Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C:15]1([NH:18]C(=O)OCC3C=CC=CC=3)[CH2:17][CH2:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][C:36]=2[C:40](=[O:43])[NH:41][CH3:42])[CH:31]=1.C(O)(=O)C.Br.C(O)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.O>[NH2:18][C:15]1([CH2:14][O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([O:29][C:30]4[CH:31]=[C:32]5[C:37](=[CH:38][CH:39]=4)[C:36]([C:40]([NH:41][CH3:42])=[O:43])=[CH:35][CH:34]=[CH:33]5)=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2][CH3:1])[CH2:16][CH2:17]1
Reactant: CNC(=O)c1cccc2cc(Oc3ccnc4cc(OCC5(NC(=O)OCc6ccccc6)CC5)c(OC)cc34)ccc12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CNC(=O)c1cccc2cc(Oc3ccnc4cc(OCC5(N)CC5)c(OC)cc34)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 1 (100 mg) was mixed with acetic acid (1 ml) and 33% HBr/acetic acid (0.6 ml). The reaction was stirred at RT for 1 hour and diluted with EtOAc/H2O then basified with Na2CO3. The organic layer was dried, evaporated and purified with silica gel column to give the titled product. Mass: (M+1), 444
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[C:7](#N)C.Cl[C:11]([O:13]C)=[O:12]>C(N(CC)CC)C>[CH3:7][C:5]1[N:4]=[C:3]([C:11]([OH:13])=[O:12])[N:2]([CH3:1])[CH:6]=1
Reactant: CC#N
Reactant: COC(=O)Cl
Reactant: Cn1ccnc1
Solvent: CCN(CC)CC
Product: Cc1cn(C)c(C(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
in a nitrogen atmosphere, 41.0 g of 1-methylimidazole was added to 500 ml of acetonitrile, followed by 70 ml of triethylamine, and the mixture was cooled in an ice bath. 38.63 g of methyl chloroformate was added dropwise over 30 minutes, the mixture was stirred at room temperature overnight, and filtered. The filtrate was stripped of volatiles; the residue was dissolved in 500 ml of methylene chloride and the solution was washed with brine, then water, then dried (Na2SO4) and stripped of solvent. The residue was flash chromatographed on silica gel, with a 975:25 v:v mixture of methylene chloride and methanol as eluent. Evaporation of the solvent gave methyl 1-methylimidazole-2-carboxylic acid (37A), as a light yellow oil.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl.Cl[CH2:12][C:13]1[N:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]2=[N:15][C:14]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)CC)C>CN(C=O)C.O>[O:7]([CH2:12][C:13]1[N:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]2=[N:15][C:14]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1nc2ccccn2c1CCl
Reactant: Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc2ccccn2c1COc1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 39.8 %

Procedure:
A solution of a mixture of phenol (2.20 g) and sodium hydride (95 wt %, 500 mg) in DMF (40 ml) was added dropwise to a solution of ethyl 3-(chloromethyl)imidazo[1,2-a]pyridine-2-carboxylate hydrochloride (3.5 g) in DMF (50 ml) at 0° C. Triethylamine (2.7 ml) was added at the same temperature over 30 min. The reaction mixture was stirred at 50° C. for 3 hr, and the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (6:1) was concentrated under reduced pressure to give the object product (1.5 g).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][C:21]#[N:22])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[C:5]([NH:13][C@H:14]2[CH2:15][CH2:16][C@H:17]([CH2:20][C:21]#[N:22])[CH2:18][CH2:19]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1
Reactant: N#CC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Agent: [Pd]
Solvent: CO
Product: N#CC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Reaction time: 5 h

Procedure:
A mixture of {trans-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}acetonitrile (1.0 g, 3.2 mmol) and 10% palladium on carbon (0.3 g, 0.3 mmol) in methanol (30 mL) was hydrogenated under balloon pressure of H2 at room temperature for 5 h. The reaction mixture was filtered. The filtrate was concentrated, diluted with dichlormethane, dried over MgSO4, and concentrated. The residue was purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product. (0.63 g, 70%). LCMS calculated for C15H19N4S (M+H)+: m/z=287.1. Found: 287.1.
Reaction SMILES: [Cl:1][CH2:2][CH2:3]/[C:4](/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:5](/[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)\[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C([O-])(=O)C.[Na+]>C(O)C>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][NH:18][C:15]1[CH:14]=[CH:13][C:12](/[C:5](/[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:4](\[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)/[CH2:3][CH2:2][Cl:1])=[CH:17][CH:16]=1)[CH3:31]
Reactant: Nc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccccc2)cc1

Procedure:
(Z)-4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenylamine (2.0 g, 5.99 mmol), ethanol (30 ml), ethyl bromoacetate (2.5 g, 15 mmol) and sodium acetate (2.4 g, 17.9 mmol) are added to the reaction vessel and refluxed for three hours. Then the solvent is evaporated and the residue is dissolved in water and ethyl acetate. Ethyl acetate phase is dried and evaporated to dryness. Yield 2.9 g.
Reaction SMILES: Br[CH:2]([CH2:25][CH3:26])[CH2:3][CH2:4][CH2:5][N:6]([C@H:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:18]([NH2:20])=[O:19])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8].CCN(CC)CC.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(Cl)Cl>[O:37]1[CH2:38][CH2:39][N:34]([CH:2]([CH2:25][CH3:26])[CH2:3][CH2:4][CH2:5][N:6]([C@H:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:18]([NH2:20])=[O:19])[S:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:35][CH2:36]1
Reactant: C1COCCN1
Reactant: CCC(Br)CCCN([C@H](CC(C)C)C(N)=O)S(=O)(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CCCN([C@H](CC(C)C)C(N)=O)S(=O)(=O)c1ccc(Cl)cc1)N1CCOCC1
Yield: 53.7 %

Procedure:
A solution of (2R)-2-[N-(4-bromohexyl)-N-(4-chlorobenzenesulfonyl)amino]-4-methylpentanoic acid amide (Example 24; prepared as described in Reaction Scheme 1; 0.20 g, 0.44 mmol), Et3N (0.25 mL, 1.7 mmol), and morpholine (150 mg, 1.7 mmol) in CH2Cl2 (2 mL) was stirred at rt for 18 h. The reaction was then concentrated to give a crude white wax which was purified by flash chromatography (SiO2, 85% EtOAc/5% hexanes/10% MeOH) to afford the title compound (112 mg) as a white solid in 54% yield. MS (ESI), (M+H)+474.4; 1H NMR (DMSO-d6) δ 7.82 (d, 2H, J=8.0), 7.64 (d, 2H, J=8.0), 7.42 (br s, 1H) 6.99 (s, 1H), 4.25 (m, 1H), 3.51-3.60 (br s, 4H), 3.18-3.41 (m, 2H), 2.25-2.35 (br s, 4H), 2.27 (m, 2H) 1.15-1.62 (m, 9H), 0.80 (d, 6H, J=6.0).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[OH:12]O>C(Cl)Cl.C[Re](=O)(=O)=O>[F:1][C:2]1[CH:3]=[N+:4]([O-:12])[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:11])[F:10]
Reactant: Fc1cnccc1C(F)(F)F
Reactant: OO
Agent: C[Re](=O)(=O)=O
Solvent: ClCCl
Product: [O-][n+]1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-fluoro-4-(trifluoromethyl)pyridine (5.00 g; 30.3 mmol) in CH2Cl2 (10 mL) was cooled to 0° C., then methyltrioxorhenium(VII) (0.062 g; 0.249 mmol) and hydrogen peroxide (30%; 6.2 mL; 61 mmol) were added and the mixture was warmed to room temperature. After stirring for 2 hours, the reaction was quenched by the addition of MnO2 (5 mg) and 30 minutes additional stirring. After dilution with additional CH2Cl2, the mixture was filtered through Solka Floe, dried (MgSO4) and concentrated in vacuo to provide 3-fluoro-4-(trifluoromethyl)pyridine 1-oxide of sufficient purity to be used directly. The N-oxide (3.70 g; 20.4 mmol) was dissolved in trifluoroacetic anhydride (21.6 mL; 153 mmol) in a hydrogenation bomb and heated to 85° C. for 15 hours. After cooling to 0° C., water was added, followed by solid K2CO3 until pH 9. The aqueous fraction was extracted with EtOAc and Me-THF, and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification by ISCO CombiFlash (70:30 to 0:100 hexanes:EtOAc) provided the title compound as a pink solid. 1H NMR (400 MHz, Acetone): δ 11.48 (s, 1 H); 7.55 (d, J=7.1 Hz, 1 H); 6.39 (t, J=6.2 Hz, 1 H).
Reaction SMILES: [CH2:1]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:17]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:29]([O:31]C)=[O:30])[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH3:28])=[CH:20][CH:21]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:29]([OH:31])=[O:30])[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.5 %

Procedure:
In THF (15.8 ml)/methanol (15.8 ml) was dissolved methyl 1-isobutyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylate (0.79 g). To the solution was added 1N sodium hydroxide solution (7.9 ml) and the mixture was stirred at room temperature for 20 hours. pH was adjusted to approximate 4 with 1N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate, and the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed With hexane/ethyl acetate (=6/1) to give 1-isobutyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.57 g).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3]O.[CH3:7][C:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[NH:10][N:9]=1.CCOCC.[OH-].[NH4+]>C(O)C>[F:1][C:2]([F:6])([F:5])[CH2:3][N:10]1[C:11]([C:13]([OH:15])=[O:14])=[CH:12][C:8]([CH3:7])=[N:9]1
Reactant: OCC(F)(F)F
Reactant: CCOC(=O)c1cc(C)n[nH]1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: Cc1cc(C(=O)O)n(CC(F)(F)F)n1
Temperature: 70 °C
Yield: 72 %

Procedure:
A mixture of 100 g (0.35 mol) of the trichloromethanesulfonate ester of 2,2,2-trifluoroethanol [J. Med. Chem. 16 1354 (1973)] and 55 g (0.35 mol) of ethyl 3-methylpyrazole-5-carboxylate is heated at 150°-155° C. for two hours. The cooled (70° C.) melt is poured with stirring into 400 ml of ether, 80 ml of conc. ammonium hydroxide, and 150 g ice. The ether layer is separated and distilled to give 48 g bp 100°-110°/11 mm. The ester is stirred under reflux two hours in 175 ml of ethanol and 40 ml of water containing 14 g of potassium hydroxide and evaporated in vacuo. The residue is dissolved in 60 ml of water and acidified with conc. HCl to give 32 g (72%) of 1-(2,2,2-trifluoroethyl)-3-methylpyrazole-5carboxylic acid, mp 135°-139° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([S:7](Cl)(=[O:9])=[O:8])=[C:5]([CH3:11])[O:4][N:3]=1.[CH2:12]([O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[CH:32][CH:31]=1)[NH:25][CH2:24][CH2:23]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(CC)CC>C1COCC1>[CH2:12]([O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[CH:32][CH:31]=1)[N:25]([S:7]([C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[CH3:11])(=[O:9])=[O:8])[CH2:24][CH2:23]2)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: c1ccc(COc2ccc3c(c2)CCNC3c2ccc(OCCN3CCCC3)cc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1S(=O)(=O)N1CCc2cc(OCc3ccccc3)ccc2C1c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 104 %

Procedure:
3,5-Dimethylisoxazole-4-sulfonyl chloride (0.034 g, 0.18 mmol) was added to a solution of 6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline (0.075 g, 0.18 mmol) and Et3N (0.037 ml, 0.26 mmol) in anhydrous THF (10 ml) at rt under N2. The resulting suspension was stirred at rt for 21 hr, then evaporated in vacuo to a residue that was suspended in a mixture of saturated NaHCO3 solution (4 ml) and H2O (4 ml). This was extracted with CHCl3 (4×5 ml) and the combined extracts were dried over MgSO4, then concentrated in vacuo to give 0.110 g of yellow oil. Purification by flash chromatography, eluting with EtOAc:MeOH (1:1) gave 0.078 g (76% yield) of white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]([CH2:16][C:17]([CH3:25])=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)=[O:7].C(=O)(O)[O-].[Na+].[CH2:38](Br)[CH3:39]>ClCCl>[CH2:38]([N:12]1[CH2:13][CH2:14][CH2:15][CH:11]1[CH2:10][CH2:9][N:8]([CH2:16][C:17]([CH3:25])=[CH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:6](=[O:7])[C:5]1[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:39]
Reactant: COc1cc(C(=O)N(CCC2CCCN2)CC(C)=Cc2ccccc2)cc(OC)c1OC
Reactant: CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CCCC1CCN(CC(C)=Cc1ccccc1)C(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 3,4,5-trimethoxy-N-(2-methyl-3-phenyl-allyl)-N-(2-pyrrolidin-2-yl-ethyl)-benzamide 0.1 g (2.28 mmol) in dry dichloromethane 5 ml, sodium bicarbonate 0.01 g (2.7 mmol) was added followed by ethyl bromide 0.037 g (3.4 mmol) at 0° C. The reaction mixture was stirred at room temperature for 14 hrs. Inorganics were filtered off and filtrate was concentrated. Crude material was subjected to column chromatography on silica gel, elution with chloroform-methanol to yield desired compound as a free amine. This was converted to its hydrochloride salt 42 mg as a yellow semi-solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[CH:17][C:16]=1[NH2:27].C(N(CC)C(C)C)(C)C.[CH2:37]([N:39]1[CH2:45][CH2:44][C:43]2[CH:46]=[C:47]([NH2:50])[CH:48]=[CH:49][C:42]=2[CH2:41][CH2:40]1)[CH3:38].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[CH2:37]([N:39]1[CH2:45][CH2:44][C:43]2[CH:46]=[C:47]([NH:50][C:2]3[N:7]=[C:6]([NH:27][C:16]4[CH:17]=[CH:18][C:19]([N:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)=[CH:20][C:15]=4[O:14][CH3:13])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=3)[CH:48]=[CH:49][C:42]=2[CH2:41][CH2:40]1)[CH3:38]
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: COc1cc(N2CCOCC2)ccc1N
Reactant: CCN1CCc2ccc(N)cc2CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCc2ccc(Nc3ncc(C(F)(F)F)c(Nc4ccc(N5CCOCC5)cc4OC)n3)cc2CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
2,4-Dichloro-5-trifluoromethylpyrimidine (124 mg, 0.571 mmol), 2-methoxy-4-morpholin-4-yl-phenylamine (104 mg, 0.499 mmol), and N,N-diisopropylethylamine (97 mg, 0.75 mmol) were dissolved in 3 mL isopropyl alcohol and stirred at room temperature overnight. The reaction was concentrated and the organics dissolved in dichloromethane. The dichloromethane solution was washed with saturated sodium bicarbonate solution, was dried (sodium sulfate) and was concentrated. ISCO chromatography (0.75% MeOH:dichloromethane) afforded an inseparable mixture of both possible regioisomers (211 mg). This mixture (30 mg) was microwaved (130° C., 3 hours) with 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (16 mg, 0.084 mmol) and 10-camphorsulfonic acid 22 mg, 0.095 mmol) in isopropyl alcohol (3 mL). On cooling, the mixture was concentrated and the organics were extracted in dichloromethane. The dichloromethane solution was washed with saturated sodium bicarbonate solution, was dried (sodium sulfate), and was concentrated. ISCO chromatography (gradient elution: 1 to 10% MeOH:dichloromethane) affords the title compound—a white solid (20 mg, 50%). Mp: 167-70° C. LCMS (m/e) 543 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.30 (s, 1H), 8.06 (d, J=9 Hz, 1H), 7.55 (br s, 2H), 7.36 (s, 1H), 7.22 (br s, 1H), 7.10 (d, J=9 Hz, 1H), 6.78 (s, 1H), 6.50 (s, 1H), 6.38 (br s, 1H), 3.90 (m, 7H), 3.15 (m, 4H), 3.00 (m, 4H), 2.80-2.60 (m, 6H), 1.20 (d, J=7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](=[O:11])[O:9][CH2:8][C:5]2=[N:6][CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([CH2:8][O:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[C:4]([CH:3]=1)[C:10]([OH:9])=[O:11]
Reactant: Oc1ccc(F)cc1
Reactant: O=C1OCc2ncc(Cl)cc21
Product: O=C(O)c1cc(Cl)cnc1COc1ccc(F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from 3-chlorofuro[3,4-b]pyridin-5(7H)-one (step 1 of Example 18) and 4-fluorophenol:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12]2[C:13](=O)[C:14](=[O:19])[C:15]=2[O:16]CC)[CH:2]=1.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>C(O)C>[C:21]([NH:25][C:13]1[C:14](=[O:19])[C:15](=[O:16])[C:12]=1[NH:11][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOc1c(Nc2cnc3ccccc3c2)c(=O)c1=O
Reactant: CC(C)(C)N
Solvent: CCO
Product: CC(C)(C)Nc1c(Nc2cnc3ccccc3c2)c(=O)c1=O
Temperature: 60 °C
Yield: 84.6 %

Procedure:
To the product from Example 13, Step 1 (0.30 g, 1.12 mmol) in ethanol (8 mL) was added tert-butylamine (0.35 mL, 3.36 mmol) and the resulting mixture was heated at 60° C. overnight. The mixture was concentrated, and the residue was dissolved in ethylacetate. Addition of hexanes induced precipitation of product which was filtered and triturated with diethylether/hexanes. Filtration and drying afforded 0.28 g (85%) of the title compound as a yellow solid, three -quarter hydrate: mp 257°-260° C.; 1H NMR (DMSO-d6) d 10.00 (br d, 1H), 8.9 (d, 1H), 8.4 (m, 1H), 8.02 (d, 1H), 7.96 (br d, 1H), 7.86 (dd, 1H), 7.66-7.54 (m, 2H), 1.45 (s, 9H). IR (KBr) 3400, 3200, 2980, 1785, 1680cm-1 ; MS (m/z) 296 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][NH2:49])=[CH:44][CH:43]=1>CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]([C:8]([NH:49][CH2:48][C:45]2[CH:46]=[CH:47][C:42]([F:41])=[CH:43][CH:44]=2)=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1nc(N)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N)sc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To a solution of 2-amino-4-methylthiazole-5-carboxylic acid (4.20 g, 26.0 mmol) in anhydrous N,N-dimethylformamide (100 mL) was added 1-hydroxybenzotriazole (9.30 g, 69.0 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (6.60 g, 34.0 mmol), diisopropylethylamine (4.40 g, 34.0 mmol), and (4-fluorophenyl)methanamine (3.97 g, 32.0 mmol). The reaction mixture was stirred at ambient temperature for 18 hours and N,N-dimethylformamide was removed in vacuo. The residue was dissolved in ethyl acetate (400 mL) and washed with saturated aqueous sodium bicarbonate (2×100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo to afford the title compound as a yellowish solid in 80% yield (5.60 g): 1H NMR (300 MHz, CDCl3) δ 7.39-7.17 (m, 2H), 7.01 (t, J=8.3 Hz, 2H), 5.78 (br s, 1H), 5.34 (br s, 2H), 4.50 (d, J=5.6 Hz, 2H), 2.47 (s, 3H); MS (ES+) m/z 266.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1B(O)O>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:23]4[S:22][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[CH:24]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Reactant: OB(O)c1cc2ccccc2s1
Product: COc1ccc(-c2nc3cc(-c4cc5ccccc5s4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and benzothiophene-2-boronic acid (153 mg, 0.85 mmol) the subtitle compound was obtained (200 mg, 15%). MS 403.1 m/z (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[CH:22]2.C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[CH3:15][O:14][C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:16][CH3:17])[N:5]=[CH:4][CH:3]=[C:2]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[CH:22]2)=[O:13]
Reactant: COC(=O)c1cc2c(Cl)ccnc2cc1OC
Reactant: Oc1ccc2[nH]ccc2c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2c(Oc3ccc4[nH]ccc4c3)ccnc2cc1OC
Temperature: 130 °C
Reaction time: 5 h
Yield: 29.8 %

Procedure:
After mixing methyl 4-chloro-7-methoxyquinoline-6-carboxylate (described in WO0050405, p. 34, 8.5 g, 33.77 mmol), 5-hydroxyindole (7 g), diisopropylethylamine (8.9 ml) and N-methylpyrrolidone (8.9 ml), the mixture was heated and stirred at 130° C. for 5 hours and then at 150° C. for 8 hours. After standing to cool, the solution was adsorbed onto silica gel and purified with a silica gel column (hexane-ethyl acetate system). Ethanol, diethyl ether and hexane were added to the obtained yellow oil, and crystals precipitated after a period of standing. The crystals were filtered out, washed with diethyl ether and hexane and then dried by aspiration to obtain light yellow crystals (3.506 g, 10.06 mmol, 29.80%).
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:13][C:12]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[N:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.C1CC=CCC=1>CCO.[Pd]>[CH2:28]([N:25]([CH2:26][CH3:27])[C:12]1[N:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][C:10]=2[N:11]=1)[CH3:29]
Reactant: CCN(CC)c1nc2c(c(-c3ccc(F)cc3)n1)CCN(Cc1ccccc1)C2
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: CCN(CC)c1nc2c(c(-c3ccc(F)cc3)n1)CCNC2
Temperature: 85 °C

Procedure:
To a solution of [7-benzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-2-yl]-diethyl-amine (0.052 g, 0.13 mmol) in EtOH (1.5 mL) was added 10 wt % Pd/C and 1,4-cyclohexadiene (0.062 mL, 0.66 mmol). The mixture was heated at 85° C. for 2 h and cooled to rt. The mixture was concentrated and the residue was purified by FCC (2 M NH3/MeOH in CH2Cl2) to afford the title compound. HPLC: Rt=9.7 min. MS (ESI): mass calcd. for C17H21FN4, 300.4; m/z found, 301.4 [M+H]+. 1H NMR (CDCl3): 7.60 (dd, J=8.8, 5.5, 2H), 7.11 (t, J=8.8, 2H), 3.93 (s, 2H), 3.63 (q, J=7.0, 4H), 3.02 (t, J=5.7, 2H), 2.64 (t, J=5.7, 2H), 1.18 (t, J=7.0, 6H).