Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:21])=[C:12]([CH:15]([OH:20])[C:16]([O:18][CH3:19])=[O:17])[C:13]([I:14])=[C:8]2[CH:7]=[CH:6]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].O>ClCCl>[F:1][C:2]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:21])=[C:12]([C:15](=[O:20])[C:16]([O:18][CH3:19])=[O:17])[C:13]([I:14])=[C:8]2[CH:7]=[CH:6]1
Reactant: COC(=O)C(O)c1c(C)nc2c(ccn2Cc2cccc(F)c2F)c1I
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(=O)c1c(C)nc2c(ccn2Cc2cccc(F)c2F)c1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To a solution of methyl 2-(1-(2,3-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-hydroxyacetate (7.95 g, 14.65 mmol) in dichloromethane (DCM) (130 mL) at 0° C. was added in two portions Dess-Martin periodinane (6.83 g, 16.11 mmol) and the mixture was stirred at ambient temperature for 30 min and then a 20% Na2S2O3/water was added and stirring at ambient temperature continued for 20 min. The mixture was diluted with dichloromethane and the organic phase was washed with NaHCO3/water (2×), dried (Na2SO4), concentrated, purified by chromatography (silica gel, EtOAc/hexanes 0-20% then 100%, product eluted at 20-60%) to provide methyl 2-(1-(2,3-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-oxoacetate (5.8 g, 11.10 mmol, 76% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.54-2.64 (m, 3 H), 3.94 (s, 3 H), 5.53 (s, 2 H), 6.39 (d, J=3.71 Hz, 1 H), 6.84-6.95 (m, 1 H), 6.99 (m, 1 H) 7.10 (m, 1 H), 7.28 (d, J=3.52 Hz, 1 H); LCMS (m/z) ES+=471 (M+1).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:24])[NH:6][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:9]=1)(=[O:3])[CH3:2].[CH:25](=O)[C:26]([CH3:29])([CH3:28])[CH3:27].N1CCCC1>C(#N)C>[C:26]([CH:29]1[O:24][C:5]2=[N:6][C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[CH:9]=[C:4]2[C:1](=[O:3])[CH2:2]1)([CH3:28])([CH3:27])[CH3:25]
Reactant: CC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Reactant: CC(C)(C)C=O
Solvent: CC#N
Solvent: C1CCNC1
Product: CC(C)(C)C1CC(=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nc2O1
Temperature: 70 °C

Procedure:
To the product of Example 4 Step A (0.75 g, 2.09 mmol) was added pivalaldehyde (2. mL, 20.9 mmol), pyrrolidine (0.26 mL, 3.14 mmol) and acetonitrile (15 mL). The reaction was heated to 70° C. for 19 h. The reaction was then concentrated and the residue was purified directly by flash chromatography on silica gel gradient eluted with 0-35% EtOAc in hexane to afford the title compound. (LC-2) HPLC/MS: 426.3 (M+1), 428.3 (M+3); Rt=4.32 min.
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([Si:2]([CH3:12])([CH3:11])[CH3:1])=[CH:4][CH:5]=2)=[CH:16][CH:15]=1
Reactant: C[Si](C)(C)c1ccc(C=O)cc1
Reactant: NCCc1ccc(Cl)cc1
Product: C[Si](C)(C)c1ccc(CNCCc2ccc(Cl)cc2)cc1

Procedure:
[2-(4-chloro-phenyl)-ethyl]-(4-trimethylsilanyl-benzyl)-amine was prepared in analogy to example 1 from 4-trimethylsilanyl-benzaldehyde and 2-(4-chloro-phenyl)-ethylamine. MS (ISP): 318.1/320.3 (100/39) (M+H)+. 1HNMR (CDCl3, 300 MHz): δ 7.47 (d, 2H), 7.23-7.28 (m, 4H), 7.12 (d, 2H), 3.79 (s, 2H), 2.75-3.00 (m, 4H), 0.26 (s, 9H).
Reaction SMILES: COC1C=CC(N=CC2C=CC(C#N)=CC=2)=CC=1.[CH:19](=[N:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.F[C:36]1[CH:41]=[CH:40][C:39]([CH:42]([OH:60])[CH2:43][CH2:44][CH2:45][C:46](N2C(C3C=CC=CC=3)COC2=O)=[O:47])=[CH:38][CH:37]=1.C1(C(O)CCCC(N2C(C3C=CC=CC=3)COC2=O)=O)C=CC=CC=1>[Ni]>[NH2:32][CH2:31][C:30]1[CH:29]=[CH:28][C:27]([N:26]2[CH:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:45]([CH2:44][CH2:43][CH:42]([OH:60])[C:39]3[CH:40]=[CH:41][CH:36]=[CH:37][CH:38]=3)[C:46]2=[O:47])=[CH:34][CH:33]=1
Reactant: N#Cc1ccc(N=Cc2ccccc2)cc1
Reactant: O=C(CCCC(O)c1ccc(F)cc1)N1C(=O)OCC1c1ccccc1
Agent: [Ni]
Agent: COc1ccc(N=Cc2ccc(C#N)cc2)cc1
Agent: O=C(CCCC(O)c1ccccc1)N1C(=O)OCC1c1ccccc1
Product: NCc1ccc(N2C(=O)C(CCC(O)c3ccccc3)C2c2ccccc2)cc1

Procedure:
Compound (16) was prepared as described in example IIIa-d, the differences being that: a) instead of 4-[(4-methoxyphenylimino)methyl]benzonitrile, 4-(benzylideneamino)benzonitrile was used, b) instead of 3-[5-(4-fluorophenyl)-5-hydroxy-pentanoyl-4-phenyloxazolidin-2-one, 3-[5-(phenyl)-5-hydroxypentanoyl]-4-phenyl-oxazolidin-2-one was used, and c) the product IIId was subjected to reduction with Raney nickel.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]1[N:16]=[CH:15][C:14]([CH3:18])([CH3:17])[CH2:13][S:12]1)([CH3:3])[CH3:2].[F:19][C:20]([F:29])([F:28])[C:21]1[CH:22]=[CH:23][C:24](Cl)=[N:25][CH:26]=1.[H-].[Na+].O>CN(C)C=O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]1[N:16]([C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:29])([F:28])[F:19])=[CH:26][N:25]=2)[CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][S:12]1)([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CC(C)c1ccccc1N=C1N=CC(C)(C)CS1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccccc1N=C1SCC(C)(C)CN1c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
To a solution of 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.26 g), 5-trifluoromethyl-2-chloropyridine (0.24 g) in N,N-dimethylformamide (3 ml) was added 60% sodium hydride (0.05 g) under ice-cooling. The mixture was stirred at room temperature for 2 h. To a reaction mixture was added water (80 ml), extracted with diethylether (100 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 2-(2-isopropylphenyl)imino-3-(5-trifluoromethyl-2-pyridyl)-5,5-dimethyl-1,3-thiazine (0.13 g, yield: 32%) as colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH2:12][CH2:11][C@:10]3([CH2:16][CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[N:9]=2)[CH:3]=1.[CH2:19]([O:21][C:22]1[CH:23]=[CH:24][C:25]([F:31])=[C:26](B(O)O)[CH:27]=1)[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>CC#N.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:19]([O:21][C:22]1[CH:23]=[CH:24][C:25]([F:31])=[C:26]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[CH2:12][CH2:11][C@:10]4([CH2:16][CH2:15][N:14]([CH3:17])[C:13]4=[O:18])[N:9]=3)[CH:3]=2)[CH:27]=1)[CH3:20]
Reactant: CN1CC[C@]2(CCC(c3cc(Br)ccn3)=N2)C1=O
Reactant: CCOc1ccc(F)c(B(O)O)c1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOc1ccc(F)c(-c2ccnc(C3=N[C@]4(CC3)CCN(C)C4=O)c2)c1
Temperature: 100 °C
Yield: 100.4 %

Procedure:
To a solution of (5R)-2-(4-bromo-pyridin-2-yl)-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 3) (0.1670 g, 0.5419 mmol) in MeCN (2 mL) and water (0.3000 mL) in a Smith microwave vessel was added (5-ethoxy-2-fluoro-phenyl)boronic acid (0.1097 g, 0.5961 mmol), bis(triphenylphosphine)palladium (II) dichloride (0.0114 g, 0.0163 mmol) and sodium carbonate (0.1149 g, 1.0838 mmol). The reaction vessel was sealed and purged with nitrogen. The reaction mixture was heated by microwave at 100° C. for 40 min. The reaction mixture was treated with water and was extracted with DCM twice and the organic layers were collected by passing down a PhaseSep cartridge. Evaporation of solvents gave an amber oil, which was further purified by silica gel chromatography to give the desired product (5R)-2-[4-(5-ethoxy-2-fluoro-phenyl)-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (0.2000 g, 0.5443 mmol) (D55) as an amber oil;
Reaction SMILES: Cl[C:2]1[N:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.O.[NH2:26][NH2:27]>N1C=CC=CC=1>[C:12]([C:10]1[CH:11]=[C:6]([C:4]2[C:3]3[C:2](=[N:24][CH:23]=[CH:22][CH:21]=3)[NH:27][N:26]=2)[CH:7]=[C:8]([C:17]([CH3:19])([CH3:20])[CH3:18])[C:9]=1[OH:16])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(C(=O)c2cccnc2Cl)cc(C(C)(C)C)c1O
Reactant: NN
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Yield: 96.7 %

Procedure:
A solution of 69.1 g of 4-(2-chloronicotinoyl)-2,6-di-tertiary butylphenol and 45 g of hydrazine hydrate in 380 ml of pyridine is refluxed for 5 hours. After the pyridine is distilled off under reduced pressure, to the obtained residue is added water. The crude crystals precipitated are recrystallized from ethanol to give 62.5 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine as white crystals, melting at 216°-217° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[C:27]1(B(O)O)[CH2:31][CH2:30][CH2:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CCO.O1CCOCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[C:27]2[CH2:31][CH2:30][CH2:29][CH:28]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccc(F)cc2C1
Reactant: OB(O)C1=CCCC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2C2=CCCC2)Cc2ccc(F)cc2C1
Yield: 69.3 %

Procedure:
To a solution of 5-fluoro-2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (400 mg, 0.85 mmol) and cyclopenten-1-ylboronic acid (383 mg, 3.42 mmol) in EtOH (10 mL) and dioxane (5 mL) is added palladium anchored homogeneous catalyst, FibreCatPd(0) (4.84% Pd, 186 mg, 8.5% mmol) and 2M aqueous solution of K2SO4 (1.71 mL, 3.42 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 8 h. After concentration in vacuo, the residue is purified HPLC to give a pure product (151) as white solid (240 mg, 69%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:4][CH2:3]1.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:26]([N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:6][CH2:7]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: Clc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)N1CCC(c2[nH]nc(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Reaction time: 3 h

Procedure:
To a stirred suspension of 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole hydrochloride (Example C-74) (1 g, 2.4 mmol) in 24 mL of CH2Cl2 was added 4-dimethylamino pyridine (0.88 g, 7.2 mmol) and acetyl chloride (0.21 g, 2.6 mmol). The solution was stirred for 3 h and the solvent was removed under reduced pressure. The residue was treated with saturated NH4OH (20 mL) and the suspension was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine (1×50 mL), dried over MgSo4, filtered and concentrated to leave a solid. The solid was triturated with ether and was filtered to leave the title compound: MS (M+H): 381 (base peak).
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[CH3:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26]I.[H-].[Na+]>C1COCC1.CCOCC>[CH3:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][O:1][CH:2]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[CH2:4]1
Reactant: COCCCCI
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCCCCOC(c1ccccc1)C1CCN(C(=O)OC(C)(C)C)C1
Yield: 17.5 %

Procedure:
To a stirred solution of tert-butyl 3-(hydroxy(phenyl)methyl)pyrrolidine-1-carboxylate (205 mg, 0.74 mmol) and 4-methoxybutyl iodide (750 mg, 3.5 mmol) in dry THF (5 mL) under N2 was added 60& NaH in oil (0.14 g, 3.5 mmol). H2 evolution occurred. The mixture was heated at reflux for 8 h. The mixture was cooled, diluted with ether (90 mL), and washed with water (25 mL) and brine (25 mL), and dried over MgSO4. Removal of the solvent left an oil which was purified by flash chromatography on a 12-g silica cartridge eluted with a 0 to 100% EtOAc in hexanes gradient to afford tert-butyl 3-((4-methoxybutoxy)(phenyl)methyl)pyrrolidine-1-carboxylate (47 mg, 17%) as an oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[F-].[K+].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CN(C)C=O>[CH3:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:6]#[N:7]
Reactant: C1COCCN1
Reactant: Cc1cc(C#N)ccc1Br
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C#N)ccc1N1CCOCC1
Temperature: 145 °C
Yield: 11.5 %

Procedure:
To a solution of 4-bromo-3-methylbenzonitrile (11 g, 56 mmol) and potassium fluoride (3.3 g, 56 mmol) in anhydrous N,N-dimethylformamide (150 mL) was added morpholine (15 g, 170 mmol) and the reaction was heated at 145° C. for 4 days. The solvent was evaporated in to vacuo and the residue was partitioned between diethyl ether and water. The phases was separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo. Purification on a silica gel column using toluene followed by chloroform as eluents gave 1.3 g (11% yield) of the title compound as white crystals: mp 85-86° C.; EIMS (70 eV) m/z (relative intensity) 202 (71, M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)=[C:22]=[O:23]>CN(C=O)C>[F:32][C:31]([F:33])([F:34])[O:30][C:27]1[CH:26]=[CH:25][C:24]([NH:21][C:22]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:23])=[CH:29][CH:28]=1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(OC(F)(F)F)cc4)CC3)c2cc1OC
Yield: 52.1 %

Procedure:
A solution of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (20 mg, 0.0733 mmol), as prepared in Example 1d, in DMF (1 mL) was treated with 1-isocyanato-4-trifluoromethoxy-benzene (22 mg, 0.108 mmol) at RT overnight. The reaction was then partitioned between EtOAc (10 mL) and H2O (10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a yellow solid (18.2 mg, 52%). 1H NMR (300 MHz, CDCl3) δ 9.08 (s, 1H), 7.39 (m, 3H), 7.16 (m, 2H), 7.00 (m, 1H), 6.52 (br s, NH), 4.30-4.27 (m, 2H), 4.07 (s, 6H), 3.62 (m, 1H), 3.20 (m, 2H), 2.18-2.11 (m, 2H), 2.03-1.99 (m, 2H); LC/MS (ESI) calcd mass 476.2, found 477.3 [M+1]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].COC(OC)N(C)C.[CH3:19][OH:20]>>[N:8]1[CH:9]=[CH:10][C:5]([C:1](=[O:4])[CH:2]([CH3:3])[CH:19]=[O:20])=[CH:6][CH:7]=1
Reactant: CO
Reactant: CCC(=O)c1ccncc1
Agent: COC(OC)N(C)C
Product: CC(C=O)C(=O)c1ccncc1
Temperature: 25 °C
Yield: 81 %

Procedure:
A mixture of 4-propionylpyridine (5 g, 36.99 mmol) and dimethylformamide dimethylacetal(10 mL, 75.28 mmol) was heated to reflux overnight. After cooling to room temperature, methanol generated in situ was removed from reaction mixture under reduced pressure, providing a brown color solid. The crude product was purified by column chromatography (silica gel, 3:7 EtOAc/haxane) to give the named compound (5.73 g, 81%) as a brown oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[C:31]([NH:35][CH3:36])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([N:35]([CH3:36])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Reactant: CNC(C)(C)C
Product: CN(CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1)C(C)(C)C

Procedure:
The product from Example 44E and tert-butyl(methyl)amine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.96 (m, 3H), 7.59 (d, J=8.7 Hz, 1H), 6.85 (s, 1H), 3.3-3.8 (m, 12H), 2.93 (s, 3H), 1.48 (s, 9H); MS (DCI) m/z 422 (M+H)+;
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Mg].Br[C:17]1[S:21][C:20]([C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:25]([C:37]3[S:38][C:39](Br)=[CH:40][CH:41]=3)=[CH:24][C:23]=2[O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:19][CH:18]=1>C1COCC1.C(OCC)(=O)C>[CH2:7]([C:6]1[CH:5]=[CH:4][S:3][C:2]=1[C:17]1[S:21][C:20]([C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:25]([C:37]3[S:38][C:39]([C:2]4[S:3][CH:4]=[CH:5][C:6]=4[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:40][CH:41]=3)=[CH:24][C:23]=2[O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCOc1cc(-c2ccc(Br)s2)c(OCCCCCCCC)cc1-c1ccc(Br)s1
Reactant: CCCCCCCCc1ccsc1Br
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCOc1cc(-c2ccc(-c3sccc3CCCCCCCC)s2)c(OCCCCCCCC)cc1-c1ccc(-c2sccc2CCCCCCCC)s1
Temperature: 25 °C
Yield: 30 %

Procedure:
A solution of 2-bromo-3-octylthiophene (1.800 grams, 6.533 mmol) in 7 milliliters of anhydrous THF was added slowly over a period of 20 minutes to a mechanically stirred suspension of magnesium turnings (0.238 grams, 9.79 mmol) in 3 milliliters of THF in a 250 milliliter round-bottomed flask under an inert argon atmosphere. The resultant mixture was stirred at 60° C. for 4 hours, and then cooled down to room temperature. The resultant mixture was then added via a cannula to a mixture of 1,4-bis(5-bromo-2-thienyl)-2,5-dioctyloxybenzene (1.650 grams, 2.513 mmol) and [1,3-bis(diphenylphosphinopropane]dichloronickel (II) (0.057 gram, 0.105 mmol) in 20 milliliters of anhydrous THF in a 250 milliliter round-bottomed flask under an inert atmosphere, and refluxed for 48 hours. Subsequently, the reaction mixture was diluted with 200 milliliters of ethyl acetate, was washed twice with water and dried with anhydrous magnesium sulfate. A brown solid, obtained after evaporation of the solvent, was purified by column chromotography on silica gel and recrystallized yielding 1,4-bis[5-(3-octyl-2-thienyl)-2-thienyl]-2,5-dioctyloxybenzene as a yellow crystalline product in 30 percent yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].Cl[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28].C(N(CC)CC)C>C(O)C>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])=[C:20]([N+:27]([O-:29])=[O:28])[CH:21]=1)#[N:24]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CCCC1Cc1c[nH]c2ccc(Nc3ccc(C#N)cc3[N+](=O)[O-])cc12
Yield: 80 %

Procedure:
(R)-5-Amino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and 4-chloro-3-nitrobenzonitrile were used. Triethylamine was used as base, absolute ethanol was used as solvent, and the reaction was heated at reflux for 4 hours. Column chromatography afforded the title compound (80%) as a red solid: mp, 170.0°-171.0° C.; 13C NMR (CDCl3) δ 147.3,137.1, 135.4, 132.0, 131.4, 128.6, 128.0, 125.3, 120.6, 117.9, 117.1, 116.3, 113.1, 111.9, 99.1, 68.1, 57.3, 40.6, 31.2, 28.1, 21.9. Anal. calcd for C21H21N5O2.0.05 CH2Cl2 : C, 66.59; H, 5.60; N, 18.44. Found: C, 66.56; H, 5.26; N, 18.42.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:15][N:16]4[C:21]=3[CH:20]=[CH:19][N:18]=[C:17]4SC)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=O.[C:42]([NH2:46])([CH3:45])([CH3:44])[CH3:43]>ClCCl.O>[C:42]([NH:46][C:17]1[N:16]2[N:15]=[C:14]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:13]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[N:12]=3)=[C:21]2[CH:20]=[CH:19][N:18]=1)([CH3:45])([CH3:44])[CH3:43]
Reactant: CSc1nccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn12
Reactant: CC(C)(C)N
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)Nc1nccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
To a solution of N-cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amine (40 mg, 0.095 mmol) in dichloromethane (2 mL) was added 3-chloroperoxybenzoic acid (12 mg, 0.14 mmol) and the reaction mixture stirred at room temperature for 1 hour. t-Butylamine (3 mL) was added and heated to reflux for 3 hours. The reaction was allowed to cool and diluted with water. The mixture was extracted with ethyl acetate and the organic phase washed with brine before being concentrated under vacuum. The residue was purified by silica gel chromatography eluting with SO/5 acetone in dichloromethane to yield a 1:1 mixture of starting material and product. The residue was dissolved in dichloromethane (2 mL) and 3-chloroperoxybenzoic acid (18 mg, 0.21 mmol) was added. The mixture was stirred for 2 hours and then t-butylamine (3 mL) was added. The reaction mixture was stirred for 3 hours, diluted with water, extracted with ethyl acetate, washed with brine, concentrated, and the residue purified by silica gel chromatography eluting with 5% acetone in dichloromethane to yield N-(tert-butyl)-3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-7-amine (6 mg, 14%), 1H NMR (CDCl3): δ 8.02 (d, 1H), 7.72 (d, 1H), 7.60 (dd, 2H), 7.47 (d, 1H), 7.13 (t, 2H), 6.42 (s, 1H), 6.25 (d, 1H), 5.14 (bs, 1H), 4.28 (m, 1H), 2.04 (m, 2H), 1.45–1.78 (m, 15H). MS m/z 446 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:7][CH:6]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OCc2ccccc2)cc1
Reaction time: 12 h
Yield: 90.7 %

Procedure:
(4-Hydroxy-phenyl)-acetic acid methyl ester (1.0 g, 6.02 mmol) was dissolved in DMF (10 mL), and K2CO3(2.5 g, 18.06 mmol) was added thereto. Benzyl chloride (0.83 mL, 7.22 mmol) was added slowly thereto, and the mixture was stirred at 40˜50° C. for 12 hours. The reactant was cooled and concentrated under reduced pressure. The residue was added with water and then extracted with EtOAc. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent, EtOAc/Hex=1/4) to obtain the title compound (1.4 g, 91%).