Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.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.Cl.[NH:67]1[CH2:72][CH2:71][CH:70]([N:73]2[CH2:78][CH2:77][O:76][CH2:75][CH2:74]2)[CH2:69][CH2:68]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:67]3[CH2:72][CH2:71][CH:70]([N:73]4[CH2:78][CH2:77][O:76][CH2:75][CH2:74]4)[CH2:69][CH2:68]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: C1CC(N2CCOCC2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cn(CC(=O)N2CCC(N3CCOCC3)CC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (100 mg) in DMF (2 mL) was added HATU (100 mg, 0.26 mmol), DIEA (85 mg, 0.66 mmol), and 4-(piperidin-4-yl)morpholine hydrochloride (67 mg, 0.32 mmol). The resulting solution was stirred at room temperature overnight. The crude product (60 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 10 mM NH4CO3 and MeCN (20.0% MeCN up to 35.0% in 8 min); Detector, 254/220. This resulted in 28.3 mg (21%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(morpholin-4-yl)piperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a yellow solid. LCMS (Method 20) [M+H]+=615.2, RT=1.84 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz), 7.02 (t, 1H, J=73.2 Hz), 5.24-5.21 (m, 2H), 4.42-4.31 (m, 1H), 4.02-3.95 (m, 1H), 3.55 (t, 4H, J=4.5 Hz), 3.16-3.02 (m, 1H), 2.78-2.64 (m, 1H), 2.49-2.45 (m, 5H), 1.90-1.76 (m, 2H), 1.54-1.21 (m, 2H).
Reaction SMILES: O[Li].O.[CH2:4]([O:11][CH2:12][C:13](=[O:24])[CH:14]([CH3:23])[C:15](=[O:22])[CH:16]([CH3:21])[C:17]([O:19]C)=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.C1C[O:29][CH2:28][CH2:27]1>>[C:28]([O:22][C:15]1[C:14]([CH3:23])=[C:13]([CH2:12][O:11][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:24][C:17](=[O:19])[C:16]=1[CH3:21])(=[O:29])[CH3:27]
Reactant: C1CCOC1
Reactant: COC(=O)C(C)C(=O)C(C)C(=O)COCc1ccccc1
Agent: Cl
Agent: [Li]O
Solvent: O
Product: CC(=O)Oc1c(C)c(COCc2ccccc2)oc(=O)c1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
An aqueous solution (6 ml) of LiOH-hydrate (64 mg) was added to a solution of methyl 6-benzyloxy-2,4-dimethyl-3,5-dioxohexanoate (430 mg) in THF (10 ml), and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was neutralized with diluted hydrochloric acid, and after distilling off the volatile components under reduced pressure, extraction was performed with AcOEt at pH 3. The organic layer was dried with MgSO4 and then filtered and concentrated. Ac2O (6 ml) was added to the residue, and after stirring at room temperature for 30 minutes, pyridine (4 ml) was added and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/AcOEt=3/1→12/5) to obtain 4-acetyloxy-6-(benzyloxy)methyl-3,5-dimethyl-2H-pyran-2-one.
Reaction SMILES: [CH3:1][C:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1)([CH3:5])[C:3]#[CH:4]>ClC1C=CC=CC=1Cl>[CH3:5][C:2]1([CH3:1])[CH:3]=[CH:4][C:8]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:14])=[O:15])[CH:11]=[CH:12][C:7]=2[O:6]1
Reactant: C#CC(C)(C)Oc1ccc(S(C)(=O)=O)cc1
Solvent: Clc1ccccc1Cl
Product: CC1(C)C=Cc2cc(S(C)(=O)=O)ccc2O1
Temperature: 200 °C
Reaction time: 2 h
Yield: 59.2 %

Procedure:
To 1,2-dichlorobenzene (230 ml) at 200° C. was added 3-methyl-3-(4-mesylphenoxy)-1-butyne (130 g) dropwise over a period of 1.5 hours. The reaction mixture was stirred at 200° C. for an additional 2 hours followed by removal of 1,2-dichlorobenzene by distillation under reduced pressure. The residue was dissolved in diisopropyl ether (100 ml) and treated with activated carbon. The mixture was filtered and the filtrate afforded the precipitate, which was collected, washed with diisopropyl ether, and dried to give 2,2-dimethyl-6-mesyl-2H-1-benzopyran (77 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[OH:24][CH2:25][C:26]([NH:29][S:30]([C:33]1[S:34][C:35]([Cl:39])=[C:36]([NH2:38])[CH:37]=1)(=[O:32])=[O:31])([CH3:28])[CH3:27]>>[Cl:39][C:35]1[S:34][C:33]([S:30](=[O:32])(=[O:31])[NH:29][C:26]([CH3:27])([CH3:28])[CH2:25][OH:24])=[CH:37][C:36]=1[NH:38][C:21]([C:20]1[CH:19]=[N:18][N:11]2[C:12]([C:14]([F:15])([F:17])[F:16])=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9][C:10]=12)=[O:22]
Reactant: CC(C)(CO)NS(=O)(=O)c1cc(N)c(Cl)s1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) according to general procedure II. Yellow solid. MS (ISP) 605.8 [(M−H)−]; mp 272° C.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][C:7]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)([CH3:10])[C:8]#[N:9].N>O>[CH3:10][C:7]([N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)([CH3:6])[C:8]([NH2:9])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C#N)N1CCOCC1
Agent: N
Solvent: O
Product: CC(C)(C(N)=O)N1CCOCC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
272 ml of concentrated sulfuric acid are slowly added, with stirring, to 57.9 g of 2-methyl-2-morpholino-propionitrile (exothermic reaction). After the addition of 43 ml of water, the mixture is stirred for 2 hours at 100°-110° C. The reaction mixture is cooled to 50° C. and added dropwise at 0° C. to a solution of 846 ml of 20% ammonia in 242 ml of water. The mixture is then extracted repeatedly with dichloromethane. The organic phases are washed with saturated sodium chloride solution and with sodium sulfate. The crude title compound is obtained from the concentrated filtrate: 1H NMR (CDCl3), δ(ppm)=7.08 (1H, bs), 5.38 (1H, bs), 3.72 (4H,m), 2.53 (4H, m), 1.22 (6H,s)
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:19]1(=[O:33])[N:23]([CH2:24][CH2:25][CH2:26]Cl)[C:22](=[O:28])[C:21]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:20]12>>[C:22]1(=[O:28])[N:23]([CH:24]([C:14]2[C:13]([Cl:16])=[CH:12][CH:11]=[C:10]3[C:15]=2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][NH:9]3)[CH2:25][CH3:26])[C:19](=[O:33])[C:20]2=[CH:32][CH:31]=[CH:30][CH:29]=[C:21]12
Reactant: Clc1ccc2[nH]nc(-c3ccccc3)c2c1
Reactant: O=C1c2ccccc2C(=O)N1CCCCl
Agent: [H-]
Agent: [Na+]
Product: CCC(c1c(Cl)ccc2[nH]nc(-c3ccccc3)c12)N1C(=O)c2ccccc2C1=O
Yield: 62.2 %

Procedure:
By the procedure similar to that described in Example 24, 3-phenyl-5-chloroindazole (9.2 g), sodium hydride 50% pure (2.3 g) and phthalimidopropyl chloride (9.0 g) were treated to obtain 10.4 g of 1-phthalimidopropyl-3-phenyl-5-chloroindazole. Recrystallization from methanol gave a product having a melting point between 121°-122° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH:19]1([C:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=3)[N:27]([CH2:38][C:39]#[CH:40])[C:26]=2[C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][C:42]=2[CH2:49][O:50][Si](C(C)C)(C(C)C)C(C)C)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1.CCOC(C)=O>[CH:19]1([C:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=3)[N:27]([CH2:38][C:39]#[CH:40])[C:26]=2[C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][C:42]=2[CH2:49][OH:50])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C#CCn1c(-c2ccc(OC)cc2CO[Si](C(C)C)(C(C)C)C(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#CCn1c(-c2ccc(OC)cc2CO)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
Tetrabutylammonium fluoride (1.3 eq., 1M solution in THF) was added dropwise to an ice cooled solution of methyl 3-cyclohexyl-2-(4-methoxy-2-{[(triisopropylsilyl)oxy]methyl}phenyl)-1-prop-2-yn-1-yl-1H-indole-6-carboxylate in THF (0.036M). The mixture was stirred at 0° C. for 1 h then diluted with EtOAc, washed with saturated aq. NH4Cl, water and brine. The organic phase was dried over Na2SO4 and evaporated in vacuo. The residual material was subjected to flash chromatography (PE:EtOAc, 3:1). After evaporation of the solvent the product was obtained as white solid (64%). MS (ES+): 432.5 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[S:11]1([C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15](=[O:16])[NH:14]1)(=[O:13])=[O:12].[Na]>O1CCCC1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:14]1[C:15](=[O:16])[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:11]1(=[O:13])=[O:12])=[O:5]
Reactant: O=C(Cl)c1ccccc1F
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: [Na]
Solvent: C1CCOC1
Product: O=C(c1ccccc1F)N1C(=O)c2ccccc2S1(=O)=O

Procedure:
A mixture of 2-fluorobenzoyl chloride, from example 4A, above, and 18.5 g (0.09 mole) of sodium saccharin is refluxed in 100 ml of tetrahydrofuran (THF) overnight. The reaction mixture is filtered hot, and the filtrate is concentrated to a partial solid/oil. The product is triturated with ether and air dried to yield 10.3 g of 2-(2-fluorobenzoyl)saccharin, m.p. 148°-151° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([NH:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>O1CCCC1>[NH2:19][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([NH:13][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(Nc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 97.9 %

Procedure:
Next, to a solution of lithium aluminum hydride (1.17 g, 30.9 mmol) in tetrahydrofuran (60 mL) was added a solution of the obtained 4-phenylamino-benzonitrile (2.0 g, 10.3 mmol) in tetrahydrofuran (5 mL), and the solution was stirred at room temperature for 22 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain the title compound (2.0 g, 98%) as an orange oil. This compound was used in the next reaction without purification.
Reaction SMILES: Br[CH2:2][CH2:3]/[CH:4]=[C:5](\[CH3:15])/[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C-:16]#[N:17].[K+]>CN(C=O)C.O>[CH3:15]/[C:5](/[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4]\[CH2:3][CH2:2][C:16]#[N:17]
Reactant: CCCCCCCCC/C(C)=C/CCBr
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCC/C(C)=C/CCC#N
Temperature: 70 °C
Reaction time: 24 h
Yield: 98.2 %

Procedure:
A mixture of the (E)-1-bromo-4-methyl-3-tridecene (3) (38.0 g, 138 mmols) and KCN (11.5 g, 176 mmols) in DMF (100 ml) and water (30 ml) was stirred for 24 hours at 70° C. Then, the mixture was poured into ice water (1 L) and extracted with ether (500 ml). The ether solution was washed with water, dried (MgSO4), and concentrated in a vacuum. The residue was subjected to silica gel chromatography, and eluted with n-hexane-ether (100:1) to obtain 30.0 g (98%) of (E)-5-methyl-4-tetradecenenitrile (4) as oily matter.
Reaction SMILES: [CH3:1][Li].[C:3]([C:5]1[C:9]([S:10][C:11]([F:14])([F:13])[F:12])=[C:8]([CH:15]=[O:16])[N:7]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=2[Cl:28])[N:6]=1)#[N:4].Cl>C(OCC)C.[Cu]I>[C:3]([C:5]1[C:9]([S:10][C:11]([F:13])([F:12])[F:14])=[C:8]([CH:15]([OH:16])[CH3:1])[N:7]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:26])([F:27])[F:25])=[CH:19][C:18]=2[Cl:28])[N:6]=1)#[N:4]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(C=O)c1SC(F)(F)F
Reactant: [Li]C
Agent: [Cu]I
Agent: Cl
Solvent: CCOCC
Product: CC(O)c1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Copper (I) iodide (6.1 g, 0.032 mol) was suspended in anhydrous diethyl ether and cooled to 0° C. Methyllithium (1.6M in diethyl ether, 40 ml, 0.064 mol) was added via cannula and stirred 10 minutes. A solution of the product of Example 3 (10 g, 0.023 mol) in diethyl ether was added via cannula creating a bright yellow suspension. After 15 minutes, 10% aqueous hydrochloric acid (40 ml) was added while venting the reaction vessel. The remaining suspension was filtered through Celite® and washed with diethyl ether several times. The organic phase was washed with saturated sodium hydrogen carbonate solution, saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Trituration from pentane provided crystals that were purified by silica gel chromatography using ethyl acetate:hexanes. The title compound was isolated as a white solid (7.56 g), m.p. about 123° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[O:20])[C:7]3[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[CH3:23]C(O)C>Cl>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[O:20])[C:7]3[C:14]([C:15]([O:17][CH:18]([CH3:23])[CH3:19])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reactant: CC(C)O
Agent: Cl
Product: CC(C)OC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reaction time: 8 h
Yield: 48 %

Procedure:
A solution of 7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (500 mg, 1.56 mmol), 2-propanol (60 mL), and concentrated hydrochloric acid (3 drops) was subjected to three cycles of partial solvent removal by slow distillation (over 6 hours) followed by overnight reflux. After the third cycle, solvent was removed by rotary evaporation and the crude product was purified by flash chromatography eluting with dichloromethane:2-propanol (95:5-85:15) to yield the title compound as a white solid (256 mg, 48%, m.p. 291° C). Alternatively, the title compound can be prepared as described in Example 18 shown hereinbelow in Table 1.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-])=O)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.O1CCCC1.C([O-])=O.[NH4+].[Pd]>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)n1ccc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc2c(ccn2C(=O)c2ccccc2)c1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
1-benzoyl-5-nitro-1H-indole (50 mg) was dissolved in a mixed solvent with methanol (2 ml) and tetrahydrofuran (2 ml), and ammonium formate of an excess amount and palladium/carbon (10%) of a catalytic amount were added. The reacted solution was stirred at around 30° C. for 30 minutes to complete the reduction, filtered through celite and then, concentrated under reduced pressure. Afterward, the residue was dissolved again in ethylacetate (10 ml), washed with water and brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and then, triturated with isooctane and isopropyleter. As a result, the present compound (25 mg, productive yield 56%) was obtained as a solid.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[CH:10]=[C:9]([Sn:11]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]([CH3:24])[N:6]=1>O1CCCC1.O>[CH3:24][C:7]1[N:6]=[C:5]([S:2][CH3:1])[CH:10]=[C:9]([Sn:11]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(Cl)nc(C)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cc(SC)nc(C)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 29.8 %

Procedure:
Sodium thiomethoxide (140 mg, 2 mmol) was added to 4-chloro-2-methyl-6-(tributylstannyl)pyrimidine (835 mg, 2 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as an orange oil. The crude product was purified by silica gel chromatography, eluting with 5% EtOAc/hexanes to give 2-methyl-4-(methylthio)-6-(tributylstannyl)pyrimidine (256 mg, 30% yield). 1H NMR (300 MHz, CDCl3) δ 7.07 (s, 1H); 2.62 (s, 3H); 2.51 (s, 3H); 1.44-1.70 (m, 6H); 1.21-1.42 (m, 6H); 0.98-1.21 (m, 6H); 0.91 (t, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O.Cl>CN(C)C=O.ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([Cl:21])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(OCc2ccccc2)c1

Procedure:
A stirred mixture of 3-benzyloxybenzoic acid (22.0 g; 0.096 mol) and dry dimethylformamide (2 drops) in dry dichloromethane (100 cm3) was treated with oxalyl chloride (19 g; 0.15 mol) which was added in 4 approximately equal portions over ˜30 minutes. The mixture was stirred at room temperature until evolution of hydrogen chloride had ceased (˜6 hrs). The resulting colourless solution was evaporated in vacuo at 40° to constant weight to give a very pale tan oil that solidified rapidly to give the title compound as off-white needles.
Reaction SMILES: C([C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1)#N.N.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[N:13]1([C:3]2[O:4][C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=3[CH:7]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: N#Cc1cc2ccccc2o1
Reactant: C1CNCCN1
Agent: N
Product: c1ccc2oc(N3CCNCC3)cc2c1

Procedure:
In step 1 of Scheme C, bromophenol n undergoes iodination to form bromo-iodo-phenol o. Phenol compound o is then reacted with cinnamoyl halide p in step 2 to afford phenoxy ester compound g. Compound g undergoes a cyclization in step 3 to form benzofuran compound r. In step 4 compound r is reacted with dimethyl formamide in the presence of phosphorus oxychloride to afford benzofuran-2-carboxaldehyde s. Aldehyde compound s is converted to cyano-benzofuran compound t in step 5 by reaction with aqueous ammonia. In step 6 a Buchwald reaction is carried out by reacting compound t with piperazine compound f to afford piperazinyl benzofuran u. The nitrile group of compound u undergoes oxidation in step 7 to give benzofuran carboxamide compound v. Compound v is then deprotected in step 8 to afford compound w, which is a compound of formula II in accordance with the invention.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][NH:17][CH2:18][CH3:19])=O)C.O.[OH-].[Li+]>C(O)(=O)C(O)=O>[CH2:18]([NH:17][CH2:16][CH2:15][N:14]1[CH2:13][CH2:12][C:7]2[NH:8][CH:9]=[C:10]([CH3:11])[C:6]=2[C:4]1=[O:3])[CH3:19]
Reactant: CCNCCNCCc1[nH]cc(C)c1C(=O)OCC
Agent: O=C(O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCNCCN1CCc2[nH]cc(C)c2C1=O
Temperature: 135 °C
Yield: 30.2 %

Procedure:
A stirred mixture of 2-[2-(2-ethylamino-ethylamino)-ethyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (40 mg, 1.498 mmol), lithium hydroxide monohydrate (503 mg, 11.985 mmol) in 25 ml of oxalic acid was heated to reflux at 135° C. The mixture was concentrated under reduced pressure, added with water (10 ml) and extracted with dichloromethane (20 ml×3). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 5-(2-ethylamino-ethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-4-one (100 mg, 30.2%) as a brown oil.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15](O)=[C:16]([CH3:21])[C:17](=[O:20])[N:18]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:25]>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([Cl:25])=[C:16]([CH3:21])[C:17](=[O:20])[N:18]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(O)c2c(=O)n(Cc3ccccc3)cnc2n(C)c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1c(Cl)c2c(=O)n(Cc3ccccc3)cnc2n(C)c1=O

Procedure:
3-Benzyl-5-hydroxy-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (5.5 g, 18.5 mmol) was dissolved in excess POCl3 (50 mL) and heated at reflux for 1 hour. POCl3 was removed in vacuo and the residue dissolved in DCM then quickly washed with saturated sodium bicarbonate solution until neutral pH was observed. The organic layer was dried over MgSO4 and evaporated to dryness to give 7.3 g of the title compound as an impure reddish brown solid. [M+H] calc'd for C16H14ClN3O2, 315; found, 315.
Reaction SMILES: [NH:1]([C:33](OC(C)(C)C)=[O:34])[CH2:2][C:3]([N:5]1[CH2:32][CH2:31][CH2:30][C@H:6]1[C:7]([NH:9][C@H:10]([C:15]([NH:17][CH2:18][C:19]([NH:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])=[O:4].C(Cl)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=O>>[NH:1]([C:33]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:34])[CH2:2][C:3]([N:5]1[CH2:32][CH2:31][CH2:30][C@H:6]1[C:7]([NH:9][C@H:10]([C:15]([NH:17][CH2:18][C:19]([NH:21][O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])=[O:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)NOCc1ccccc1
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)c1ccccc1)C(=O)NCC(=O)NOCc1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To Boc-Gly-Pro-Leu-Gly-NHOBzl (0.55 g; 1.00 mmol) obtained in Example 1 (F) was added under ice cooling 4.5N HCl/AcOEt (2 ml), and the mixture was brought back to room temperature. The reaction was carried out for 1 hour. The solvent was distilled off under reduced pressure and the residue was dissolved in DMF (5 ml). The solution was cooled with a coolant at -20° C. and TEA (0.14 ml; 1.00 mmol) was added dropwise. Bz-Cl (0.17 g; 1.21 mmol) was then added dropwise and TEA was used to adjust the pH to 8-9. The reaction was carried out for 1 hour and insolubles were filtered off. The solvent was distilled off under reduced pressure. The residue was dissolved in AcOEt, and the solution was washed successively with water, 1N-HCl, water, 10% Na2CO3 and water and then dried over anhydrous MgSO4. The solvent was distilled off under reduced pressure and the residue was purified by chromatography on silica gel (Fuji Davison BW 200, 25 g; eluted with CHCl3 :MeOH (=20:1) mixed solvent) to give Bz-Gly-Pro-Leu-Gly-NHOBzl (0.43 g; 78%) as a colorless powder. m.p. 79°-84° C.,specific rotation [α]D28 -69.0 (c=1.0, EtOH).