 7.46-7.53 (m, 2H) 7.57 (d, J=2.27 Hz, 1H) 7.76 (d, J=8.08 Hz, 1H) 7.86-8.00 (m, 2H) 8.46-8.55 (m, 1H). LC/MS: MS (ES+) m/e 425.0 [M+H]+.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[N:13]1([CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH:17]=[CH:16][N:15]=[CH:14]1>C(O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:22][CH2:21][CH2:20][CH2:19][CH2:18][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)=[O:4]
Reactant: NCCCCn1ccnc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CCO
Product: Nc1ccccc1C(=O)NCCCCn1ccnc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 1.63 g of isatoic anhydride, 1.39 g of 1H-imidazole-1-butanamine and 25 ml of ethanol was stirred at room temperature for 22 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and cooled. The desired product was isolated by filtration, mp 91°14 93° C.
Reaction SMILES: CNCCN(C)C.[Li]CCCC.[O:13]1[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14]1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl>O1CCCC1>[C:21]([C:14]1[O:13][CH:17]=[CH:16][C:15]=1[CH:18]=[O:19])([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)Cl
Reactant: O=Cc1ccoc1
Agent: CNCCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1occc1C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 7.02 g (68.7 mmol) of N,N'-trimethylethylene diamine in 100 ml of anhydrous tetrahydrofuran (chilled to -78° C.) was added 44.6 ml (71.4 mmol) of 1.6M n-BuLi in hexanes. A dark yellow solution was formed. The solution was stirred at -78 C under a blanket of argon for 15 minutes. To the solution was added 6.24 g (64.9 mmol) of distilled 3-furaldehyde and the solution was stirred at -78° C. for 20 minutes. To this solution was added 55.0 ml (71.4 mmol) of 1.3M solution of BuLi in hexanes and the solution was stirred at -78° C. for 3 hours. The anion formed was transfered via cannula onto a solution of 7.75 g (6.8 ml, 71.4 mmol) of ethyl chloroformate in 20 ml of anhydrous tetrahydrofuran (chilled to -78° C.). The resulting solution was allowed to warm to room temperature and stirred overnight (16.33 h). The solution was poured onto 1:10 10% HCl: ice (v/v) and the layers were separated. The aqueous layer was extracted with ether and the organic phases combined, dried over MgSO4, filtered and concentrated in vacuo to yield a brown oil. Purification by flash chromatography (silica gel, 5% ethyl acetate in hexane) yielded the title compound as a white solid.
Reaction SMILES: C1COCC1.C(NC(C)C)(C)C.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].[CH3:19][O:20][C:21]([C:23]1[C:24]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:36]=2[F:42])=[C:25]([F:33])[C:26]2[N:27]([C:29](I)=[CH:30][N:31]=2)[CH:28]=1)=[O:22]>C(OCC)(=O)C.[Cu]I.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>[CH3:19][O:20][C:21]([C:23]1[C:24]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:36]=2[F:42])=[C:25]([F:33])[C:26]2[N:27]([C:29]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:30][N:31]=2)[CH:28]=1)=[O:22]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1cn2c(I)cnc2c(F)c1Nc1ccc(C)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cn2c(C#C[Si](C)(C)C)cnc2c(F)c1Nc1ccc(C)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.5 %

Procedure:
THF (1.0 mL), diisopropylamine (95 μL, 0.68 mmol) and trimethylsilylacetylene (38 μL, 0.27 mmol) were added to a mixture of 8-fluoro-7-(2-fluoro-4-methylphenylamino)-3-iodo-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (100 mg, 0.23 mmol), CuI (4.0 mg, 0.023 mmol) and PdCl2(PPh3)2 (16 mg, 0.023 mmol). The solution was stirred at room temperature for 16 hours. The reaction was diluted with ethyl acetate, washed with saturated NaHCO3 (3×), brine (2×), dried over Na2SO4 and concentrated to a dark brown solid. Flash column chromatography (40:1 dichloromethane/MeOH) provide desired product (30 mg, 32%) as a yellow liquid. MS APCI (+) m/z 414 (M+1) detected. 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.61 (s, 1H), 7.80 (s, 1H), 6.90 (m, 3H), 4.00 (s, 3H), 2.32 (s, 3H), 0.33 (s, 9H). 19F NMR (376 MHz, CDCl3)−129.12 (s, 1F), −141.99 (s, 1F).