Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[CH:12][N:13]=[C:7]2[CH:6]=1)=O)[NH2:2].[CH3:29][N:30]=[C:31]=[S:32]>CCO>[CH3:29][N:30]1[C:31](=[S:32])[NH:2][N:1]=[C:3]1[C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[CH:12][N:13]=[C:7]2[CH:6]=1
Reactant: CN=C=S
Reactant: NNC(=O)c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Solvent: CCO
Product: Cn1c(-c2ccn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)n[nH]c1=S
Yield: 33 %

Procedure:
A mixture of 1-[3-(7-hydrazinocarbonyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (90 mg, 0.23 mmol) and methyl isothiocyanate (17 mg, 0.23 mmol) were heated in EtOH (3 ml) at 70° C. for 18 h. The reaction mixture was allowed to cool and the precipitate formed filtered off to give the product (34 mg). MS: [M+H]+ 447
Reaction SMILES: [O:1]=[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH:7]2[C:10]2[NH:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=3[N:11]=2)[CH2:4][CH2:3]1.[CH3:27][Mg+].[Br-]>C1COCC1>[OH:1][C:2]1([CH3:27])[CH:8]2[CH2:9][CH:5]([CH2:6][CH:7]2[C:10]2[NH:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=3[N:11]=2)[CH2:4][CH2:3]1
Reactant: CCCn1c(=O)c2[nH]c(C3CC4CCC(=O)C3C4)nc2n(CCC)c1=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C3CC4CCC(C)(O)C3C4)nc2n(CCC)c1=O
Reaction time: 2 h

Procedure:
8-(4-Oxo-bicyclo[3.2.1]oct-6-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (51 mg) was taken in THF (3 ml) at 0° C. CH3MgBr (1 ml, 3.0 M) was added and stirred for 2 hrs. The reaction was quenched with sat. NH4Cl, and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over Na2SO4. Concentration followed by purification on silica column gave the desired product. Mass (ES+ 375).
Reaction SMILES: [NH2:1][CH:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:3][CH2:4][OH:5].[Cl:10][C:11]1[C:16]([C:17]#[N:18])=[CH:15][C:14]([F:19])=[C:13](Cl)[N:12]=1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:10][C:11]1[C:16]([C:17]#[N:18])=[CH:15][C:14]([F:19])=[C:13]([NH:1][CH:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:3][CH2:4][OH:5])[N:12]=1
Reactant: CC(C)(C)C(N)CCO
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(CCO)Nc1nc(Cl)c(C#N)cc1F
Temperature: 75 °C
Reaction time: 12 h
Yield: 89.1 %

Procedure:
To a solution of 3-amino-4,4-dimethylpentan-1-ol (2.00 g, 8.64 mmol) in ethanol (20 mL) was added racemic 2,6-dichloro-5-fluoro-pyridine-3-carbonitrile (1.65 g, 8.64 mmol) and 5 mL of N,N,-diisopropylethylamine. The solution was stirred at 75° C. for 12 hours and concentrated in vacuo. The residue was purified by silica gel chromatography (methylene chloride), yielding 2.2 g of 2-chloro-5-fluoro-6-(1-hydroxy-4,4-dimethylpentan-3-ylamino)pyridine-3-carbonitrile, 95a: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=3.02 minutes (M+H) 286.16
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[N:3]=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[NH2:1][C:2]1[N:3]=[C:4]([CH3:11])[C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:14]3[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[CH3:12])[CH2:21][CH2:22]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1nc(N)ccc1C(=O)O
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N)nc3C)CC2)c(C)c1
Yield: 16.9 %

Procedure:
Using 6-amino-2-methylnicotinic acid (500 mg) and 1-(2,4-dimethylphenyl)piperazine (657 mg) and by the reaction and treatment in the same manner as in Preparation Example 109, the title compound (180 mg) was obtained.
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([O:13][CH3:14])=[C:7]2[C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:6]2=O.C([SnH](CCCC)CCCC)CCC.[F-].[K+]>C1C=CC=CC=1>[CH3:12][O:11][C:10]1[CH:2]=[C:3]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=1)[CH2:6][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH2:4]2
Reactant: COc1cc(OC)c2c(c1Br)CN(Cc1ccc(Cl)cc1)C2=O
Agent: CCCC[SnH](CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: c1ccccc1
Product: COc1cc2c(c(OC)c1)CN(Cc1ccc(Cl)cc1)C2
Temperature: 25 °C
Yield: 46.1 %

Procedure:
To a solution of 4-bromo-5,7-Dimethoxy-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.100 g, 0.25 mmol) in benzene under N2 atmosphere was added 2,2′-azobis(2-methyl propionitrile) AIBN (5.0 mg), followed by tributyl tin hydride (0.132 mL, 0.5 mmol). The resulting mixture was refluxed in an oil bath for 2 h. The reaction was monitored by GC-MS for the disappearance of starting material. The reaction mixture was cooled to room temperature and stirred with potassium fluoride (200 mg) for 45 min. The solids were filtered and the filtrate was concentrated. The resulting material was purified using column chromatography (typically 40% ethyl acetate in hexanes) to give 5,7-Dimethoxy-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-lone (0.035 g, 44%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.82 (s, 3H), 3.95 (s, 3H), 4.15 (s, 2H), 4.69 (s, 2H), 6.43 (d, 2H), 7.25 (m, 4H). GC-MS: m/z 317 (M)+, 299 (M−18)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][O:14][CH3:15].[Cl-].[NH4+]>C(O)C.O.[Fe]>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][O:14][CH3:15])[NH2:8]
Reactant: COCCOc1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COCCOc1ccc(N)cc1F
Temperature: 25 °C
Yield: 91.6 %

Procedure:
A mixture of 2-fluoro-1-(2-methoxyethoxy)-4-nitrobenzene (12.0 g , 55.7 mmol), iron powder (10.3 g, 180 mmol) and ammonium chloride (14.5 g , 270 mmol) in 170 mL of ethanol and 50 mL of water is heated at reflux for 1.5 hours then filtered hot through a pad of Diatomaceous earth, washing with ethanol. The filtrate is cooled to room temperature and the precipitated solids are removed by filtration. The filtrate is concentrated to a small volume and partitioned between ethyl acetate and water. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo to provide 9.45 g of 3-fluoro-4-(2-methoxyethoxy)aniline as a brown liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)#[N:11].[BH3-]C#N.[Na+]>C(=O)(O)[O-].[Na+].[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH2:16][C:15]2[CH:18]=[CH:19][C:12]([C:10]#[N:11])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: N#Cc1ccc(C=O)cc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Cl-]
Product: N#Cc1ccc(CNCc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a methanolic solution (20 mL) of 4-chlorobenzylamine (1.02 g, 7.2 mmol) was added successively ZnCl2 (0.981 g, 7.2 mmol), 4-cyanobenzaldehyde (1.007 g, 7.3 mmol), and NaCNBH3 (0.452 g, 7.2 mmol). The reaction mixture was stirred at r.t. for 2 days. It was diluted with aq. sodium bicarbonate and the reaction mixture was extracted with methylene chloride. The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated. The product (compound 22) was purified by silica gel chromatography: 1.43 g (77%).
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[CH2:15]([NH2:18])[CH2:16][CH3:17]>CCCCCC>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[NH:18][CH2:15][CH2:16][CH3:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Reactant: CCCN
Solvent: CCCCCC
Product: CCCN[SiH]1N(C(C)(C)C)C=CN1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
In an argon atmosphere, 5.90 g (25.4 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 40 mL of hexane and after adding 3.03 g (51.3 mmol) of propylamine, the mixture was stirred at room temperature for 3 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 92° C./3.5×102 Pa) to obtain 1,3-di-tert-butyl-2-propylamino-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NHPr) as a pale yellow liquid (yielded amount: 5.99 g, yield: 92%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[CH2:18][CH2:19][CH3:20])[C:3]1=[O:21].C(N(CC)CC)C.Cl[C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:43])([F:42])[F:41])[CH:38]=2)[N:33]=[CH:32][N:31]=1>CCO.O.C(#N)C>[CH:15]([N:13]([CH3:14])[C@@H:10]1[CH2:11][CH2:12][C@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:42])([F:43])[F:41])[CH:38]=4)[N:33]=[CH:32][N:31]=3)[C:3]2=[O:21])[C@H:8]([CH2:18][CH2:19][CH3:20])[CH2:9]1)([CH3:16])[CH3:17]
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: CCC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CC#N
Product: CCC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 75 °C

Procedure:
To a solution of (S)-3-amino-1-[(1S,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl]pyrrolidin-2-one (7.0 mmol) in EtOH (23 mL) was added triethylamine (2.5 mL, 17.5 mmol) and 4-chloro-6-(trifluoromethyl)quinazoline (2.03 g, 8.75 mmol). The mixture was heated at 75° C. for 14 h and then concentrated in vacuo. [Note: on smaller reaction scales, this residue could be diluted in water/acetonitrile, filtered, and purified directly by RP-HPLC.] The residue was dissolved in 60 mL of 2:1 H2O/AcOH and extracted with Et2O twice. The aqueous phase was basified to pH 14 with solid NaOH (the temperature of this exothermic process was controlled through the intermittent use of an external ice bath) and then extracted with EtOAc thrice. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give a solid. The material was recrystallized from EtOAc twice to provide the title compound, (S)-1-[(1S,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl]-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one, as a white microcrystalline solid (1.83 g, 52% yield). MS found: (M+H)+=492.4. [Note: Purification of the mother liquors using RP-HPLC provided more of the title compound as its bis-TFA salt.]
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][C@H:12]([C:14]2[N:15]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:16](=[O:28])[C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])[CH3:13])[CH:5]=[CH:4][N:3]=1.[SH-:35].[Na+]>CO>[SH:35][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][C@H:12]([C:14]2[N:15]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:16](=[O:28])[C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])[CH3:13])[CH:5]=[CH:4][N:3]=1
Reactant: C[C@H](Nc1ccnc(Cl)c1[N+](=O)[O-])c1cc2cccc(C(F)(F)F)c2c(=O)n1-c1ccccc1
Reactant: [SH-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](Nc1ccnc(S)c1[N+](=O)[O-])c1cc2cccc(C(F)(F)F)c2c(=O)n1-c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of (S)-3-(1-(2-chloro-3-nitropyridin-4-ylamino)ethyl)-2-phenyl-8-(trifluoromethyl) isoquinolin-1 (2H)-one III-33 (500 mg, 1.0 mmol, 1 eq) in MeOH (10 mL), sodium hydrosulphide (69 g, 1.29 mmol, 1.2 eq) was added and the resulting mixture was stirred at reflux for 2 h. The mixture was allowed to cool to RT and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (2-3% MeOH-DCM) to afford the product, (S)-3-(1-(2-mercapto-3-nitropyridin-4-ylamino) ethyl)-2-phenyl-8-(trifluoromethyl)isoquinolin-1(2H)-one III-34.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([NH:34][CH2:35][CH2:36][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: NCCN1CCOCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(NCCN4CCOCC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 4-(2-aminoethyl)-morpholine. ES-MS m/e (%): 499 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[C:28]=1[C:29](Cl)=[O:30].O=C1CC(=O)N(C2C=CC(C(O)=O)=CC=2)C2C=CC3C(C=2N1)=CC=CC=3>>[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[C:28]=1[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:30]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: COc1cccc(C(F)(F)F)c1C(=O)Cl
Agent: O=C1CC(=O)N(c2ccc(C(=O)O)cc2)c2ccc3ccccc3c2N1
Product: COc1cccc(C(F)(F)F)c1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 74 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 2-methoxy-6-(trifluoromethyl)benzoyl chloride, the title compound (yield 74%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [CH2:1]([O:3][NH:4][C:5](=[C:8]1[C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10][C:9]1=[O:17])[CH2:6][CH3:7])[CH3:2].[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:17][C:9]2[CH2:10][C:11]([CH3:15])([CH3:16])[CH2:12][C:13](=[O:14])[C:8]=2[C:5](=[N:4][O:3][CH2:1][CH3:2])[CH2:6][CH3:7])=[O:24])=[CH:21][CH:20]=1
Reactant: CCONC(CC)=C1C(=O)CC(C)(C)CC1=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: CCON=C(CC)C1=C(OC(=O)c2ccc(Cl)cc2)CC(C)(C)CC1=O

Procedure:
The same reaction procedures as Example 1 were carried out by using 2.4 g of 2-[1-(N-ethoxyamino)propylidene]-5,5-dimethylcyclohexane-1,3-dione and 1.75 g of 4-chlorobenzoylchloride, and chloroform was distilled off under reduced pressure and thereby the desired product as a white crystal was obtained after recrystallization the residual material from n-hexane.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C@@H:11]2[CH2:13][C@H:12]2[CH2:14]OS(C)(=O)=O)=[O:10])[CH2:4][CH2:3]1.Cl.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>C(#N)C>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C@@H:11]2[CH2:13][C@H:12]2[CH2:14][N:31]2[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=3)[CH2:33][CH2:32]2)=[O:10])[CH2:4][CH2:3]1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CS(=O)(=O)OC[C@@H]1C[C@H]1C(=O)N[C@H]1CC[C@H](C)CC1
Agent: Cl
Solvent: CC#N
Product: C[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2CN2CCN(c3cccc(Cl)c3)CC2)CC1

Procedure:
Reflux a solution of methane sulfonic acid 2-(trans-4-methyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester (Example 11d) (30.0 mg, 0.1 mmol), 1-(3-chloro-phenyl)-piperazine hydrochloride (29.0 mg, 0.13 mmol) triethylamine (0.05 mL, 0.4 mmol) in acetonitrile (5 ml) for 15 h. Concentrate the reaction mixture under vacuum and chromatograph the residue over silica gel to obtain 11.3 mg (28%) of solid, LC/MS, m/z=390 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26]CC)=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([O:43][C@H:44]([CH2:46][CH:47]=[CH2:48])[CH3:45])[C:37]=1[CH2:49][OH:50].[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:50][CH2:49][C:37]4[C:38]([O:43][C@H:44]([CH2:46][CH:47]=[CH2:48])[CH3:45])=[CH:39][C:40]([F:42])=[CH:41][C:36]=4[F:35])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([OH:26])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@H](C)Oc1cc(F)cc(F)c1CO
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3cc(COCc4c(F)cc(F)cc4O[C@@H](C)CC=C)nn23)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.5 %

Procedure:
To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.2 g, 0.342 mmol) and (S)-(2,4-difluoro-6-(pent-4-en-2-yloxy)phenyl)methanol (0.094 g, 0.411 mmol) in DMF (1 mL) was added sodium hydride (0.021 g, 0.513 mmol) and the mixture was stirred at rt. After 4 h, the mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried (Na2SO4), filtered and concentrated and purified by Prep HPLC: to afford (S)-2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2,4-difluoro-6-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid (0.030 g, 0.046 mmol, 13.35% yield) as a colorless oil. LCMS (M+H) calcd for C35H47F2N4O6: 657.34. found: 657.5.
Reaction SMILES: [CH3:1][N:2]([CH2:26][CH2:27][OH:28])[C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34](Cl)=[O:35]>>[CH3:1][N:2]([CH2:26][CH2:27][O:28][C:34]([C:30]1[O:29][CH:33]=[CH:32][CH:31]=1)=[O:35])[C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C(Cl)c1ccco1
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)N(C)CCO
Product: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)N(C)CCOC(=O)c1ccco1

Procedure:
N-methyl-N-(2-furoyloxyethyl)erucamide was prepared by the procedure of example 1 from 39.5 gms. (0.1 mole) of N-methyl-N-(2-hydroxyethyl)erucamide and 13 gms. (0.1 mole) of furoyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[C:6]1([CH2:12][CH2:13][N:14]2[C:20](=[O:21])[C@H:19]3[CH2:22][CH2:23][CH2:24][C@H:18]3[NH:17][C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]2=3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])O.[Na+]>ClCCl>[Br:1][CH2:2][C:3]([N:17]1[C@@H:18]2[CH2:24][CH2:23][CH2:22][C@@H:19]2[C:20](=[O:21])[N:14]([CH2:13][CH2:12][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:15]2[CH:28]=[CH:27][CH:26]=[CH:25][C:16]1=2)=[O:4]
Reactant: O=C(Br)CBr
Reactant: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1[C@H]2CCC[C@H]2N(C(=O)CBr)c2ccccc2N1CCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.1 %

Procedure:
To a solution of bromoacetyl bromide (0.29 mL, 3.3 mmol) in dichloromethane (5 mL) was added dropwise a solution of (3aR*,10aS*)-9-(2-phenylethyl)-2,3,3a,4,9,10a- hexahydrobenzo [b]cyclopenta[e][1,4]diazepin-10(1H)-one (0.92 g, 3.0 mmol) in dichloromethane (5 mL). The solution was stirred for 3 hours at room temperature. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was separated, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and subjected to filtration. The filtrate was concentrated under reduced pressure. The concentrate was purified by silica-gel column chromatography (hexane - ethyl acetate 5:1,then 1:1) to afford the desired product (924 mg, 72%). Oily product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24][O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.CCCCCC.C(OCC)(=O)C>C(O)C.C(O)(=O)C>[F:18][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)=[N:7][C:2]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([O:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH3:19])=[CH:27][CH:28]=2)=[N:3][CH:4]=1
Reactant: COCCOCOc1ccc(N)cc1
Reactant: O=[N+]([O-])c1cccc(Nc2nc(Cl)ncc2F)c1
Solvent: CCO
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COCCOCOc1ccc(Nc2ncc(F)c(Nc3cccc([N+](=O)[O-])c3)n2)cc1
Yield: 62.6 %

Procedure:
To a solution of 2-chloro-5-fluoro-N-(3-nitrophenyl)pyrimidin-4-amine (0.400 g) and 4-[(2-methoxyethoxy)methoxy]aniline (0.458 g), in ethanol (20 mL), was added acetic acid (4.65 mg). The reaction mixture was heated to reflux for 24 hr. Completion of reaction was monitored by TLC using hexane:ethyl acetate (8:2) as mobile phase. After completion of the reaction, ethanol was removed under reduced pressure at 40° C. To the residue water (25 mL) was added and mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and distilled under reduced pressure to give 0.4 g of 5-fluoro-N2-(4-((2-methoxyethoxy)methoxy)phenyl)-N4-(3-nitrophenyl)pyrimidine-2,4-diamine as a solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5]2[C:6]([N:10]=[CH:11][CH:12]=2)=[C:7](O)[N:8]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:26])=O>>[CH3:1][S:2][C:3]1[NH:4][C:5]2[C:6]([N:10]=[CH:11][CH:12]=2)=[C:7]([Cl:26])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc(O)c2nccc-2[nH]1
Solvent: CCN(CC)c1ccccc1
Product: CSc1nc(Cl)c2nccc-2[nH]1

Procedure:
Compound (3.2) (8.7 g, 48 mmol) was mixed with phosphorus oxychloride (350 ml) and N,N-diethylaniline (17.5 ml). This mixture was heated under reflux for 4 hrs; the brown solution was then concentrated under reduced pressure. The residual oil was treated with an ice-water mixture and stirred until the ice had melted. The resultant mixture was extracted repeatedly with ether until no more UV-active material was being extracted, the combined aqueous extracts were dried (MgSO4), filtered and evaporated to a light beige solid. Dried under vacuum at 50° C. to give (3.3), 7.3 g (76%). δH (300 MHz, DMSO-d6) 1.78 (3H, s, SCH3), 5.70 (1 H, d, J 3.7 Hz, H7) and 6.51 (1H, d, J 3.7 Hz, H8) ppm.