Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[N:13][OH:14])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[C:15]([C:17]1[C:18]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[N:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[N:21][CH:22]=1)#[CH:16].C(N(CC)CC)C>C1COCC1>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][O:29][C:18]2[C:17]([C:15]3[O:14][N:13]=[C:2]([C:3]4[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=4)[CH:16]=3)=[CH:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:19]=2)=[CH:36][CH:35]=1
Reactant: C#Cc1cnc(-c2ccccn2)nc1OCc1ccc(OC)cc1
Reactant: COC(=O)c1ccc(C(Cl)=NO)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2cc(-c3cnc(-c4ccccn4)nc3OCc3ccc(OC)cc3)on2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
To a mixture of compound 37-e (517 mg, 2.43 mmol), compound 37-j (700 mg, 2.21 mmol) in THF (5 mL) was added triethylamine (335 mg, 3.31 mmol) dropwise. The mixture was stirred overnight at room temperature. The residue obtained from removal of the solvent was purified by flash chromatography (PE:EA=1:2) to afford compound 37-k (420 mg, 38%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.786 (s, 1H), 8.753-8.731 (d, J=6.6 Hz, 1H), 8.172-8.144 (d, J=8.4 Hz, 2H), 8.004-7.976 (d, J=8.4 Hz, 2H), 7.838-7.806 (m, 1H), 7.645 (s, 1H), 7.615 (s, 1H), 7.495-7.470 (s, 1H), 6.875-6.846 (d, J=8.7 Hz, 2H), 6.697-6.668 (d, J=8.7 Hz, 2H), 5.786 (s, 2H), 3.960 (s, 3H), 3.723 (s, 3H), LC-MS (ESI): 495 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([C:9](OCC)=[O:10])=[CH:7][N:6]=[C:5]([S:14][CH3:15])[N:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][NH:2][C:3]1[C:8]([CH2:9][OH:10])=[CH:7][N:6]=[C:5]([S:14][CH3:15])[N:4]=1
Reactant: CCOC(=O)c1cnc(SC)nc1NC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1nc(SC)ncc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate (30 g, 132 mmol) in THF (300 mL) was added LiAlH4 (7.5 g, 198 mmol). The reaction mixture was stirred for 1 h at RT. The reaction was carefully quenched with 10 mL water, 7 mL of 10% aq NaOH. The mixture was stirred for 1 h, filtered and the filtrate was concentrated to give (4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol (22.0 g, 90% yield). 1H NMR (300 MHz, DMSO-d6): 7.79 (s, 1 H), 6.79 (m, 1 H), 5.04 (t, J=5.4 Hz, 1 H), 4.27 (d, J=5.4 Hz, 2H), 2.83 (d, J=4.8 Hz, 3 H), 2.40 (s, 3 H). MS (ESI) m/z: 186.1 (M+H+).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:23]3[CH:24]=[C:25]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:26]([NH:28][CH:29]3[CH2:31][CH2:30]3)=[O:27])[CH:19]=2)[C:14]1=[O:36])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.BrC1C=C2C(=CC=1)[C:44](=[O:48])NC=C2>CN(C=O)C>[CH2:6]([N:13]1[CH:22]=[C:21]([CH:44]=[O:48])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:23]3[CH:24]=[C:25]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:26]([NH:28][CH:29]3[CH2:31][CH2:30]3)=[O:27])[CH:19]=2)[C:14]1=[O:36])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccccc3)ccc2c1
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccccc3)cc(C=O)c2c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
DMF (5 mL) was cooled in an ice bath and phosphorus oxychloride (0.11 mL) added. The solution was stirred for 10 minutes. 3-(2-Benzyl-1-oxo-1,2-dihydroisoquinolin-6-yl)-N-cyclopropyl-4-methylbenzamide, Example 1 (0.4 g) was then added in one portion and the mixture heated at 80° C. for 6 hours. The mixture was allowed to cool then poured onto ice and stirred for 10 minutes. This was then extracted with ethyl acetate. The organics were combined and evaporated under reduced pressure. The residue was purified (SiO2, 1:1 isohexane/ethyl acetate) to give the sub titled compound (0.15 g).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8](B(O)O)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].Br[CH:16]=[C:17]1[C:23]2[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:22]=2[CH2:21][CH2:20][C:19]2[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:18]1=2>>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:18]2[C:17](=[CH:16][C:8]3[CH:7]=[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:11]=[CH:10][CH:9]=3)[C:23]3[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:22]=3[CH2:21][CH2:20][C:19]=2[CH:30]=1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: COc1ccc2c(c1)CCc1cc(OC)ccc1C2=CBr
Product: COc1ccc2c(c1)CCc1cc(OC)ccc1C2=Cc1cccc(NS(C)(=O)=O)c1
Yield: 39 %

Procedure:
Following procedures essentially as described in Example 219, below, and using 3-methanesulfonamidophenyl boronic acid (473 mg, 2.2 mmol) with 5-bromomethylene-2,8-dimethoxy-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (690 mg, 2 mmol) to give 1.3 g crude product. Purify the crude product using column chromatography eluting with 10% EtOAc/hexane to 30% EtOAc/hexane to give 340 mg (39%) product as a pale yellow solid, mp 109.6° C. MS (ES) 436 (M+1), 434 (M−1). HPLC shows 91% purity at t=3.11 min.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([N:23]1[CH2:40][CH2:39][C:26]2([C:30](=[O:31])[N:29]([C:32]3[CH2:33][O:34][C:35](=[O:38])[C:36]=3[CH3:37])[CH2:28][CH2:27]2)[CH2:25][CH2:24]1)[CH2:11][C:12]1[C:13]([CH3:22])=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[O:16][CH2:15]2)(C(C)(C)C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:8][CH2:9][CH:10]([N:23]1[CH2:40][CH2:39][C:26]2([C:30](=[O:31])[N:29]([C:32]3[CH2:33][O:34][C:35](=[O:38])[C:36]=3[CH3:37])[CH2:28][CH2:27]2)[CH2:25][CH2:24]1)[CH2:11][C:12]1[C:13]([CH3:22])=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[O:16][CH2:15]2
Reactant: CC1=C(N2CCC3(CCN(C(CO[Si](C)(C)C(C)(C)C)Cc4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1=C(N2CCC3(CCN(C(CO)Cc4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 8-(1-((tert-butyldimethylsilyl)oxy)-3-(4-methyl-1-oxo-1,3-dihydro isobenzofuran-5-yl)propan-2-yl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (0.10 g, 0.18 mmol) in DCM (3 mL) was added trifluoroacetic acid (3 mL) at 0° C. After stirring at room temperature for 24 h, solvent was removed under reduced pressure and the residue was purified by preparative-HPLC to give the title compound, which was separated by SFC chiral chromatography into two single enantiomers Isomer A (faster elting) and Isomer B (slower eluting. Column: CHIRALPAK AD 250×30 mm I.D., 20 μm; Mobile phase: Supercritical CO2/EtOH (0.2% NH3H2O)=45/55; Flow rate: 80 ml/min. For both isomers: LC-MS (ESI, m/z): 455 [M+1].
Reaction SMILES: C[C:2]1[O:3][C:4](=O)[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([N:13]2[CH:4]=[C:5]3[C:6]([CH:8]=[CH:9][CH:10]=[CH:11]3)=[N:7][C:2]2=[O:3])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1nc2ccccc2c(=O)o1
Reactant: Nc1ccccc1
Product: O=c1nc2ccccc2cn1-c1ccccc1
Temperature: 160 °C
Yield: 35.2 %

Procedure:
A mixture of 2-methyl-4H-Benzo[d][1,3]oxazin-4-one (12; 1.0 g, 6.2 mmol) and aniline (13, R═H, 0.57 mL, 6.2 mmol, 1.0 eq) were heated at 160° C. (oil bath) for 12 hours. The reaction was cooled to room temperature and the resulting solid was recrystallized from EtOH to yield 485 mg (31%) of 14 as a yellow-orange crystalline solid: 1H NMR (CDCl3): 8.28 (d, 1H), 7.80-7.67 (m, 2H), 7.60-7.44 (m, 4H), 7.29-7.28 (m, 2H), 2.25 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([NH:20][C:21](=[O:31])[CH2:22][NH:23]C(=O)OC(C)(C)C)[N:19]=[C:6]2[N:5]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)[C:4]=1[CH3:42])#[N:2].[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>ClCCl>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([NH:20][C:21](=[O:31])[CH2:22][NH2:23])[N:19]=[C:6]2[N:5]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:40])([F:41])[F:39])[CH:33]=2)[C:4]=1[CH3:42])#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)CNC(=O)OC(C)(C)C)nc2N1c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)CN)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 0.67 h

Procedure:
Under an atmosphere of argon protective gas, tert-butyl [2-((7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-ylamino)-2-oxoethyl]carbamate (6.4 mg, 11 μmol) was dissolved in dry dichloromethane (5 ml). At room temperature, trifluoroacetic acid (1 ml) was added, and the mixture was stirred for 40 min. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (˜6 mg, quant.).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][CH2:8][O:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:12][N:11]=1>>[C:15]1([C:13]2[O:12][N:11]=[C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:14]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: BrCCOc1cc(-c2ccccc2)on1
Reactant: C1CCNC1
Product: c1ccc(-c2cc(OCCN3CCCC3)no2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
Pyrrolidine (710 mg) was added to 3-(2-bromoethoxy)-5-phenylisoxazole (268 mg), and the mixture was stirred at 100° C. for one hour. After ice-cold water (20 ml) was added to the reaction mixture and the mixture was extracted with ether (20 ml×2), the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain the title compound (211 mg, 82%) as colorless crystals.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[CH:2]=1.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:14][C:15]([OH:17])=[O:16])[CH:2]=1
Reactant: O=Cc1cnc2ccccc2c1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.006 g (6.4 mmol) of quinoline-3-carbaldehyde were dissolved in 10 ml of pyridine and 0.794 g (7.6 mmol) of malonic acid and 54 mg (0.6 mmol) of piperidine were added. The resulting solution was boiled under reflux for 6 h. The solution was allowed to cool to room temperature and kept for 16 h whereupon the product precipitated. The product was isolated by filtration. Yield: 0.765 g.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:9][OH:10])(C)(C)C.[CH:19]1(O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:15]([O:14][C:12](=[O:13])[NH:11][CH:8]1[CH2:7][C:6](=[O:5])[O:18][CH:9]1[O:10][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH:16]=[CH2:17]
Reactant: OC1CCCCC1
Reactant: C=CCOC(=O)NC(CO)CC(=O)OC(C)(C)C
Product: C=CCOC(=O)NC1CC(=O)OC1OC1CCCCC1
Yield: 85 %

Procedure:
Prepared from 3-allyloxycarbonylamino-4-hydroxy-butyric acid tert-butyl ester as described for 40 using cyclohexanol to afford the title compound as a mixture of diastereomers (pale yellow oil) (4.62 g, 85% yield). Flash column chromatography using hexanes/EtOAc (90/10 to 80/20) gave 394 mg (7% yield) of the syn diastereomer of the title compound. 1H NMR (500 MHz, CDCl3) 6.1.11-2.09 (m, 10H), 2.35-2.61 (dd, 1H), 2.72-2.98 (dd, 1H), 3.60-3.83 (m, 1H), 4.32-4.72 (m, 3H), 5.06-5.43 (m, 2H), 5.60 (d, 1H), 5.82-6.03 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]([CH2:8][NH:9][C:10](=[O:26])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2[NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:6][CH:5]=1)([OH:3])=O.Cl.C[N:31](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.O>CN(C)C=O.N>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10](=[O:26])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2[NH:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:27][CH:28]=1)(=[O:3])[NH2:31]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2NC2CCCC2)cc1
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2NC2CCCC2)cc1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
A mixture of N-(4-carboxybenzyl)-2-(cyclopentylamino)-5-nitrobenzamide (120 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (90.0 mg) and 1-hydroxybenzotriazole (63.4 mg) in anhydrous dimethylformamide (2 mL) was stirred for an hour at ambient temperature. After addition of 28% ammonia solution (10 drops), the mixture was stirred for 15 hours at ambient temperature and poured into water. The resulting precipitates were collected by filtration, washed with water and purified by a silica gel column chromatography eluting with 10% methanol in chloroform. The obtained product was triturated with diisopropyl ether to give N-(4-carbamoylbenzyl)-2-(cyclopentylamino)-5-nitrobenzamide (107 mg) as yellow powders.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH2:18][CH3:19]>CN(C)C=O>[CH2:17]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)[CH2:18][CH3:19]
Reactant: CCCI
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1cnc2ccccc21
Yield: 55.3 %

Procedure:
To a flask were added 2.0 g benzimidazole, 3.5 g potassium carbonate, 4.3 g 1-iodopropane and 20 ml N,N-dimethylformamide. The mixture was heated to 45 C under nitrogen for 16 hours and then quenched with 30 ml water and the product was extracted with ethyl acetate. Following removal of the solvent, the product was purified by silica gel chromatography using 66% ethyl acetate in hexane. The brown oil was again purified by silica gel chromatography using ethyl acetate, giving a slightly yellow oil 1.5 g.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26]([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=2[O:35][CH3:36])[CH:27]=1.OS(O)(=O)=O.CCOC(C)=O>CN1C(=O)CCC1>[Cl:22][C:23]1[N:24]=[CH:25][N:26]([C:28]2[CH:34]=[CH:33][C:31]([NH:32][C:2]3[N:3]=[C:4]([NH:17][CH:18]4[CH2:19][CH2:20][CH2:21]4)[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[C:6]=4[N:7]=3)=[CH:30][C:29]=2[O:35][CH3:36])[CH:27]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: Clc1nc(NC2CCC2)c2c(n1)C(c1ccccc1)CC2
Agent: O=S(=O)(O)O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1cc(Nc2nc(NC3CCC3)c3c(n2)C(c2ccccc2)CC3)ccc1-n1cnc(Cl)c1
Temperature: 97 °C
Reaction time: 20 h
Yield: 71.6 %

Procedure:
To a mixture of 2-chloro-N-cyclobutyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (165 mg, 0.55 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (135 mg, 0.605 mmol) in NMP (2 mL) was added Conc. H2SO4 (0.041 mL, 0.771 mmol). The mixture was stirred at 97° C. for 20 hours. After cooled down to room temperature, 100 mL of EtOAc was added, washed with saturated NaHCO3/water and water, dried over Na2SO4, and finally removed. The residue was purified via Biotage (12 g, hexanes-80% EtOAc) to give N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-cyclobutyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (202 mg, 0.394 mmol, 71.6% yield). LC-MS (M+H)+=487.14. 1H NMR (500 MHz, CDCl3) δ ppm 7.92 (1H, d, J=1.8 Hz), 7.51 (1H, d, J=1.2 Hz), 7.28-7.33 (2H, m), 7.18-7.24 (3H, m), 7.13 (1H, s), 7.03 (1H, d, J=8.5 Hz), 7.01 (1H, d, J=1.2 Hz), 6.74 (1H, dd, J=8.5, 2.1 Hz), 4.64-4.80 (2H, m), 4.17-4.23 (1H, m), 3.49 (3H, s), 2.72-2.81 (1H, m), 2.61-2.71 (2H, m), 2.43-2.53 (2H, m), 2.09 (1H, td, J=8.0, 2.3 Hz), 1.92-2.04 (2H, m), 1.70-1.88 (2H, m).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:24]O>>[F:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:16])([F:17])[C:12]([F:13])([F:14])[F:15])[C:5]([O:7][CH3:24])=[O:6]
Reactant: CO
Reactant: Cc1c(C(=O)O)ccc(C(F)(F)C(F)(F)F)c1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C(F)(F)C(F)(F)F)c(F)c1C

Procedure:
2.33 g (8.56 mmol) of 3-fluoro-2-methyl-4-(pentafluoroethyl)benzoic acid were introduced into 30 ml of methanol and admixed with 2 ml of concentrated sulfuric acid. The mixture was subsequently heated at reflux until a check by HPLC indicated full conversion. The contents were freed from the solvent on a rotary evaporator, and the residue was taken up in water. The mixture was extracted twice with ethyl acetate, and the combined organic phases were washed once with saturated aqueous sodium hydrogencarbonate solution. The organic phase was dried and freed from the solvent. The residue obtained was 2.1 g of clean product.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:13][CH2:12][O:11][C:10]2=O)[CH2:5][CH2:4]1.[OH-].[NH4+:16]>C(O)C>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:13][CH2:12][NH:16][C:10]2=[O:11])[CH2:5][CH2:4]1
Reactant: [NH4+]
Reactant: COC1CCC(C2CCOC2=O)CC1
Agent: [OH-]
Solvent: CCO
Product: COC1CCC(C2CCNC2=O)CC1

Procedure:
Heat a mixture of 3-(4-methoxycyclohexyl)-dihydro-furan-2-one (0.91 g), ammonium hydroxide (20 mL) and ethanol (20 mL) at 230° C. in a sealed steel bottle for 12 hours. Cool the reaction and remove the solvent in vacuo. Partition the residue with ethyl acetate (100 mL) and HCl (1N, 60 mL). Dry the organic over sodium sulfate. After filtration and concentration, recrystallize with 1:3 ethyl acetate:hexane to afford 0.71 gram of the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:14]=3[CH:15]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[H-].[Na+].CC1C=CC(S(O[CH2:34][C@@H:35]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH3:36])(=O)=O)=CC=1.O>CN(C=O)C>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([O:20][CH2:36][C@@H:35]([NH:37][C:38](=[O:39])[O:40][C:41]([CH3:42])([CH3:44])[CH3:43])[CH3:34])[CH:17]=[CH:16][C:14]=3[CH:15]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C)NC(=O)OC(C)(C)C)cc1
Reactant: CCCOc1ccc(-c2cc3ccc(O)cc3o2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(-c2cc3ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc3o2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.6 %

Procedure:
To a solution of 2-(4-propoxyphenyl)-1-benzofuran-6-ol (918 mg) in DMF (10 mL) was added sodium hydride (60% oil, 137 mg), and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added (2S)-2-[(tert-butoxycarbonyl)amino]propyl 4-methylbenzenesulfonate (1.13 g), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (460 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]#[N:13])=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:24][C:25]([NH:27][NH2:28])=O)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:24][C:25]1[NH:13][C:12]([C:3]2[C:2]([OH:1])=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[N:10]3)=[CH:5][N:4]=2)=[N:28][N:27]=1
Reactant: COc1ccc(CC(=O)NN)cc1OC
Reactant: N#Cc1ncc2cccnc2c1O
Product: COc1ccc(Cc2nnc(-c3ncc4cccnc4c3O)[nH]2)cc1OC

Procedure:
The title compound was prepared in a similar manner to that described in example 1 from of 8-hydroxy-1,6-naphthyridine-7-carbonitrile (50 mg, 0.29 mmol) and 2-(3,4-dimethoxyphenyl)acetic hydrazide (315 mg, 1.5 mmol) as a yellow solid (36 mg, 34%). 1H NMR (CDCl3): δ 9.19 (m, 1 H), 8.93 (s, 1 H), 8.32 (d, J=8.4 Hz, 1 H), 7.63 (m, 1 H), 6.98-6.95 (m, 2 H), 6.82 (d, J=8.0 Hz, 1 H), 4.19 (s, 2 H), 3.88 (s, 3 H), 3.85 (s, 3 H); MS m/z 364 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.Cl.[Cl:17][C:18]1[C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1>O1CCCC1>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:24]([C:23]1[C:18]([Cl:17])=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:25]
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)c1cccnc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
As described in J. Med. Chem., 37, 519 (1994), a solution of 1.09 g of 2-aminophenol in 15 ml of tetrahydrofuran is added dropwise to a mixture of 2.1 g of triethylamine and 2.33 g of 2-chloropyridine-3-carbonyl chloride hydrochloride in 10 ml of tetrahydrofuran. The mixture is stirred at room temperature for one hour under argon and then refluxed for one hour. The solvent is removed under vacuum and the residue triturated with water: The solid is filtered off and washed with water to give 1.02 g of solid. Recrystallization from 2-propanol gives crystals, m.p. 145°-146° C.
Reaction SMILES: [CH2:1]([PH2:5])[CH:2]([CH3:4])[CH3:3].[CH:6]([CH:8]=[O:9])=[O:7]>O1CCCC1>[CH2:1]([P:5]1[CH:6]([OH:7])[CH:8]([OH:9])[P:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH:6]([OH:7])[CH:8]1[OH:9])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CP
Reactant: O=CC=O
Solvent: C1CCOC1
Product: CC(C)CP1C(O)C(O)P(CC(C)C)C(O)C1O
Yield: 97 %

Procedure:
In a suitable autoclave, equipped with mechanical stirring and external heating are added 200 parts of mono-isobutylphosphine (85%) and 300 parts of tetrahydrofuran, as solvent. With no external heating applied to the reactor, 275 parts of a 40% aqueous glyoxal solution are added with stirring at 20°-25° C. The resultant solid product is filtered, and dried to give 276 parts (97% yield) of 1,4-diisobutyl-2,3,5,6-tetrahydroxy-1,4-diphosphorinane, m.p. 173°-175° C.
Reaction SMILES: [NH2:1][C:2]1[N:12]=[CH:11][C:10]([C:13]2[C:14]([Cl:40])=[C:15]3[C:21]([C:22]4[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=4[O:30][CH3:31])=[CH:20][N:19](COCC[Si](C)(C)C)[C:16]3=[N:17][CH:18]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].C(N)CN>FC(F)(F)C(O)=O>[NH2:1][C:2]1[N:12]=[CH:11][C:10]([C:13]2[C:14]([Cl:40])=[C:15]3[C:21]([C:22]4[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=4[O:30][CH3:31])=[CH:20][NH:19][C:16]3=[N:17][CH:18]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:7])[CH3:8])=[O:5]
Reactant: COc1cc(F)c(F)cc1-c1cn(COCC[Si](C)(C)C)c2ncc(-c3cnc(N)c(C(=O)N(C)C)c3)c(Cl)c12
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)c(F)cc1-c1c[nH]c2ncc(-c3cnc(N)c(C(=O)N(C)C)c3)c(Cl)c12
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 79.4 %

Procedure:
2-Amino-5-[4-chloro-3-(4,5-difluoro-2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-nicotinamide (76 mg, 0.136 mmol) was dissolved in trifluoroacetic acid (3 mL) and stirred at 23° C. for 45 minutes. The solution was concentrated under vacuum and taken up in methanol (10 mL). Ethylenediamine (100 μL, 5.39 mmol) was added, and the mixture was stirred at 35° C. for 20 minutes. Methanol was removed under vacuum. The crude was taken up in methanol (0.5 mL) and water (1 mL) was added. The resulting precipitate was collect by filtration to afford 2-Amino-5-[4-chloro-3-(4,5-difluoro-2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-nicotinamide (49.6 mg, 0.108 mmol, 80% yield). 1H-NMR [500 MHz, d6-DMSO] δ: 8.18 (s, 1H), 8.05 (d, 1H), 7.56 (s, 1H), 7.47 (d, 1H), 7.35 (m, 1H), 7.15 (m, 1H), 6.15 (s, 2H), 6.68 (s, 2H), 2.95 (s, 6H); MS [MH+] m/z: 458.