Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[N:8]1([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[CH:25]=[C:24]([NH:26][CH:27]4[CH2:29][CH2:28]4)[N:23]4[N:30]=[C:31]([CH3:35])[C:32]([CH:33]=O)=[C:22]4[N:21]=3)=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[N:9]1.N1CCCCC1>C(O)C.O>[N:8]1([C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:20]3[CH:25]=[C:24]([NH:26][CH:27]4[CH2:29][CH2:28]4)[N:23]4[N:30]=[C:31]([CH3:35])[C:32]([CH:33]=[C:7]5[NH:1][C:2](=[O:3])[NH:4][C:5]5=[O:6])=[C:22]4[N:21]=3)=[CH:17][CH:18]=2)[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: Cc1nn2c(NC3CC3)cc(Nc3ccc(-n4cccn4)cc3)nc2c1C=O
Reactant: O=C1CNC(=O)N1
Solvent: CCO
Solvent: O
Solvent: C1CCNCC1
Product: Cc1nn2c(NC3CC3)cc(Nc3ccc(-n4cccn4)cc3)nc2c1C=C1NC(=O)NC1=O
Temperature: 80 °C
Yield: 69.5 %

Procedure:
Hydantoin (3 mg, 0.03 mmol) and 5-(4-(1H-pyrazol-1-yl)phenylamino)-7-(cyclopropylamino)-2-methylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde (12 mg, 0.03 mmol) were dissolved in ethanol (0.4 mL) along with piperidine (3 uL, 0.03 mmol). The reaction was heated at 80° C. in the microwave for 2 hours. The reaction was then cooled to r.t., diluted with water, and the precipitate was collected and washed with water, 1:1 ethanol:water, then ethanol. The yellow solid was dried in vacuo to give 5-((5-(4-(1H-pyrazol-1-yl)phenylamino)-7-(cyclopropylamino)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (9.5 mg, 65% yield). LCMS (M+1=456)
Reaction SMILES: C([Li])CCC.[CH2:6]([C:8]12[CH2:15][O:14][C:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[CH:23])=[CH:18][CH:17]=3)([O:12][CH2:13]1)[O:10][CH2:9]2)[CH3:7].Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>O1CCCC1>[CH2:6]([C:8]12[CH2:9][O:10][C:11]([C:16]3[CH:17]=[CH:18][C:19]([C:22]#[C:23][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:21]=3)([O:14][CH2:15]1)[O:12][CH2:13]2)[CH3:7]
Reactant: CCOC(=O)Cl
Reactant: C#Cc1ccc(C23OCC(CC)(CO2)CO3)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1ccc(C23OCC(CC)(CO2)CO3)cc1
Temperature: 25 °C

Procedure:
n-Butyl lithium solution (0.67 ml, 1.6M in hexane) was added to a stirred solution of 4-ethyl-1-(4-ethynylphenyl)-2,6,7-trioxabicyclo[2,2,2]octane (200 mg) in tetrahydrofuran (5 ml) at 0° C. under nitrogen. The solution was maintained at 0° C. for 10 minutes when ethyl chloroformate (0.1 ml) was added neat. The solution was allowed to warm to room temperature over 1.5 hours. The reaction was quenched with water (1 ml) and the solvent was removed under vacuum. The residue was taken up in ether and washed with water and brine. The ethereal solution was dried over anhydrous magnesium sulphate and then evaporated in vacuo. The residue was extracted with boiling hexane and afforded ethyl 3-[4-(4-ethyl-2,6,7-trioxabicyclo[2,2,2]oct-1-yl)phenyl]prop-2-ynoate (67 mg) as an off-white crystalline solid on cooling.
Reaction SMILES: [O-:1][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[CH2:9]([N+:11]12[CH2:18][CH2:17][N:14]([CH2:15][CH2:16]1)[CH2:13][CH2:12]2)[CH3:10].[O-:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21].[Li+]>C(#N)C>[O-:4][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:3])=[O:1].[O-:22][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:21])=[O:19].[CH2:9]([N+:11]12[CH2:18][CH2:17][N+:14]([F:24])([CH2:15][CH2:16]1)[CH2:13][CH2:12]2)[CH3:10]
Reactant: CC[N+]12CCN(CC1)CC2
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: CC[N+]12CC[N+](F)(CC1)CC2
Yield: 159.9 %

Procedure:
The reaction described in Example ID was repeated, using 1-ethyl-4-aza-1-azoniabicyclo[2,2,2]octane triflate (1.5 g, 5.2 mmol) in dry acetonitrile (200 cm3) in place of its N-methyl analogue and an equimolar proportion of lithium triflate (0.8 g). Work-up of the product, as in Example ID, afforded 1-ethyl-4-fluoro-1,4-diazoniabicyclo[2,2,2]octane ditriflate (1.9 g, 4.1 mmol, 80%), m.p. 236°-238° C. (dec.), δF (soln. in D2O; ext. TFA) 0.02 (s; CF3SO3-), 124.0 (br. m; FN+) p.p.m., δH (same soln.) 1.48 (t: CH3), 3.79 (q; CH2CH3), 4.40 (m: 3×ring CH2), 4.95 (m; 3 ring CH2) p.p.m. [residual H in D2O, 4.78 (s) p.p.m⟧
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13]C)=O)(C(C)(C)C)(C)C.[H-].[Na+].[C:19](#[N:21])[CH3:20]>C1(C)C=CC=CC=1>[OH:8][CH2:9][C:10]([CH3:15])([CH3:16])[C:11](=[O:13])[CH2:20][C:19]#[N:21]
Reactant: COC(=O)C(C)(C)CO[Si](C)(C)C(C)(C)C
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(CO)C(=O)CC#N
Temperature: 90 °C
Reaction time: 6 h
Yield: 88.7 %

Procedure:
Methyl 3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropanoate (0.63 g, 2.557 mmol) was added to toluene and NaH (0.4090 g, 10.23 mmol) and acetonitrile (0.534 mL, 10.23 mmol) and stirred overnight in a sealed vessel for 6 hours at 90° C. The solids were removed by filtration and rinsed with toluene. The toluene filtrate was concentrated, and the resulting solids were added to 3 N HCl, stirred for 30 minutes and then washed with ether. The mixture was concentrated and the resulting solids were rinsed several times with DCM. The DCM was dried over MgSO4, filtered and evaporated to provide the title compound as an oil (320 mg), which was used directly in the next step.
Reaction SMILES: N(CC(O)=O)C.[CH:7]1([S:10]([NH2:13])(=[O:12])=[O:11])[CH2:9][CH2:8]1.[OH:14][C:15]1[C@H:24]2[C@H:19]([C@H:20]3[CH2:25][C@@H:23]2[CH2:22][CH2:21]3)[N:18]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:17](=[O:31])[C:16]=1[C:32]1[NH:37][C:36]2[CH:38]=[CH:39][C:40](I)=[CH:41][C:35]=2[S:34](=[O:44])(=[O:43])[N:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I>[OH:14][C:15]1[C@H:24]2[C@H:19]([C@H:20]3[CH2:25][C@@H:23]2[CH2:22][CH2:21]3)[N:18]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:17](=[O:31])[C:16]=1[C:32]1[NH:37][C:36]2[CH:38]=[CH:39][C:40]([NH:13][S:10]([CH:7]3[CH2:9][CH2:8]3)(=[O:12])=[O:11])=[CH:41][C:35]=2[S:34](=[O:44])(=[O:43])[N:33]=1
Reactant: CC(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]21
Reactant: NS(=O)(=O)C1CC1
Agent: [Cu]I
Agent: CNCC(=O)O
Agent: O=P([O-])([O-])[O-]
Product: CC(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)C4CC4)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]21
Temperature: 100 °C
Reaction time: 3 h
Yield: 21.9 %

Procedure:
A reaction flask was charged with copper (I) iodide (20 mg, 0.11 mmol), sarcosine (N-methyl glycine) (14.7 mg, 0.17 mmol), cyclopropanesulfonamide (125 mg, 1.04 mmol), (1R,2S,7R,8S)-6-hydroxy-5-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-(3-methyl-butyl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (prepared as described in Example 34, 115 mg, 0.21 mmol) and potassium phosphate (176 mg, 0.83 mmol). The flask was degassed and backfilled with nitrogen, and then anhydrous N,N-dimethylformamide (5 mL) was added. The resulting suspension was vigorously stirred at 100° C. for 3 h, and then allowed to cool to 25° C. The mixture was passed through a plug of Celite and rinsed with 10% methanol/dichloromethane. The filtrate was concentrated in vacuo, and the residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 150×21.2 mm, 5 micron, 30%-95% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, cyclopropanesulfonic acid {3-(1R,2S,7R,8S)-[6-hydroxy-3-(3-methyl-butyl)-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-amide (25 mg, 0.046 mmol, 22%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.92-0.98 (10H, m), 1.20-1.64 (9H, m), 2.52 (1H, m), 2.62 (1H, s), 2.68 (1H, m), 3.00 (1H, d, J=9.6 Hz), 3.07 (1H, m), 3.61 (1H, d, J=10.4 Hz), 3.66 (1H, m), 7.50-7.59 (3H, m), 10.17 (1H, s). LC-MS (ESI) calcd for C25H32N4O6S2 548.18. found 549.4 [M+H+].
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[CH:4]=[C:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][Si:2]([CH3:10])([CH3:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH2:9][Br:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc([Si](C)(C)C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](C)(C)c1cccc(CBr)c1

Procedure:
A mixture of 3-trimethylsilyltoluene (3.28 g, 10 mmol), N-bromosuccinimide (1.78 g, 10 mmol) and benzoylperoxide (10 mg) in CCl4 (20 ml) was stirred under reflux for 3 hours, then cooled and filtered. The solvent was removed under reduced pressure and 3-trimethylsilylbenzylbromide was purified by distillation.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1(=[O:12])[CH2:11][CH2:10][CH2:9]1>>[OH:12][C:8]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: O=C1CCC1
Reactant: Brc1ccccn1
Product: OC1(c2ccccn2)CCC1

Procedure:
Prepared from 2-bromopyridine and cyclobutanone by the method described in Example 10 to give the title compound (7.62 g, quantitative) as an orange oil; NMR δH (400 MHz, DMSO) 8.54 (1H, m), 7.75 (1H, td, J 7.6, 1.7 Hz), 7.59 (1H, m), 7.22 (1H, m), 5.70 (1H, s), 2.58 (2H, m), 2.23 (2H, m), 1.91 (2H, m); (M+H)+ 151.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[C:12]([OH:14])=[O:13].C[Si](Cl)(C)C.N1C=CC=CC=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>ClCCl.CC(N(C)C)=O>[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:1][C:2]2[CH:11]=[CH:10][C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[C:3]=2[C:12]([OH:14])=[O:13])(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Nc1ccc2c(c1C(=O)O)CCCC2
Agent: C[Si](C)(C)Cl
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(O)c1c(NS(=O)(=O)c2ccc(F)cc2)ccc2c1CCCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of Example 128C (0.033 g, 0.200 mmol) in dichloromethane (1 mL) was treated with 1M trimethylsilyl chloride in dichloromethane (440 μL, 0.044 mmol) and pyridine (56.6 μL, 0.70 mmol), shaken for 4 hours at ambient temperature, treated with a solution of 4-fluorobenzenesulfonyl chloride (0.042 g, 0.24 mmol) in dimethylacetamide (1 mL), shaken for 16 hours at ambient temperature, and concentrated. The concentrate was acidified to pH 1.0 with 5% aqueous HCl and extracted with dichloromethane. The extracts were washed sequentially with water and brine, dried (MgSO4); filtered, and concentrated. The concentrate was purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product. MS (ESI(+)) m/e 367 (M+NH4)+, 372 (M+Na)+; MS (ESI(−)) m/e 348 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 9.62 (s, 1H), 7.77 (dd, 2H), 7.40 (t, 2H), 7.00 (d, 1H), 6.65 (d, 1H), 2.65 (m, 4H), 1.67 (m, 4H).
Reaction SMILES: C([O:3][P:4]([C:9]1[C:13]([P:14]([O:19]CC)([O:16]CC)=[O:15])=[C:12]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[S:11][C:10]=1[C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)([O:6]CC)=[O:5])C.I[Si](C)(C)C>C(#N)C>[P:4]([C:9]1[C:13]([P:14]([OH:16])([OH:19])=[O:15])=[C:12]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[S:11][C:10]=1[C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)([OH:5])([OH:6])=[O:3]
Reactant: CCOP(=O)(OCC)c1c(-c2cccs2)sc(-c2cccs2)c1P(=O)(OCC)OCC
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: O=P(O)(O)c1c(-c2cccs2)sc(-c2cccs2)c1P(=O)(O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
In acetonitrile, 0.2478 g (0.476 mmols) of 3′,4′-bis(diethoxyphosphoryl)-[2,2′;5′,2″]-terthiophene was dissolved, to which 0.4762 g (2.380 mmols) of commercially available iodotrimethylsilane was added at room temperature. Thereafter, the mixture was stirred at room temperature for 12 hours. After the reaction, the solvent was removed by distilling off under reduced pressure, followed by addition of methanol and stirring at room temperature for further 12 hours. The methanol was removed by distilling off under reduced pressure, followed by addition of distilled water under stirring and separation of an aqueous phase. The thus separated aqueous phase was washed several times with chloroform and the aqueous phase was concentrated and evaporated to dryness to obtain the specified substance in the form of yellow crystals at a yield of 0.1742 g (yield: 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[N:16]1([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C:29]3[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=3)=[CH:23][CH:22]=2)[CH:20]=[CH:19][N:18]=[CH:17]1>>[N:16]1([C:21]2[CH:22]=[CH:23][C:24]([CH2:27][N:28]([C:29]3[CH:30]=[CH:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=3)[C:13]([CH:10]3[C:11]4[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=4)[CH2:7][CH2:8][CH2:9]3)=[O:15])=[CH:25][CH:26]=2)[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: CC(C)c1ccc(NCc2ccc(-n3ccnc3)cc2)cc1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(-n3ccnc3)cc1)c1ccc(C(C)C)cc1)CCC2
Yield: 30.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.39 g) and {[4-(imidazol-1-yl)phenyl]methyl}(4-isopropylphenyl)amine (0.55 g) as starting materials, N-{[4-(imidazol-1-yl)phenyl]methyl}-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide ½ hydrate (0.28 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
To a stirred solution of (1-tert-butoxycarbonyl-(2S)-pyrrolidinyl)methanol (4.02 g, 20.0 mmol), methyl 4-hydroxybenzoate (3.04 g, 20.0 mmol) and Ph3P (6.28 g, 24.0 mmol) in THF (50 ml) was added DIAD (4.85 g, 24.0 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 hr. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (5:1, v/v) as eluent to give methyl 4-(1-tert-butoxycarbonyl-(2S)-pyrrolidinyl)methoxybenzoate (5.4 g, 81%) as a pale yellow oil. 1H-NMR (CDCl3) δ 1.47 (s, 9H), 1.88–2.04 (m, 4H), 3.41 (m, 2H), 3.91 (s, 3H), 3.90–3.92 (m, 1H), 4.11–4.16 (m, 2H), 6.94 (d, J=8.6 Hz, 2H), 7.94 (d, J=8.3 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:14].[C:15](Cl)(=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[CH3:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[O:10][C:6]=2[CH:5]=[C:4]([C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[C:3]=1[CH3:14]
Reactant: Cc1ccc2oc(C(=O)O)cc2c1C
Reactant: CCCCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC(=O)c1cc2oc(C(=O)O)cc2c(C)c1C
Temperature: 5 °C
Reaction time: 48 h

Procedure:
A stirred suspension of 4,5-dimethylbenzofuran-2-carboxylic acid (18 g.) and valeryl chloride (15 g.) in methylene chloride (300 ml.) is cooled to 5°C. and treated with aluminum chloride (40 g.) in portions during a 1/2 hour period during which time the suspended reactant dissolves. The reaction mixture is stirred at 25° for 2 days then poured into ice water (500 ml.) containing hydrochloric acid (50 ml.). The product (21 g.) separates from the biphasic solution, is filtered and recrystallized from ethanol-water affording 4,5-dimethyl-6-valerylbenzofuran-2-carboxylic acid which melts at 188°-9°C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH:12]3[CH2:13][CH2:14][CH2:15][CH:11]3[N:10]([CH2:16][CH3:17])[C:9]2=[O:18])=[N:6][CH:7]=1.[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)#[CH:20].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:16]([N:10]1[CH:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[N:8]([C:5]2[N:4]=[CH:3][C:2]([C:20]#[C:19][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:7][N:6]=2)[C:9]1=[O:18])[CH3:17]
Reactant: C#Cc1ccccc1
Reactant: CCN1C(=O)N(c2ncc(Br)cn2)C2CCCC21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN1C(=O)N(c2ncc(C#Cc3ccccc3)cn2)C2CCCC21
Temperature: 75 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
In a microwave tube were dissolved 80 mg (0.26 mmol) of (rac)-1-(5-bromopyrimidin-2-yl)-3-ethylhexahydrocyclopenta[d]imidazol-2(1H)-one (Example 1, step 4) in 3 ml DMF. Argon was bubbled through the solution. Ethynylbenzene (57 μl, 53 mg, 0.52 mmol, 2 equiv.), Bis(triphenylphosphine)palladium(II) chloride (9 mg, 0.013 mmol, 0.05 equiv.), copper (I) iodide (1.5 mg, 7.7 μmol, 0.03 equiv.), triphenylphosphine (2.0 mg, 7.7 μmol, 0.03 equiv.) and 107 μl of triethylamine (78 mg, 0.77 mmol, 3 equiv.) were added. The dark brown solution was stirred at 75° C. overnight, adsorbed on silica and purified by flash chromatography (silica gel, 20 g, 0% to 80% EtOAc in heptane gradient) to yield 72.7 mg (85%) of the title compound as a brown solid, MS: m/e=333.3 (M+H+).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[CH:10]=1.[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)[C:24]=1[C:25](O)=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)[C:24]=1[C:25]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[CH:10]=3)[CH2:3][CH:4]2[CH2:8]1)=[O:26]
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: CN(C)c1cc(N2CC3CNCC3C2)nc(C(F)(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C)c1cc(N2CC3CN(C(=O)c4c(F)cccc4-n4nccn4)CC3C2)nc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
A mixture of [6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-trifluoromethyl-pyrimidin-4-yl]-dimethyl-amine (50 mg, 0.17 mmol), 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (37.8 mg, 0.18 mmol), HATU (94.6 mg, 0.25 mmol) and DIPEA (0.09 mL, 0.50 mmol) in DMF (4.0 mL) was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (19.0 mg, 23.4%). MS (ESI) mass calcd. for C22H22F4N8O, 490.46; m/z found [M+H]+. 1H NMR (CDCl3): 7.89-7.79 (m, 2H), 7.74 (s, 1H), 7.55-7.37 (m, 1H), 7.21-7.05 (m, 1H), 5.25-5.09 (m, 1H), 4.25-3.51 (m, 6H), 3.50-2.95 (m, 10H).
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][NH:8][C:9]([C:11]1[C:16]([OH:17])=[C:15]([CH3:18])[N:14]=[C:13]([CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:42]=[CH:41][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][N:33]=4)=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)[N:12]=1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O.Cl>ClCCl>[CH2:39]([O:38][C:36]([C:35]1[CH:41]=[CH:42][C:32]([C:29]2[CH:30]=[CH:31][C:26]([N:23]3[CH2:24][CH2:25][CH:20]([CH2:19][C:13]4[N:12]=[C:11]([C:9]([NH:8][CH2:7][C:6]([OH:43])=[O:5])=[O:10])[C:16]([OH:17])=[C:15]([CH3:18])[N:14]=4)[CH2:21][CH2:22]3)=[CH:27][CH:28]=2)=[N:33][CH:34]=1)=[O:37])[CH3:40]
Reactant: CCOC(=O)c1ccc(-c2ccc(N3CCC(Cc4nc(C)c(O)c(C(=O)NCC(=O)OC(C)(C)C)n4)CC3)cc2)nc1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(-c2ccc(N3CCC(Cc4nc(C)c(O)c(C(=O)NCC(=O)O)n4)CC3)cc2)nc1
Reaction time: 12 h
Yield: 50.7 %

Procedure:
Ethyl 6-{4-[4-({4-[(2-tert-butoxy-2-oxoethyl)carbamoyl]-5-hydroxy-6-methylpyrimidin-2-yl}methyl)piperidin-1-yl]phenyl}nicotinate (0.043 g, 0.073 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added at room temperature, followed by stirring for 12 hours. Hydrochloric acid (1 M) was added to the reaction solution, followed by extraction with ethyl acetate, and subsequently the organic layer was concentrated under reduced pressure. After the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: ethyl acetate/methanol), a fraction corresponding to the Rf value=0.10 (ethyl acetate/methanol=4/1) by thin layer chromatography was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, followed by addition of diisopropyl ether, and subsequently the deposited solid was collected by filtration using diisopropyl ether to afford the title compound (0.020 g, 0.037 mmol) as a pale yellow solid (yield 51%).
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][CH:9]=[CH:8][C:7]=2[CH:6]=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH3:21][CH:22]1[NH:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1>CC#N>[CH3:21][CH:22]1[N:27]([CH2:2][C:3]2[C:11]3[O:10][CH:9]=[CH:8][C:7]=3[CH:6]=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=2)[CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:23]1
Reactant: O=[N+]([O-])c1cc(CBr)c2occc2c1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1CN(C(=O)OC(C)(C)C)CCN1Cc1cc([N+](=O)[O-])cc2ccoc12
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 78.5 %

Procedure:
A mixture of 7-(bromomethyl)-5-nitro-1-benzofuran (120 mg, 70 mol %, 0.39 mmol; Intermediate 64), K2CO3 (162 mg, 1.17 mmol) and tert-butyl 3-methylpiperazine-1-carboxylate (94 mg, 0.47 mmol) in dry MeCN (5 mL) was heated at 80° C. while stirring for 1 h 45 min using a StemBlock. The solvent was evaporated under reduced pressure and the residue was partitioned between water and DCM (×2). The organic layers were combined, dried (Na2SO4) and purified using flashtube (10% MeOH in DCM). This afforded the title product (115 mg, 78%) as a light yellow sticky oil. HPLC 99%, RT=2.47 min (System A; 5-60% MeCN over 3 min), 99%, RT=2.27 min (System B; 5-60% MeCN over 3 min). MS (ESI+) for C19H25N3O5 m/z 376 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[OH:20].C([O-])([O-])=O.[K+].[K+].[CH2:27](Br)[CH:28]=[CH2:29]>CC(C)=O>[CH2:29]([O:20][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[N:10]=[CH:9][N:8]=[C:7]2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:28]=[CH2:27]
Reactant: C=CCBr
Reactant: COc1cc2ncnc(Nc3ccccc3)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc2c(Nc3ccccc3)ncnc2cc1OC
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of 7-methoxy-4-phenylamino-quinazolin-6-ol (0.56 g, 2.1 mmol) (from Example 15, Step B, supra) in acetone (50 mL) was added K2CO3 (1.45 g, 10 mmol), and allyl bromide (0.2 mL, 2.3 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4 hours. The mixture was cooled to room temperature, filtered and the filtrate was concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:4:0.04) as eluent to give the desired (6-allyloxy-7-methoxy-quinazolin-4-yl)-phenyl-amine as a yellow solid. (Yield 0.6 g, 93%).