Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH:17]=O)=[C:12]([O:19][CH:20]([CH3:22])[CH3:21])[CH:11]=2)[CH2:6][CH2:5]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:34]3[N:35]=C(S(C)(=O)=O)[N:37]=[CH:38][C:33]=3[S:32][C:31]=2[C:43]([NH2:45])=[O:44])=[CH:26][CH:25]=1>CN(C)C=O.CO>[F:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[C:34]3[N:35]=[C:17]([NH:16][C:13]4[CH:14]=[CH:15][C:10]([N:7]5[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][CH2:6]5)=[CH:11][C:12]=4[O:19][CH:20]([CH3:22])[CH3:21])[N:37]=[CH:38][C:33]=3[S:32][C:31]=2[C:43]([NH2:45])=[O:44])=[CH:28][CH:29]=1
Reactant: CS(=O)(=O)c1ncc2sc(C(N)=O)c(-c3ccc(F)cc3)c2n1
Reactant: CC(C)Oc1cc(N2CCN(C)CC2)ccc1NC=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)Oc1cc(N2CCN(C)CC2)ccc1Nc1ncc2sc(C(N)=O)c(-c3ccc(F)cc3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
27 mg of sodium hydride (at 60%) are added to a solution of 126 mg of N-[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]formamide in 2 ml of dimethylformamide. The suspension is stirred at ambient temperature for 30 min, and is then diluted with 1 ml of dimethylformamide, and a solution of 80 mg of 7-(4-fluorophenyl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxamide in 2 ml of dimethylformamide is added. The mixture is stirred at ambient temperature for 30 min, and then diluted with 50 ml of methanol. The mixture is stirred at ambient temperature for 1 h, and then concentrated under vacuum. The residue is purified on 40 g of silica, elution being carried out with 0-20% of methanol in dichloromethane, and then by high performance liquid chromatography (Macherey-Nagel 250×40 mm reverse phase C18 Nucleodur 10μ column. Eluent: MeCN containing 0.07% TFA and H2O containing 0.07% TFA. 10% MeCN hold: 3 min, gradient up to 95% MeCN in 37 min and then 95% MeCN hold of 8 min. Flow rate: 70 ml/min). The fractions containing the expected material are loaded on to a 2 g Varian Bond Elut SCX cartraige (preconditioned with MeOH). Washing the cartridge four times with methanol, followed by elution of the expected material with 2N ammonia in methanol gives, after drying, 10 mg of 7-(4-fluorophenyl)-2-{[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide.
Reaction SMILES: Cl.[C:2]1([CH2:8][C:9]2([NH2:12])[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[C:16]([NH2:21])[N:15]=1.CCN(CC)CC.C([O-])([O-])=O.[K+].[K+]>C(O)C>[Cl:13][C:14]1[N:15]=[C:16]([NH2:21])[N:17]=[C:18]([NH:12][C:9]2([CH2:8][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:11][CH2:10]2)[CH:19]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: NC1(Cc2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1nc(Cl)cc(NC2(Cc3ccccc3)CC2)n1
Temperature: 140 °C
Yield: 41.2 %

Procedure:
A mixture of 1-(phenylmethyl)cyclopropanamine_hydrochloride (530 mg, 2.88 mmol), 4,6-dichloro-2-pyrimidinamine (295 mg, 1.80 mmol), Et3N (911 mg, 9 mmol) and K2CO3 (249 mg, 1.80 mmol) in ethanol (6 mL) was stirred and heated at 140° C. for 4 hours in a Biotage Initiator microwave synthesizer. The mixture was cooled to room temperature and concentrated to dryness. The resulting solids were partitioned between EtOAc and water. The organic layer was separated, dried (Na2SO4), concentrated to dryness and purified by reverse phase chromatography using CH3CN in water from 32% to 42% (0.05% trifluoroacetic acid in water) in 8 min to afford the title compound (204 mg) as a white solid. LC-MS (ES) m/z=275 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([Cl:11])[S:9][CH:10]=1)=[O:5])C.[OH-].[K+]>C(O)C.O.O>[Cl:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1
Reactant: CCOC(=O)c1csc(Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1csc(Cl)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
14.0 g (73.1 mmol) of 2-chlorothiazole-4-carboxylic acid ethyl ester were slowly added to a solution of 11.0 g (0.17 mol, 85% purity) of potassium hydroxide in ethanol/water (1:3, 200 ml) at 0° C. The reaction mixture was stirred at room temperature for 16 h, diluted with water and washed twice with diethyl ether. The aqueous layer was acidified (pH=5.5) with conc. HCl and stirred at room temperature for three days. The formed precipitate was collected by filtration and dried at 40° C. under vacuum to yield 7.0 g (56%, 95% purity) of the title compound as a brown solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[CH:9][C:10]=1[Br:11])[CH:2]=[CH2:3].[C:13]([O-:16])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)C>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:10]=1[Br:11])[O:12][C:5]1[CH:6]=[CH:7][C:8]([CH:13]=[O:16])=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCOc1cc(O)ccc1Br
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCOc1cc(Oc2ccc(C=O)cc2)ccc1Br
Temperature: 100 °C
Yield: 166.3 %

Procedure:
4-Flurorbenzaldehyde (1.15 mL, 10.76 mmoles) was added to a solution of the product from Example 63B (1.76 g, 7.69 mmoles) and K2CO3 (3.19 g, 23.1 mmoles) in DMF (7.7 mL). The reaction mixture was heated to 100° C. for 14 h and was cooled to room temperature The crude products were diluted with diethyl ether, extracted with sat. NH4Cl, extracted with H2O (2×), rinsed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography on a prepacked Biotage colum (hexane to 4:1 hexane:ethyl acetate) on silica gel to provide the title compound (2.13 g, 83%) as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([Br:27])=[CH:20][C:19]=1Br)[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2].[CH2:29]=[N:30]O.N1C(C)=CC=CC=1C.[N+](C1C=CC=CC=1)([O-])=O>[Cu]I>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([Br:27])=[CH:20][C:19]=1[C:29]#[N:30])[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2]
Reactant: C=NO
Reactant: CCN(CC)c1ccc(N=Nc2c(Br)cc(Br)cc2[N+](=O)[O-])c(NC(C)=O)c1
Agent: [Cu]I
Solvent: O=[N+]([O-])c1ccccc1
Solvent: Cc1cccc(C)n1
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc(Br)cc2[N+](=O)[O-])c(NC(C)=O)c1
Temperature: 90 °C
Yield: 18.3 %

Procedure:
A stirred mixture of 3-acetylamino-4-(2',4'-dibromo-6'-nitrophenylazo)-N,N-diethylaniline (5.3 parts), copper (I) iodide (1.9 parts), formaldoxime trimer (1.8 parts), 2,6-lutidine (2.15 parts), and nitrobenzene (100 parts), was heated to 90° C. for 10 hours when thin layer chromatography showed reaction to be effectively complete. The mixture was filtered, cooled, and the solvent was removed by steam distillation. Crystallisation of the solid product from ethanol gave 3-acetylamino-4-(2'-cyano-4'-bromo-6'-nitrophenylazo)-N,N-diethylaniline (Found; C, 49.5; H, 4.3; Br, 17.7; N, 18.3. C19H19BrN6O3 requires C, 49.65; H, 4.15; Br, 17.4; N, 18.3%)
Reaction SMILES: [H-].[Na+].O[C@H:4]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:5][C:6]([O:8][CH3:9])=[O:7].BrC(CCCCCC)C(Cl)=O>O1CCCC1>[CH3:9][O:8][C:6](=[O:7])[CH2:5][CH2:4][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)OC
Agent: CCCCCCC(Br)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC(=O)OC
Reaction time: 0.42 h

Procedure:
98 mg(3.3 mmol)Sodium hydride(80% in mineral oil)was added to a solution of 764 mg (2.96 mmol) methyl(R)-3-hydroxytetradecanoate in 20.0 mL tetrahydrofuran. After 25 minutes, a solution of 732 mg (3.03 mmol) 2-bromooctanoyl chloride in 10.0 mL tetrahydrofuran was added dropwise via syringe to the cloudy offwhite mixture. After 10 minutes at 0° C., the reaction flask was removed from the cold bath for 24 hours. The mixture was poured into 100 mL 10% NaHCO3 and extraction with ether (3×50 mL) was performed. Drying over MgSO4 and removal of the solvent by rotary evaporation gave yellow oil. Purification by flash chromatography (3×24 cm column, 50% CH2Cl2 /hexane) gave 407 mg (30% yield based on methyl (R)-3-hydroxytetradecanoate)(R)-3-[2-bromo-1-oxooctyl)oxy]tetradecanoic acid methyl ester.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:14]3=[C:15]([C:17](=[O:20])[CH:18]=[CH:19][N:13]3[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=3)[CH:16]=1)(=[O:3])N.N([O-])=[O:22].[Na+].O>[N+]([O-])(O)=O>[C:1]([C:4]1[CH:5]=[C:6]2[C:14]3=[C:15]([C:17](=[O:20])[CH:18]=[CH:19][N:13]3[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=3)[CH:16]=1)([OH:22])=[O:3]
Reactant: O=N[O-]
Reactant: NC(=O)c1cc2c(=O)ccn3c4ccccc4c(c1)c23
Agent: [Na+]
Solvent: O
Solvent: O=[N+]([O-])O
Product: O=C(O)c1cc2c(=O)ccn3c4ccccc4c(c1)c23
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.4 %

Procedure:
2-carbamoyl-4H-pyrido[3,2,1-jk]carbazole-4-one (350 mg) produced in Example 174 was suspended in conc. nitric acid (13 ml), and sodium nitrite (1.84 g) was added to the suspension in an ice bath. The mixture was stirred at room temperature for 12 hours, and water was added to the reaction mixture. The crystals precipitated were recovered by filtration, and washed with methanol and ether in succession to obtain the title compound (300 mg, 85%).
Reaction SMILES: CS(O[CH2:6][C:7]1[O:8][CH:9]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[CH:23][N:22]=2)[C:11](=[O:13])[CH:12]=1)(=O)=O.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>ClCCl>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:10]2[C:11](=[O:13])[CH:12]=[C:7]([CH2:6][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[O:8][CH:9]=2)=[N:22][CH:23]=1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OCc1cc(=O)c(OCCCCCOc2ncnc3ccccc23)co1
Solvent: ClCCl
Product: O=c1cc(CN2CCOCC2)occ1OCCCCCOc1ncnc2ccccc12
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Methanesulfonic acid 4-oxo-5-[5-(quinazolin-4-yloxy)-pentyloxy]-4H-pyran-2-ylmethyl ester 20 (100 mg, 0.23 mmol) was dissolved in dichloromethane (3 mL). Morpholine (51 μL, 0.575 mmol) was added via syringe. The mixture was stirred at 45° C. for 1 h. CH2Cl2 (50 ml) was added and the solution washed with NaHCO3 10% (3×50 mL) and brine (3×50 mL). The product was extracted with CH2Cl2 (5×50 mL). The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent CH2Cl2:MeOH=99:01. 5-(5-(Quinazolin-4-yloxy)pentyloxy)-2-(morpholinomethyl)-4H-pyran-4-one EHT 3726 was obtained (8.2 mg, 8.5%) as a white solid.
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[CH:22][CH:23]=1
Reactant: CCOc1c(Nc2ccncc2)c(=O)c1=O
Reactant: NCCCCCCSc1ccc(Cl)cc1
Product: O=c1c(NCCCCCCSc2ccc(Cl)cc2)c(Nc2ccncc2)c1=O
Yield: 62 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-4-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 7A and 6-(4-chloro-phenylsulfanyl)-hexylamine
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][P:9](=[O:12])([OH:11])[OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]([C:19]([CH2:24][CH3:25])([CH2:22]O)[CH2:20]O)[CH2:16][CH2:17][CH3:18]>>[CH2:15]([C:19]1([CH2:24][CH3:25])[CH2:22][O:11][P:9](=[O:10])([CH2:8][C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[O:12][CH2:20]1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCC(CC)(CO)CO
Reactant: O=[N+]([O-])c1ccc(CP(=O)(O)O)cc1
Product: CCCCC1(CC)COP(=O)(Cc2ccc([N+](=O)[O-])cc2)OC1

Procedure:
With 4-nitrobenzylphosphonic acid and 2-butyl-2-ethyl-1,3-propanediol, the same procedure as in Reference Example 11 was followed, to yield 5-butyl-5-ethyl-2-(4-nitrobenzyl)-1,3,2-dioxaphosphorinane-2-oxide, which was then recrystallized from ethanol-hexane to yield colorless prisms having a melting point of 111° to 112° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCBr)C=CC=CC=1.[Mg].Cl[Si:22]([CH2:25][Cl:26])([CH3:24])[CH3:23].Cl>O1CCCC1.O>[Cl:26][CH2:25][Si:22]([CH3:24])([CH3:23])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(Cl)CCl
Reactant: Br[Mg]CCc1ccccc1
Agent: BrCCc1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(CCl)CCc1ccccc1
Yield: 48.5 %

Procedure:
To a solution of 2-phenylethylmagnesium bromide, prepared from 2-phenylethyl bromide (9.25 g, 50 mmol) and magnesium (1.34 g, 55 mmol) in tetrahydrofuran (50 ml), is added chlorochlormethyldimethylsilane (6.43 g, 45 mmol) in tetrahydrofuran (25 ml). The mixture is refluxed for 18 hours, cooled to 0° C. and hydrolyzed with 3N HCl (50 ml). The mixture is then poured in water (50 ml) and diethyl ether (50 ml), the organic layer is washed with water, brine, dried over MgSO4 and the solvents removed in vacuo. Fractional distillation affords the title compound (5.15 g, 48.5% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22](=[O:24])[CH3:23])([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](OC)(=[O:30])[C:26]([O:28]C)=[O:27].[H-].[Na+].Cl>C(COC)OC.C1COCC1>[ClH:21].[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22](=[O:24])[CH2:23][C:25](=[O:30])[C:26]([OH:28])=[O:27])([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)C1(Cc2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: O=C(O)C(=O)CC(=O)C1(Cc2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A solution of N-Benzyl-4-Acetyl-4-(4-Chlorobenzyl)-piperidine (600 mg, 1.75 mmol) and dimethyl oxalate (310 mg, 2.63 mmol) in dimethoxyethane (20 mL) was treated with sodium hydride (105 mg of a 60% dispersion in mineral oil, 2.63 mmol) and heated to reflux for 3 hours. The reaction was then cooled to room temperature, poured into 1 N aqueous HCl (200 mL) and extracted with ethyl ether (1×50 mL). The ether extract was discarded. The pH of the aqueous phase was adjusted to pH 8 and extracted with ethyl acetate (3×200 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The crude ester thus obtained was dissolved in THF (5 mL) and 3 N HCl (20 mL) and heated to reflux for 1 hour. The reaction was then cooled to room temperature, and concentrated at reduced pressure. The residue was triturated with tetrahydrofuran and the solid collected by filtration and crystallized from isopropanol to give 200 mg of the title compound. mp. 189°-181° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:19][CH3:20])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])[C:6]=2[N:7]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1>C1COCC1.C(O)(=O)C>[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH:31][C:2]3[N:3]=[C:4]([NH:19][CH3:20])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=5[F:18])[C:6]=4[N:7]=3)=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1F
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccc(F)cc1F
Yield: 59.6 %

Procedure:
A solution of 2-chloro-7-(2,4-difluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (184.6 mg, 0.624 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (140 mg, 0.624 mmol) in THF (1095 μL) and acetic acid (1095 μL) was heated 80° C. in a capped vial overnight. The solvent was evaporated in vacuum and the residue was partitioned between aqueous sodium bicarbonate solution and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. the combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(2,4-difluorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (179.6 mg, 0.372 mmol, 59.6% yield) as brown solid. LC-MS (M+H)+=483.1. 1H NMR (500 MHz, CDCl3) δ ppm 7.97 (1H, d, J=2.1 Hz), 7.49 (1H, d, J=1.5 Hz), 7.01-7.10 (2H, m), 7.00 (1H, d, J=1.5 Hz), 6.73-6.84 (3H, m), 4.44 (1H, s), 3.61 (3H, s), 3.11 (3H, d, J=4.9 Hz), 2.59-2.77 (2H, m), 1.95-2.05 (2H, m).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=S)=[CH:5][CH:4]=1.C1[O:24]C1CC>CO>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:24])=[CH:5][CH:4]=1
Reactant: S=C(NCCN1CCOCC1)c1ccc(Cl)cc1
Reactant: CCC1CO1
Agent: Cl
Solvent: CO
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1

Procedure:
1.0 G. of p-chloro-N-(2-morpholinoethyl)-thiobenzamide hydrochloride is boiled in 100 ml. of methanol with 35 ml. of 1,2-butylene oxide for 14 hours under reflux. The mixture is evaporated to dryness. The residue is recrystallized from isopropanol, and 0.6 g. of p-chloro-N-(2-morpholinoethyl)-benzamide is obtained, which is identical to the product obtained in Example 1.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[O:27][C:26](=[O:28])[NH:25][N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:29]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:37][C:38](=[O:40])[CH3:39].O>CN(C=O)C>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[O:27][C:26](=[O:28])[N:25]([CH2:37][C:38](=[O:40])[CH3:39])[N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:29]=1
Reactant: CC(=O)CCl
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3n[nH]c(=O)o3)c1)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(CC(C)=O)c(=O)o3)c1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
(S)-5-[3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3,4-oxadiazol-2(3H)-one (140 mg, 0.34 mmol) obtained in Step 1 of Example 89 was dissolved in DMF (3.0 mL), and the mixture was stirred at room temperature for 1 hour after adding potassium carbonate (94 mg, 0.68 mmol) and chloroacetone (0.030 mL, 0.38 mmol). Thereafter, water was added to the mixture, and the precipitated pale yellow solid was filtered off to obtain (S)-5-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-3-(2-oxopropyl)-1,3,4-oxadiazol-2(3H)-one (144 mg, 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.[C:13](OC(=O)C)(=[O:15])C.C(O)=O>>[CH:13]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2)=[O:15]
Reactant: Nc1cccc2ccc(O)cc12
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNc1cccc2ccc(O)cc12
Temperature: 50 °C

Procedure:
Ten grams of 8-amino-2-naphthol were added to a mixture of acetic anhydride/formic acid (40 mL:20 mL). The mixture was warmed at 50° C. for one hour and then quenched on ice. After stirring for some time, the product solidified and was filtered off. Recrystallization from ethanol gave 6 g of 8-formamido-2-naphthol melting at 203°-205° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][CH3:22])=[O:20])[CH:14]=1)=[CH:7]2.C([O-])(O)=O.[Na+].[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33].C(Cl)(Cl)Cl>C(Cl)Cl>[CH3:22][NH:21][C:19]([C:15]1[CH:14]=[C:13]([O:12][C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[NH:1][C:32]([C:31]3[CH:35]=[CH:36][CH:37]=[C:29]([Cl:28])[CH:30]=3)=[O:33])[CH:7]=2)[CH:18]=[CH:17][N:16]=1)=[O:20]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CNC(=O)c1cc(Oc2ccc3c(N)cccc3c2)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc3c(NC(=O)c4cccc(Cl)c4)cccc3c2)ccn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of 4-(5-aminonaphthalen-2-yloxy)-N-methylpicolinamide (40 mg, 0.14 mmol) and NaHCO3 (33 mg, 0.44 mmol)in CH2Cl2, 3-chlorobenzoyl chloride (17 □L, 0.14 mmol) was added. The reaction was stirred at RT for 12 h then taken up into CHCl3 and washed with water and brine, dried over Na2SO4, and filtered. The title compound was isolated after purification by column chromatography. MS (ESI pos. ion) m/z: 432.4 (M+H). Calc'd for C24H18ClN3O3−431.87.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].[S:11](Cl)(=[O:14])(=[O:13])[NH2:12]>>[C:4]([C:3]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:2]=1[NH:1][S:11]([NH2:12])(=[O:14])=[O:13])#[N:5]
Reactant: N#Cc1cc(Cl)ccc1N
Reactant: NS(=O)(=O)Cl
Product: N#Cc1cc(Cl)ccc1NS(N)(=O)=O

Procedure:
Prepared as in Example 77a from 2-amino-5-chlorobenzonitrile and sulfamoyl chloride. 1H NMR (400 MHz, DMSO-d6) 7.3 (S, 2H), 7.54-7.56 (d J=9.2 Hz, 1H). 7.74-7.77 (dd J=8.4 Hz, 2 Hz, 1H), 9.67 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[C:7]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)#[N:8].N1C=CC=CC=1>C(Cl)Cl>[C:7]([C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:4](=[O:5])[CH2:3][CH2:2][Cl:1])=[CH:11][CH:10]=1)#[N:8]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(Cl)CCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(NC(=O)CCCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
3-Chloropropionylchloride (1.08 g; 8.5 mmol) was added to a cooled (10° C.) solution of 4-cyanoaniline (1.0 g; 8.5 mmol) and pyridine (0.69 mL; 8.5 mnol) in DCM (40 mL), and the reaction mixture was stirred at rt. for 1 h. The reaction mixture was extracted with HCl (2N), washed with water, dried and concentrated to give the sub-title compound in a 81% yield.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29](O)(=[O:33])[CH2:30][CH:31]=[CH2:32].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:33])[CH2:30][CH:31]=[CH2:32])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCC(=O)O
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCC(=O)N1CCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Reaction time: 27 h

Procedure:
Piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (4) (1.00 g; 2.64 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. 3-Butenoic acid (0.27 g; 3.17 mmol), N,N-diisopropylethylamine (0.75 g; 5.81 mmol) and PyBOP (1.65 g; 3.17 mmol) are added sequentially. The reaction is stirred for 27 hr. at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography with gradient elution (70%→90% ethyl acetate in hexanes) affording the desired product (27) as a solid. CIMS (NH3Cl): 447 (MH+)