Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH2:15]1[O:23][C@@H:16]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1OC1C1C=CC=CC=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@@H:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[OH:23])[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: c1ccc([C@@H]2CO2)cc1
Agent: c1ccc(C2CO2)cc1
Solvent: CC#N
Product: COc1ccccc1N1CCN(C[C@H](O)c2ccccc2)CC1
Yield: 11 %

Procedure:
2-Methoxyphenylpiperazine (19.84 g, 0.103 m) in dry acetonitrile (150 ml) was refluxed with (R)-styrene oxide (12.4 g, 0.104 m). The residue on evaporation was chromatographed on silica using ethyl acetate as eluant to give two main fractions. The first fraction (4.3 g) contained some styrene oxide, which was removed by acid-base extraction to give 3.55 g of pure title compound. The second fraction (9.5 g) was 95% title compound and approximately 5% of the regioisomer.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:23])[C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])=[CH:9][CH:8]=2)=[C:4]([CH3:24])[CH:3]=1.[C:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)#[CH:26].CCN(CC)CC>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[S:6][C:2]([CH2:26][CH2:25][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:3][C:4]=2[CH3:24])=[CH:8][CH:9]=1)=[O:23]
Reactant: C#Cc1cccnc1
Reactant: Cc1cc(Br)sc1-c1ccc(NC(=O)c2c(F)cccc2F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(CCc2cccnc2)sc1-c1ccc(NC(=O)c2c(F)cccc2F)cc1

Procedure:
N-(4-(5-bromo-3-methylthiophen-2-yl)phenyl)-2,6-difluorobenzamide (a, 1 mmol), 3-ethynylpyridine (1 mmol), CuI (0.05 mmol), PdCl2(PPh3)2 (0.05 mmol) in THF (6 mL), and Et3N (3 mL) was heated in sealed tube at 100° C. for 1 h. The mixture was filtered through celite and purified by column chromatography to give a white solid (b, 46 mg).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C:9]1[N:10]=[C:11]([NH:14]C(OCC=C)=O)[S:12][CH:13]=1)([OH:8])[CH3:7])(=[O:3])[CH3:2].C(N)CCC.C(O)=O.Cl>C1COCC1>[C:1]([O:4][CH2:5][C:6]([C:9]1[N:10]=[C:11]([NH2:14])[S:12][CH:13]=1)([OH:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)Nc1nc(C(C)(O)COC(C)=O)cs1
Agent: Cl
Solvent: C1CCOC1
Solvent: O=CO
Solvent: CCCCN
Product: CC(=O)OCC(C)(O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
To a solution of 2-(2-{[(allyloxy)carbonyl]amino}-1,3-thiazol-4-yl)-2-hydroxypropyl acetate (790 mg) in THF (10 mL) were added n-butylamine (0.52 mL), formic acid (0.20 mL), and tetrakistriphenylphosphine palladium (33 mg) at room temperature, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added 1 M hydrochloric acid (30 mL) at room temperature, followed by extraction with ethyl acetate. The aqueous layer was adjusted to pH 9 using saturated aqueous sodium bicarbonate, followed by extraction with a solvent (ethyl acetate:isopropyl alcohol=3:1, 100 mL×3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration, 2-(2-amino-1,3-thiazol-4-yl)-2-hydroxypropyl acetate (261 mg) was obtained as a pale yellow oily substance. The obtained pale yellow oily substance was subjected to optical resolution with chiral column chromatography (Product Name: Chiralcel OJ-H, hexane:ethanol:diethylamine=30:70:0.1) to obtain optical active products of 2-(2-amino-1,3-thiazol-4-yl)-2-hydroxypropyl acetate at a first peak and a second peak in yields of 37% and 25%, respectively (>95% ee) (absolute arrangement was not determined).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][N:20]=[C:6]2[CH2:7][CH2:8][CH:3]([N:2]([CH3:10])[CH3:1])[CH2:4][CH2:5]2)=[CH:15][CH:14]=1
Reactant: CN(C)C1CCC(=O)CC1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCO
Product: CN(C)C1CCC(=NNc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.7 %

Procedure:
To a mixture of 6.0 gm (42.0 mMol) 4-dimethylaminocyclohexanone and 9.5 gm (42.0 mMol) 4-bromophenylhydrazine hydrochloride in 100 mL ethanol were added 3.4 mL (42 mMol) pyridine. The resultant mixture was then heated at reflux for 2 hours and then stirred at ambient temperature for 18 hours. The reaction mixture was then treated with aqueous potassium carbonate and extracted well with dichloromethane. The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The resultant residue was treated with toluene and concentrated again under reduced pressure to give 11.3 gm (87%) of the desired compound.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH2:10]([O:9][C:7](=[O:8])[C:6](=[CH:14][N:15]([CH3:17])[CH3:16])[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH3:11]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: COC(OC)N(C)C
Product: CCOC(=O)C(=CN(C)C)C(=O)C(C)C
Yield: 50 %

Procedure:
A mixture of ethyl isobutyrylacetate (15 mmol, 0.42 mL) and N,N-dimethylformamide dimethyl acetal (37.5 mmol, 5 mL) was heated to reflux for 16 hours, then cooled. The volatiles were removed in vacuo to give 1.60 g of 2-dimethylaminomethylene-4-methyl-3-oxo-pentanoic acid ethyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:23]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[C:8]([NH:10][S:11]([C:14]2[C:19]3=[N:20][S:21][N:22]=[C:18]3[CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:9]=1)([O-])=O.O>CCOC(C)=O.C(Cl)Cl.Cl[Sn]Cl>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:23]([N:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[O:24])=[C:8]([NH:10][S:11]([C:14]2[C:19]3=[N:20][S:21][N:22]=[C:18]3[CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:9]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1NS(=O)(=O)c1cccc2nsnc12)N1CCCCC1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: Nc1ccc(C(=O)N2CCCCC2)c(NS(=O)(=O)c2cccc3nsnc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A solution of benzo[1,2,5]thiadiazole-4-sulfonic acid [5-nitro-2-(piperidine-1-carbonyl)-phenyl]-amide (EXAMPLE 2; 90 mg, 2.0 mmol) was dissolved in 1:1 EtOAc/DCM (10 mL), and SnCl2.2 H2O (2.3 g, 10 mmol) was added. The mixture was stirred overnight at ambient temperature then concentrated in vacuo. The resulting oil was suspended in DCM and neutralized by shaking with aqueous NaHCO3. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford the title compound (69 mg, 1.7 mmol, 82%). TLC (silica gel, 3:1 EtOAc/hexanes): Rf=0.42. MS (ESI): m/z 418 [M+H]+, 440 [M+Na]+. HPLC (reversed-phase): RT=8.15 min (single peak). 1H NMR (400 MHz, CDCl3): (rotameric broadening) 9.80 (s, 1H), 8.40 (m, 2H), (dd, J=8.8 Hz, 1.0 Hz, 1H), 8.15 (dd, J=7.0 Hz, 1.0 Hz, 1H), 7.82 (dd, J=8.8 Hz, 1.0 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 6.74 (d, J=2.2 Hz, 1H), 6.19 (dd, J=8.4 Hz, 2.3 Hz, 1H), 5.75 (d, J=2.3 Hz, 2H), 2.96 (bs, 4H), 1.45 (bs, 2H), 1.24 (bs, 4H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])[CH3:3].C(N(CC)CC)C.[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH:8][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][NH:24][C:22]([O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:23])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Reactant: CCOC(=O)CCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)CCCCNC(=O)OC(C)(C)C
Yield: 59 %

Procedure:
To a suspension of 7.68 g of β-alanine ethyl ester hydrochloride in 50 ml of methylene chloride there was added, with stirring, 5.56 g of triethyl- amine. 10.86 g of N-t-butoxycarbonyl-5-aminovaleric acid, dissolved in 50 ml of methylene chloride, and portionwise 11.35 g of DCC, in that order. After completion of the addition, the reaction mixture was stirred at room temperature overnight and filtered off from separated urea. The filtrate was washed in succession with 250 ml of sodium bicarbonate solution (5%), water, 250 ml of 0.1M citric acid and, finally, with saturated sodium chloride solution. Thereafter, the solvent was evaporated under reduced pressure and the oily residue was purified by column chromatography on silica gel, to obtain N-[5-(1-t-butoxyformamido)valeryl]-β-alanine ethyl ester in 59% yield, melting point 28° (from hexane).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH:15](NC(=O)OCC)[NH:16][C:17](=[O:21])OCC)=[CH:11][CH:10]=1)#[N:8]>C1C=CC=CC=1>[Cl:2][CH:15]([N:16]=[C:17]=[O:21])[C:12]1[CH:13]=[CH:14][C:9]([C:7]#[N:8])=[CH:10][CH:11]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOC(=O)NC(NC(=O)OCC)c1ccc(C#N)cc1
Solvent: c1ccccc1
Product: N#Cc1ccc(C(Cl)N=C=O)cc1

Procedure:
Phosphorous pentachloride (83.3 g, 400 mmol) is added to a suspension of diethyl (4-cyanophenyl)methylenedicarbamate (intermediate 1, 53.0 g, 182 mmol) in benzene (200 mL) and the mixture is heated at reflux for 2 h. The benzene is evaporated and the mixture is then purified by distillation under reduced pressure. The first fraction (ca. 40° C., ca. 0.01 mbar) is discarded. The second fraction (ca. 110° C., ca. 0.6 mbar) is collected. Yield: 28.4 g; ESI mass spectrum: [M+MeOH—HCl+1-1]+=189; Retention time HPLC: it) 0.65 min (Z003—004).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[C:19]([F:26])[C:15]=1[C:16](Cl)=[O:17]>C(#N)C.CC(C)=O>[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[C:19]([F:26])[C:15]=1[C:16]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12])=[O:17]
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1F
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Solvent: CC#N
Solvent: CC(C)=O
Product: O=C(Nc1cc(Cl)c([N+](=O)[O-])cc1O)c1c(F)c(F)c(F)c(F)c1F
Yield: 84.9 %

Procedure:
In 100 ml of acetonitrile was dispersed 18.9 g (0.10 mole) of 2-amino-4-chloro-5-nitrophenol and a solution of 23.1 g (0.10 mole) of 2,3,4,5,6-pentafluorobenzoyl chloride in 50 ml of acetone was added dropwide to the resultant dispersion. After heating under reflux for 3 hours, the reaction mixture was ice-cooled and the precipitated solids were collected by filtration, washed with cooled acetonitrile and dried to obtain 32.5 g of 2-(2,3,4,5,6-pentafluorobenzamido)-4-chloro-5-nitrophenol (Yield 85%).
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13]([F:19])=[C:12]([O:20][CH2:21][CH3:22])[CH:11]=1)(C)C)(C)(C)C>CO>[CH2:21]([O:20][C:12]1[CH:11]=[C:10]([CH2:9][OH:8])[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13]=1[F:19])[CH3:22]
Reactant: CCOc1cc(CO[Si](C)(C)C(C)(C)C)cc(OCC)c1F
Solvent: CO
Product: CCOc1cc(CO)cc(OCC)c1F
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of tert-butyl-(3,5-diethoxy-4-fluoro-benzyloxy)-dimethyl-silane (1.20 g, 3.65 mmol, 1.0 equiv) in methanol (8 mL) was added Dowex 50W-X8 (0.33 g, cation exchange resin) and the reaction mixture stirred under Ar at rt for 22 h. The resin was removed by filtration and the reaction mixture concentrated by evaporation under reduced pressure yielding the title compound in quantitative yield (0.78 g). 1H NMR (400 MHz, CDCl3): δ 1.34 (t, J=7.0 Hz, 6H), 1.57 (t, J=5.4 Hz, 1H), 4.01 (q, J=7.0 Hz, 4H), 4.51 (d, J=5.4 Hz, 2H), 6.51 (d, J=6.8 Hz, 2H). MS (EI): 214.2 [M]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:21])[C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:6]=2[N:7]=1.[CH2:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)[CH3:23]>>[CH2:22]([N:24]1[CH2:25][CH2:26][N:27]([C:30]2[N:35]=[CH:34][C:33]([NH:36][C:2]3[N:3]=[C:4]([NH2:21])[C:5]4[S:10][CH:9]=[C:8]([C:11]5[CH:12]=[N:13][C:14]6[C:19]([CH:20]=5)=[CH:18][CH:17]=[CH:16][CH:15]=6)[C:6]=4[N:7]=3)=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)[CH3:23]
Reactant: CCN1CCN(c2ccc(N)cn2)CC1
Reactant: Nc1nc(Cl)nc2c(-c3cnc4ccccc4c3)csc12
Product: CCN1CCN(c2ccc(Nc3nc(N)c4scc(-c5cnc6ccccc6c5)c4n3)cn2)CC1
Yield: 68 %

Procedure:
The target compound of Example 30 (21 mg, 68% yield) was prepared in the same manner as Step 9 of Example 1 using 2-chloro-7-(quinolin-3-yl)thieno[3,2-d]pyrimidin-4-amine (20 mg, 0.064 mmol) and 6-(4-ethylpiperazin-1-yl)pyridin-3-amine (20 mg, 0.096 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][C:13]=1[S:21](=[O:24])(=[O:23])[NH2:22].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O.O>[NH2:22][S:21]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:12]=1[Cl:11])[C:16]([NH:10][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:9])=[O:17])(=[O:24])=[O:23]
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Reactant: C[C@@H](N)c1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.7 %

Procedure:
To a solution of (R)-1-(3-chlorophenyl)ethanamine (0.426 g, 2.74 mmol) and 4-chloro-3-sulfamoylbenzoic acid 37 (0.452 g, 1.92 mmol) in DMF (5 mL) at room temperature was added EDCI (0.439 g, 2.29 mmol) and HOBT (0.368 g, 2.40 mmol). The reaction mixture was stirred at room temperature for 16 h, and diluted with EtOAc and water. The organic phase was washed with water (2×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 50% to 80% EtOAc in hexanes) yielded 3-(aminosulfonyl)-4-chloro-N-((1R)-1-(3-chlorophenyl)ethyl)benzamide 38 (0.643 g, 89.8% yield) as a white solid. Mass spectrum: calculated for C15H14Cl2N2O3S 372.0. found 373.1 (M++1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].F[C:9](F)(F)[C:10](O)=[O:11].[NH2:15][CH2:16][C:17]1[CH:18]=[C:19]([C:36]2[C:37]([CH3:42])=[N:38][O:39][C:40]=2[CH3:41])[C:20]2[O:25][CH2:24][C@H:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[N:22]3[C:32](=[O:35])[NH:33][C:34]=1[C:21]=23.C(N(CC)C(C)C)(C)C.C(Cl)(=O)C>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:42][C:37]1[C:36]([C:19]2[C:20]3[O:25][CH2:24][C@H:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[N:22]4[C:32](=[O:35])[NH:33][C:34]([C:21]=34)=[C:17]([CH2:16][NH:15][C:10](=[O:11])[CH3:9])[CH:18]=2)=[C:40]([CH3:41])[O:39][N:38]=1
Reactant: Cc1noc(C)c1-c1cc(CN)c2[nH]c(=O)n3c2c1OC[C@@H]3c1ccccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Product: CC(=O)NCc1cc(-c2c(C)noc2C)c2c3c1[nH]c(=O)n3[C@@H](c1ccccn1)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
A solution of (4S)-9-(aminomethyl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one bis(trifluoroacetate) (10.0 mg, 0.0265 mmol) in methylene chloride (1.00 mL) was treated with N,N-diisopropylethylamine (13.8 μL, 0.0795 mmol) followed by acetyl chloride (2.26 μL, 0.0318 mmol) and stirred at room temperature for 1 h. The reaction mixture was concentrated to give a crude residue. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at a flow rate of 60 mL/min) gave the desired product (9 mg, 81%) as a single enantiomer. 1H NMR (500 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.52 (d, J=4.1 Hz, 1H), 8.31 (dd, J=5.7, 5.7 Hz, 1H), 7.79 (ddd, J=7.7, 7.7, 1.8 Hz, 1H), 7.41-7.27 (m, 1H), 7.14 (d, J=7.9 Hz, 1H), 6.70 (s, 1H), 5.53 (dd, J=2.4, 2.4 Hz, 1H), 4.76 (dd, J=11.5, 2.0 Hz, 1H), 4.41 (dd, J=11.5, 3.1 Hz, 1H), 4.32 (d, J=5.8 Hz, 2H), 2.22 (s, 3H), 2.05 (s, 3H), 1.87 (s, 3H); LCMS calculated for C22H22N5O4 (M+H)+: m/z=420.2. found: 420.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH:20]([OH:21])[CH2:19][NH:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.Cl[C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([O:44][CH3:45])[CH:42]=2)[N:37]=[CH:36][N:35]=1.ClC1C2C(=CC=C(OC)C=2)N=C(C)N=1>CO.CCOC(C)=O.CCOCC.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C@@H:16]3[C@@H:20]([OH:21])[CH2:19][N:18]([C:34]4[C:43]5[C:38](=[CH:39][CH:40]=[C:41]([O:44][CH3:45])[CH:42]=5)[N:37]=[CH:36][N:35]=4)[CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc2ncnc(Cl)c2c1
Reactant: O=C(c1ccc(Cl)cc1)N1CCN(C2CNCC2O)CC1
Agent: COc1ccc2nc(C)nc(Cl)c2c1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2ncnc(N3C[C@H](O)[C@@H](N4CCN(C(=O)c5ccc(Cl)cc5)CC4)C3)c2c1
Reaction time: 2.5 h
Yield: 50 %

Procedure:
To 0.326 mmoles of (4-Chloro-phenyl)-[4-(4-hydroxy-pyrrolidin-3-yl)-piperazin-1-yl]-methanone (synthesis described above in Example 5), add 1.6 mL acetonitrile and 1.6 mmoles of DBU. The stirred solution was cooled in ice and then 0.358 mmoles of 4-chloro-6-methoxy-quinazoline was added and the reaction mixture was allowed to stir for a period of 2.5 hours. To 0.326 mmoles of (4-Chloro-phenyl)-[4-(4-hydroxy-pyrrolidin-3-yl)-piperazin-1-yl]-methanone, add 1.6 mL acetonitrile and 1.63 mmoles of DBU. The stirred solution was cooled in ice and then 0.358 mmoles of 4-chloro-6-methoxy-2-methyl-quinazoline (from Step 2 above) was added and the reaction mixture was allowed to stir for a period of 2.5 hours. For the reaction workup, the reaction mixture was diluted with methanol and concentrated on the rotavap. To the concentrate about 30 mL of water was added and was extracted with 40 mL EtOAc. The organic layer was separated and washed with 30 mL of 1M aq K2CO3 solution, and brine, dried over MgSO4 and excess solvent was removed on rotavap to yield a crude oil. This was diluted with about 2 mL EtOAc and about 8 mL ether was added and the white solid obtained was filtered off and vacuum dried to give the title compound in 50% yield. LC-MS: m/z=468 (M++1).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:13][O:12][C:5]2([CH2:11][CH2:10][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3]1.[CH2:15]([NH2:18])[CH2:16][CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH3:1][C:2]1([CH3:14])[CH2:13][O:12][C:5]2([CH2:11][CH2:10][C:8](=[N:18][CH2:15][CH2:16][CH3:17])[CH2:7][CH2:6]2)[O:4][CH2:3]1
Reactant: CCCN
Reactant: CC1(C)COC2(CCC(=O)CC2)OC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCN=C1CCC2(CC1)OCC(C)(C)CO2

Procedure:
A 500 ml round bottom flask was charged with 20.32 g (0.103 mol) of 3,3-dimethyl-1,5-dioxazpiro[5.5]undecan-9-one (also known as 1,4-cyclohexanedione mono-2,2-dimethyltrimethylene ketal, from Aldrich Chemical Company, Milwaukee, Wis.), 21.6 g (0.365 mol) of n-propylamine (Eastman Chemical Company, Rochester, N.Y.), 0.01 g of p-toluenesulfonic acid and 100 ml of toluene. The reaction mixture was refluxed for 24 hours with a water separator charged with 16 g of 3-A molecular sieves. The volatiles were removed in vacuo and the residue was held for further synthetic modifications as described below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20](O)=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:24][O:25]/[N:26]=[C:27]1/[C@@H:28]([NH2:33])[CH2:29][CH2:30][CH2:31][CH2:32]/1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:24][O:25]/[N:26]=[C:27]1/[C@@H:28]([NH:33][C:20]([C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)=[O:21])[CH2:29][CH2:30][CH2:31][CH2:32]/1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Reactant: CO/N=C1\CCCC[C@@H]1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CO/N=C1\CCCC[C@@H]1NC(=O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.5 %

Procedure:
To a solution of 0.050 g 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid in 2.0 ml dimethylformamide was added 0.030 g (S)-2-amino-cyclohexanone-(E)-O-methyl-oxime hydrochloride, 0.053 g TBTU and 0.097 g N,N-diisopropyl ethyl amine and the mixture was stirred at room temperature for 16 h. The solvent was evaporated under high vacuum and the residue was purified by chromatography on silica gel with a gradient of heptane to ethyl acetate to yield 0.045 g of the title compound as colorless oil. MS (EI): 465.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:12]C.[CH3:14][Li].Cl>O1CCCC1.C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:14])[CH2:6][C:5]2=[O:12]
Reactant: [Li]C
Reactant: COc1ccnc2ccc(F)cc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1CC(=O)c2cc(F)ccc2N1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
A stirred solution of 25.8 g (0.146 mole) of 6-fluoro-4-methoxyquinoline from example 3 in 300 ml of tetrahydrofuran was heated under a nitrogen atmosphere to its reflux temperature and then cooled to -20° C. To the cold solution was added 90 ml of 182 M methyl lithium in diethyl ether over a period of 0.5 hour. After adding 40 ml of the solution, the reaction temperature was allowed to rise to 0° C. After the addition of methyl lithium was completed, the reaction temperature was allowed to rise to 15° C. The solution was then poured into 1200 ml of a mixture of ice water and hydrochloric acid. After stirring for 0.5 hour the mixture was extracted with about 1200 ml of diethyl ether. The organic layer was dried, filtered and evaporated in vacuo to provide a yellow solid. The product was recrystallized from carbon tetrachloride to give 9.5 g. (37% yield) of 6-fluoro-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([F:23])[CH:22]=1>>[F:16][C:17]1[CH:18]=[C:19]([C:2]2[CH:3]=[CH:4][C:5]3[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:14])([CH3:13])[C:6]=3[CH:15]=2)[CH:20]=[C:21]([F:23])[CH:22]=1
Reactant: CC1(C)OCC(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1cc(F)cc(F)c1
Product: CC1(C)OCC(=O)Nc2ccc(-c3cc(F)cc(F)c3)cc21

Procedure:
Prepared from 7-bromo-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3,5-difluorobenzene boronic acid generally according to the coupling procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.04 (s, 1H), 7.61-7.57 (m, 2H), 7.52-7.45 (m, 2H), 7.23-7.17 (m, 2H), 4.72 (s, 2H), 1.60 (s, 6H); MS (FI) m/z 304 [M+H]+.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:10][C:11]=1[CH3:12])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[OH:3][CH2:4][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:10][C:11]=1[CH3:12]
Reactant: CCOC(=O)Cc1nc(-c2ccccc2)[nH]c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1[nH]c(-c2ccccc2)nc1CCO
Reaction time: 8 h

Procedure:
A solution of 4-ethoxycarbonylmethyl-5-methyl-2-phenylimidazole (19.7 g) in tetrahydrofuran (100 ml) was added dropwise (in 45 min) to lithium aluminium hydride (10 g) in tetrahydrofuran (150 ml). After 2 h refluxing the reaction mixture was allowed to stand overnight at r.t. It was cooled in an ice bath and water (40 ml) and tetrahydrofuran (50 ml) were added. The solids were filtered off and washed with diethylether.