Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:6][N:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(-c2cncnc2O)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2cncnc2Cl)cc1
Yield: 71 %

Procedure:
A mixture of 4-hydroxy-5-(p-tolyl)pyrimidine (9 g, 48 mmol) and phosphorous oxychloride (44 ml) was heated under reflux for 2 hours. After the reaction mixture was concentrated to dryness, the residue was poured into iced water to precipitate crystals which were extraced with methylene chloride. The extract was washed with water, dried and concentrated to dryness. The residue was purified by column chromatography on silica gel to afford colorless powders (7 g, 71%), m.p. 67°-70° C.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24](=O)[CH2:25]Br)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:25]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(C(=O)CBr)cc1OC
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Product: COC(=S)c1cc(-c2nc(-c3ccc(OC)c(OC)c3)cs2)c(C)s1
Yield: 89.2 %

Procedure:
105 mg (0.424 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was reacted with 1-(3,4-dimethoxyphenyl)-2-bromoethan-1-one (0.467 mmol; 120 mg) in a manner similar to Example 22, step (a) to afford 148 mg (85% yield) of methyl 4-[4-(3,4-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[C:17]2[O:16][C:15](=[O:18])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.[OH-:19].[K+]>CO>[OH:16][C:17]1[C:9]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:10][CH:11]=[CH:12][C:13]=1[CH2:14][C:15]([OH:18])=[O:19]
Reactant: [OH-]
Reactant: O=C1Cc2cccc(Sc3ccccc3Cl)c2O1
Agent: [K+]
Solvent: CO
Product: O=C(O)Cc1cccc(Sc2ccccc2Cl)c1O

Procedure:
7-(2-Chlorophenylthio)-2,3-dihydrobenzofuran-2-one (0.2 g) was added to a solution of potassium hydroxide in methanol, and the mixture was stirred under warming to give 2-[2-hydroxy-3-(2-chlorophenylthio)phenyl]acetic acid (0.2 g), mp. 91°-93° C.
Reaction SMILES: [OH:1][P:2]([C:6]1[CH:7]=[C:8](/[CH:12]=[CH:13]/[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]=[CH:10][CH:11]=1)([O:4][CH3:5])=[O:3].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:31]=2N=N1.CCN(C(C)C)C(C)C.CN(C=O)C>CO>[CH3:5][O:4][P:2]([C:6]1[CH:7]=[C:8](/[CH:12]=[CH:13]/[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]=[CH:10][CH:11]=1)([O:1][CH3:31])=[O:3]
Reactant: COP(=O)(O)c1cccc(/C=C/C(=O)OC(C)(C)C)c1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COP(=O)(OC)c1cccc(/C=C/C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-butyl (2E)-3-{3-[hydroxy(methoxy)phosphoryl]phenyl}acrylate was dissolved in methanol (8 ml). BOP (0.4958 g, 1.121 mmol) and Hunig's base (0.2 ml, 1.145 mmol) were added. DMF (2 ml) was added. The reaction was allowed to stir overnight at room temperature. The reaction was not complete. The reaction was partially concentrated under reduced pressure. BOP (0.4836 g, 1.093 mmol) and Hunig's base (0.2 ml, 1.145 mmol) were added. The reaction was allowed to stir. After several hours additional BOP (0.495 g, 1.119 mmol) and Hunig's base (0.2 ml, 1.145 mmol) were added. The reaction was allowed to stir overnight at room temperature. The reaction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. The residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane. MS: calc'd 313 (MH+), exp 313 (MH+).
Reaction SMILES: [CH:1]([N:4]([CH:9]1[CH:23]=[C:22]([CH3:24])[CH2:21][CH:20]=[C:10]1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:12])[C:5]([O:7][CH3:8])=[O:6])([CH3:3])[CH3:2]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:1]([N:4]([C:9]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:12])[C:5]([O:7][CH3:8])=[O:6])([CH3:3])[CH3:2]
Reactant: COC(=O)N(C(C)C)C1C=C(C)CC=C1C(=O)c1ccc(F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COC(=O)N(c1cc(C)ccc1C(=O)c1ccc(F)cc1)C(C)C

Procedure:
20 g 2-(N-isopropyl-N-carbomethoxyamino)-4-methyl-4'-fluoro-2,5-dihydrobenzophenone and 100 g manganese dioxide in 200 ml chloroform are stirred 4 hours under reflux. The reaction mixture is cooled, filtered and evaporated in vacuo. The residue is recrystallised from hexane to obtain the heading compound, m.p. 92°-94° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:6]([NH2:8])=O.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl.O>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:6]#[N:8]
Reactant: Cc1cc(C(N)=O)cc(CO)n1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(C#N)cc(CO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 154.3 %

Procedure:
To a suspension of 2-hydroxymethyl-6-methyl-isonicotinamide (390 mg, 2.38 mmol) and pyridine (922 mg, 9.50 mmol) in DCM (80 mL), trifluoroacetic anhydride (1.25 g, 5.94 mmol) is added dropwise at 0° C. The mixture is stirred at rt for 1 h and becomes clear before it is carefully diluted with water and DCM. The mixture is washed twice with sat. aq. NaHCO3-solution. The washings are extracted twice with DCM. The combined org. extracts are dried over MgSO4, filtered and concentrated and briefly dried under HV to give crude 2-hydroxymethyl-6-methyl-isonicotinonitrile (544 mg, contains pyridine) as a brownish oil; LC-MS: tR=0.54 min, [M+1]+=148.99; 1H NMR (CDCl3): δ 2.66 (s, 3H), 3.48 (s br, 1H), 5.48 (s, 2H), 7.41 (s, 2H).
Reaction SMILES: [F:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6]C)=[O:5].O[C@@H](CCCC)CC(OC)=O>>[F:1][CH:2]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCCC[C@@H](F)CC(=O)OC
Agent: CCCC[C@H](O)CC(=O)OC
Product: CCCCC(F)CC(=O)O

Procedure:
Incidentally, methyl (R)-3-fluoroheptanoate derived from methyl (S)-3-hydroxyheptanoate (98.8%ee, [α]D20 =9.07) was hydrolyzed to obtain 3-fluoroheptanoic acid, which was then reacted with R-(+)-1-(1-naphthyl)ethylamine to form a diastereomer. The resulting diastereomer was found to have an optical purity of 98.7%ee by liquid chromatography, indicating that no racemization took place at all. NMR (ppm): 0.92 (3H, t, J=7.2 Hz), 1.36 (4H, m), 1.66 (2H, m), 2.62 (2H, m), 3.72 (3H, s), 4.93 (1H, m)
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[H-].[Na+].CS(O[CH:19]([C:21]1[CH:26]=[C:25]([Cl:27])[C:24]([CH3:28])=[C:23]([C:29]([NH:31][CH2:32][CH3:33])=[O:30])[C:22]=1[C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[C:36]([F:41])[CH:35]=1)[CH3:20])(=O)=O>CN(C)C=O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:19]([C:21]3[CH:26]=[C:25]([Cl:27])[C:24]([CH3:28])=[C:23]([C:29]([NH:31][CH2:32][CH3:33])=[O:30])[C:22]=3[C:34]3[CH:35]=[C:36]([F:41])[CH:37]=[C:38]([F:40])[CH:39]=3)[CH3:20])[N:3]=[C:2]([CH3:1])[C:10]=12
Reactant: Cc1n[nH]c2ncnc(N)c12
Reactant: CCNC(=O)c1c(C)c(Cl)cc(C(C)OS(C)(=O)=O)c1-c1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)c1c(C)c(Cl)cc(C(C)n2nc(C)c3c(N)ncnc32)c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (from ChemBridge) (26 mg, 0.17 mmol) in N,N-dimethylformamide (0.5 mL) was added sodium hydride (14 mg, 0.35 mmol). After stirring at room temperature for 30 minutes, to the resulting mixture was added to a mixture of 1-{4-chloro-6-[(ethylamino)carbonyl]-3′,5′-difluoro-5-methylbiphenyl-2-yl}ethyl methanesulfonate (50 mg, 0.1 mmol) in N,N-dimethylformamide (0.5 mL). The reaction was stirred at room temperature overnight and then quenched with water. The resultant mixture was purified on 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 the desired product. The product was isolated as a racemic mixture. LCMS calculated for C24H24ClF2N6O (M+H)+: m/z=485.2; Found: 485.1
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[N:6][CH:7]=1.[B:9]1(B2OC(C)(C)C(C)(C)O2)[O:13]C(C)(C)C(C)(C)[O:10]1.C([O-])(=O)C.[K+]>>[NH2:8][C:3]1[C:2]([B:9]([OH:13])[OH:10])=[CH:7][N:6]=[CH:5][N:4]=1
Reactant: Nc1ncncc1Br
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Product: Nc1ncncc1B(O)O
Temperature: 105 °C
Reaction time: 18 h

Procedure:
To a vial was added 5-bromopyrimidin-4-amine (0.200 g, 1.149 mmol), bis(pinacolato)diboron (0.438 g, 1.724 mmol), and potassium acetate (0.338 g, 3.45 mmol). The vial was capped with a rubber septum and then evacuated and backfilled with N2. Dioxane (volume: 0.120 ml) was added via syringe through the septum. The reaction mixture was sparged with N2, then 1,1′-bis(diphenylphosphino) ferrocenedichloropalladium(II) dichloromethane complex (0.042 g, 0.057 mmol) was added. The septum was then replaced with a Teflon screw valve and the vial sealed. The reaction mixture was heated at 105° C. in a metal pie block. After 18 h, the reaction mixture was allowed to cool to room temperature. The reaction mixture was filtered through a disposable fritted funnel and the filter cake washed with EtOAc. The filtrate was concentrated to afford a brown solid. The crude material was used without further purification. MS (ESI): m/z=140.0 [M+H]+. HPLC Peak tr=0.24 minutes. HPLC conditions: Column:Luna C18 4.6×30 mm 3u A:10:90 H2O:ACN NH4OAc/B:10:90 H2O:ACN NH4OAc; 0%-95% B in 2 min; 4 mL/min flow.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:14][CH3:15])[C:9](Br)=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1Br.C([Sn](CCCC)(CCCC)[C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)CCC>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:14][CH3:15])[C:9]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:24]1[S:23][CH:22]=[CH:26][CH:25]=1
Reactant: COc1c(Br)ccc2c(OC)c(Br)ccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1c(-c2cccs2)ccc2c(OC)c(-c3cccs3)ccc12
Yield: 95 %

Procedure:
1,5-Dimethoxy-2,6-dibromonaphthalene (1.00 g., 0.0029 mol.) and 2-(tributylstannyl)thiophene (4.314 g., 0.0116 mol.) were dissolved in 100 mL dry toluene in argon atmosphere. Pd(PPh3)4 (100 mg.) was introduced into the reaction flask using a Schlenk tube under argon. The resultant mixture was subsequently refluxed for 18 hrs. The brownish black solution was cooled and poured into 300 mL of petroleum ether to afford crude yellow solid. Upon recrystallization from CH2Cl2:petroleum ether (1:5), the desired product was obtained as a light yellow solid. Yield: 95%. M. p. 225-228° C. Anal. Calcd. for C20H16O2S2: C, 68.15%; H, 4.58%; S, 18.19%. Found: C, 67.98%; H, 4.53%; S, 18.03%. Mass spectrum: 351.84 (M+). 1 H-NMR (CDCl3; in ppm): 3.88 (s, 3H), 7.16 (dd, 2H), 7.43 (dd, 2H), 7.63 (dd, 2H), 7.83 (d, 2H, 9 Hz), 7.96 (d, 2H, 9 Hz). 13C-NMR (CDCl3; in ppm): 61.3, 119.0, 123.2, 125.7, 126.5, 126.6, 126.9, 129.2, 138.9, 152.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([CH3:30])([C:12]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)=[CH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([CH3:30])([CH:12]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[CH3:13])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C(c1ccc2c(c1)N1C(=NNC(=O)[C@H]1C)CO2)C1(C)CN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: CC(c1ccc2c(c1)N1C(=NNC(=O)[C@H]1C)CO2)C1(C)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
A mixture of 3-methyl-3-[1-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-vinyl]-azetidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.212 mmol) and Pd/C (0.258 g, 0.242 mmol, 10%) in MeOH (10 mL) was stirred under H2 at ambient temperature for 1 h. The reaction mixture was filtered and the filtrate was evaporated in vacuo to give 3-methyl-3-[1-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-ethyl]-azetidine-1-carboxylic acid tert-butyl ester (0.484 g, 96%) as a solid. LC/MS (Table 1, Method 25) Rt=0.858 min.; MS m/z: 415 [M+H]+ and 359 [M+H−56]+. 1H NMR (CDCl3, 400 MHz): δ 8.08 (brs, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.73 (s, 1H), 4.78 (m, 1H), 4.63-4.56 (m, 2H), 3.84 (m, 2H), 3.57 (d, J=8.0 Hz, 1H), 3.35 (d, J=8.0 Hz, 1H), 2.98 (m, 1H), 1.66-1.49 (m, 12H), 1.27 (d, J=7.3 Hz, 3H), 1.21 (s, 3H).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:15]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[CH2:16][CH3:17].[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=1
Reactant: OCCCCCCBr
Reactant: CCCc1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1ccc(OCCCCCCBr)cc1
Temperature: 25 °C
Yield: 66.8 %

Procedure:
A solution of diisopropylazodicarboxylate (2.12 g, 10.5 mmol) in THF (25 mL) was added via syringe pump over 1.5 h to a mixture of 4-propylphenol (purchased from Aldrich Chemical Co.) (1.36 g, 10.0 mmol), 6-bromo-1-hexanol (purchased from Aldrich Chemical Co.) (1.81 g, 10.0 mmol), and triphenylphosphine (2.75 g, 10.5 mmol) in THF (25 mL) at 0° C. under argon. The slightly yellow reaction was stirred at 0° C. for 30 min, whereupon additional triphenylphosphine (262 mg, 1.00 mmol) was added, followed by addition of diisopropylazodicarboxylate (200 mL, 1.0 mmol) over 30 min. The reaction was allowed to warm to RT, at which time silica gel (15 g) was added. The mixture was concentrated in vacuo and the white powder obtained was purified by flash chromatography on silica gel (150 g) eluted with a step gradient of hexane to 2:98 EtOAc/hexane. The slightly impure product obtained was rechromatographed on silica gel (150 g) eluted with 1:99 EtOAc/hexane to give title compound (2.00 g, 67%) as a colorless oil.
Reaction SMILES: [CH:1]([P:3](=[O:17])([CH:15]=[CH2:16])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH3:14])[CH:5]=1)=[CH2:2].Cl.[CH2:19]([NH2:21])[CH3:20].[OH-].[Na+].C(N)C>C1COCC1>[CH2:19]([N:21]1[CH2:16][CH2:15][P:3](=[O:17])([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH3:14])[CH:5]=2)[CH2:1][CH2:2]1)[CH3:20]
Reactant: C=CP(=O)(C=C)c1ccc([N+](=O)[O-])c(OC)c1
Reactant: CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN1CCP(=O)(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Temperature: 105 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide (0.480 g, 1.94 mmol), ethylamine hydrochloride (0.174 g, 2.12 mmol), and 1 N NaOH (2 mL) were dissolved in 50% aqueous THF (5 mL) and heated to 105° C. under nitrogen. After one hour, another portion of ethylamine was added to the reaction mixture. The reaction mixture was refluxed for an additional 2 h, and then cooled to it. The reaction mixture was partitioned between saturated aqueous NaHCO3 and CH2Cl2. The aqueous phase was washed once with CH2Cl2 and the organic layers were combined. The organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane) to afford the compound (0.267 g, 46% yield).
Reaction SMILES: [C:1]([C:4]1[NH:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][C:8]([C:15]([F:18])([F:17])[F:16])=[CH:9][CH:10]=2)[N:5]=1)([CH3:3])=[CH2:2].[Si]([CH:23]=[N+:24]=[N-:25])(C)(C)C>>[CH3:2][C:1]1([C:4]2[NH:13][C:12](=[O:14])[C:11]3[C:6](=[CH:7][C:8]([C:15]([F:17])([F:18])[F:16])=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH:23]=[N:24][NH:25]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=C(C)c1nc2cc(C(F)(F)F)ccc2c(=O)[nH]1
Product: CC1(c2nc3cc(C(F)(F)F)ccc3c(=O)[nH]2)CC=NN1

Procedure:
Following the procedure in Example 7, using 2-isopropenyl-7-trifluoromethyl-3H-quinazolin-4-one and TMSCHN2 as starting materials yielded the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.Cl.Cl.[N:21]1([CH2:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:30]3[CH2:29][CH2:28][CH:27]([CH2:26][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:32][CH2:31]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: C1CCN(CC2CCNCC2)C1
Agent: Cl
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(CN4CCCC4)CC3)cc2n1

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxaldehyde 10 was reacted with 4-pyrrolidin-1-ylmethyl-piperidine, dihydrochloride salt using standard reductive amination conditions. The resulting crude solid was triturated with methanol to give 2-chloro-4-morpholin-4-yl-6-(4-pyrrolidin-1-ylmethyl-piperidin-1-ylmethyl)-thieno[3,2-d]pyrimidine as an off white solid (63% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with methanol to give 331 as an off white solid (84% yield). NMR (CDCl3, 400 MHz), 1.28-1.36 (2H, m), 1.48-1.52 (1H, m), 1.77-1.82 (6H, m), 2.10 (2H, t, J=11.0), 2.34 (2H, d, J=7.0), 2.44-2.49 (4H, m), 2.99 (2H, d, J 11.0), 3.82 (2H, s), 3.88-3.91 (4H, m), 4.03-4.06 (4H, m), 5.21 (2H, br s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=495
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:20](O)[CH3:21]>O>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH2:20][CH3:21])=[O:8])[S:5][CH:6]=1
Reactant: CCO
Reactant: O=C(O)c1cc(Br)cs1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(Br)cs1
Temperature: 25 °C

Procedure:
663 mg (3.20 mmol) of the compound from Example 6A are provided in 25 ml of ethanol, 0.1 ml of concentrated sulfuric acid is added and the mixture is heated under reflux overnight. After cooling to room temperature, a saturated aqueous sodium bicarbonate solution is added and the mixture is diluted with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. 700 mg (89% of theory) of the title compound are obtained.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([CH2:9][C:10]([NH2:12])=[O:11])#[N:8].[CH3:13][C:14](=O)/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH3:19].O=O.Cl>CS(C)=O.O>[CH3:13][C:14]1[NH:12][C:10](=[O:11])[C:9]([C:7]#[N:8])=[C:16]([CH2:17][CH2:18][CH3:19])[CH:15]=1
Reactant: N#CCC(N)=O
Reactant: CCC/C=C/C(C)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: O=O
Solvent: O
Solvent: CS(C)=O
Product: CCCc1cc(C)[nH]c(=O)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of t-BuOK (20 g, 178.5 mmol) and cyanoacetamide (16.5 g, 196 mmol) in DMSO (300 mL) was added (3E)-3-hepten-2-one (20 g, 178.3 mmol) under argon atmosphere at room temperature. The reaction mixture was stirred at room temperature for 30 min and then additional t-BuOK (60 g, 535.7 mmol) was added to the reaction mixture. The argon was then displaced by oxygen gas and stirred for 48 hrs at room temperature under oxygen. Reaction mixture was cooled to 0° C. and diluted with water (80 mL) followed by 4N HCl (120 mL). The mixture was stirred for 15 min and the solid was filtered. The solid was washed with water (1 L) and dried to afford 1,2-dihydro-6-methyl-2-oxo-4-propylpyridine-3-carbonitrile as an off white solid (12 g, 38%). 1H NMR (CDCl3, 400 MHz): δ 1.030 (t, 3H, J=7.2 Hz), 1.728 (m, 2H), 2.429 (s, 3H), 2.701 (t, 2H, J=7.6 Hz), 6.083 (s, 1H). LCMS E-S (M−H)=175.11.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[F:15][C:16]1[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:17]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:33]3[C:28](=[N:29][CH:30]=[N:31][C:32]=3[NH2:34])[N:27]([CH2:35][C@H:36]3[CH2:40][CH2:39][CH2:38][NH:37]3)[N:26]=2)=[CH:21][CH:20]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:58]([CH2:60][C:61](O)=[O:62])#[N:59]>ClCCl>[NH2:34][C:32]1[N:31]=[CH:30][N:29]=[C:28]2[N:27]([CH2:35][C@H:36]3[CH2:40][CH2:39][CH2:38][N:37]3[C:61](=[O:62])[CH2:60][C:58]#[N:59])[N:26]=[C:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][C:17]4[CH:41]=[CH:42][CH:43]=[C:44]([F:45])[C:16]=4[F:15])=[CH:24][CH:23]=3)[C:33]=12
Reactant: N#CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3F)cc1)nn2C[C@H]1CCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.8 %

Procedure:
Into a 100 mL, round-bottom flask, was placed a solution of 3-[4-(2,3-difluorophenoxy)phenyl]-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine bis(trifluoroacetic acid) salt (200 mg, 0.31 mmol, 1.00 equiv) in dichloromethane (10 mL), CDI (324 mg, 2.00 mmol, 6.50 equiv), and 2-cyanoacetic acid (170 mg, 2.00 mmol, 6.50 equiv). The resulting solution was stirred for 12 h at 25° C. and the resulting mixture was washed with water and brine. The organics were dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (20/1) to give 109 mg (72%) of 3-[(2R)-2-([4-amino-3-[4-(2,3-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:8][N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:33]2[CH:34]=[CH:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[C:6](=[O:25])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN(Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 14 h
Yield: 54.4 %

Procedure:
A mixture of tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), 4-(methanesulfonyl)phenylboronic acid (300 mg), tetrakis(triphenylphosphine)palladium (115 mg), sodium carbonate (320 mg), 1,2-dimethoxyethane (10 mL) and water (10 mL) was stirred under a nitrogen atmosphere at 80° C. for 14 hr. The reaction mixture was allowed to cool to room temperature, filtered through celite, and the filtrate 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 (eluent:hexane-ethyl acetate=2:1→1:2) to give the title compound as an oil (yield 275 mg, 64%).