Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:18]=[C:19]3[C:27]4[C:26](Cl)=[N:25][CH:24]=[N:23][C:22]=4[NH:21][C:20]3=[O:29])=[C:15]([CH3:17])[CH:16]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:18]=[C:19]3[C:27]4[C:26]([N:34]5[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]5)=[N:25][CH:24]=[N:23][C:22]=4[NH:21][C:20]3=[O:29])=[C:15]([CH3:17])[CH:16]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CN1CCNCC1
Reactant: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=C1C(=O)Nc2ncnc(Cl)c21
Product: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=C1C(=O)Nc2ncnc(N3CCN(C)CC3)c21
Yield: 47 %

Procedure:
The title compound (47% yield) was prepared from 5-(4-chloro-6-oxo-6,7-dihydro-pyrrolo[2,3-d]pyrimidin-5-ylidenemethyl)-4-methyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide and 1-methylpiperazine according to the procedure described for Example 14. 1H NMR (300 MHz, DMSO-d6) δ 13.37 (br s, 1H, NH), 11.83 (br s, 1H, NH), 10.56 (v br s, 1H), 8.45 (v br s, 1H), 8.38 (s, 1H, H-vinyl), 7.09 (s, 1H), 6.87 (s, 1H), 3.4-3.6 (m, 10H, 5×CH2), 2.85 (m, 4H, 2×CH2), 2.4-2.6 (m, 6H, 3×CH2), 2.49 (under DMSO, 3H, CH3), 2.31 (s, 3H, CH3). MS 481.3 [M++1].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:23])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH3:22])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:5][CH:4]=1.[C:30](Cl)(=[O:32])[CH3:31]>>[C:30]([N:21]([CH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]([NH:12][C:10]2[S:11][C:7]3[C:6]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:23])=[CH:19][CH:18]=1)[CH3:22])(=[O:32])[CH3:31]
Reactant: CNCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Reactant: CC(=O)Cl
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN(C)C(C)=O)cc3)nc12

Procedure:
Using N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-methylaminomethyl-benzamide and acetyl chloride, the title compound was prepared as white crystals (77% yield). MS: m/e=455(M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[CH2:17][C:18]([OH:24])([CH3:23])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([OH:25])[CH2:12][C:11]1=[O:26]>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14]([CH2:15][CH2:16][CH2:17][C:18]([OH:24])([CH3:23])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([OH:25])[CH2:12][C:11]1=[O:26]
Reactant: CCCCC(C)(O)C/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC
Agent: [Pd]
Solvent: CCO
Product: CCCCC(C)(O)CCC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC
Reaction time: 0.4 h
Yield: 85.5 %

Procedure:
(±) methyl-11α,16-dihydroxy-16-methyl-9-oxoprost13E-en-1-oate (100mg) in 15 ml of ethanol containing 100 mg of 4% palladium on carbon is hydrogenated at room temperature and atmospheric pressure for 24 minutes. The solution is filtered and evaporated. The residue is chromatographed on silica gel (60% ethyl acetate/40% hexane as eluent) to give 86 mg of desired product as a viscous oil. 1H NMR (CDCl3): ∂0.93 (t, C.20CH3); 1.18 (d,C.16CH3 3.68 (s, OCH3); 4.17 (q C.11 H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:41]1([O:50]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.NO>CN(C)C=O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[CH2:11][C:12]([NH:41][OH:50])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCOC(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 14.6 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[4-(ethoxycarbonyl)-1,3-oxazol-2-yl]hexanoic acid (Preparation 63) (130 mg, 0.39 mmol) and N,N-diisopropylethylamine (67 μl, 0.39 mmol) in N,N-dimethylformamide (6 ml) was treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (220 mg, 0.58 mmol) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 45 minutes. Further N,N-diisopropylethylamine (270 μl, 1.54 mmol) was then added, followed by hydroxylamine hydrochloride (80 mg, 1.16 mmol) and the mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and pH 7 aqueous buffer. The organic layer was separated, washed sequentially with water and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (99:1) gradually changing to dichloromethane:methanol (98:2) to afford the title compound (20 mg).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N:12]([C@@H:15]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:16]([OH:19])[CH2:17][OH:18])=[N+:13]=[N-:14]>CN(C)C1C=CN=CC=1.ClCCl.N1C=CC=CC=1>[N:12]([C@@H:15]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:16]([OH:19])[CH2:17][O:18][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=N[C@@H](Cc1ccccc1)[C@H](O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](Cc2ccccc2)N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.4 %

Procedure:
1.05 g (5.5 mmol) of p-toluenesulphonyl chloride were added to a solution of 0.95 g (4.6 mmol) of 3(S)-azido-4-phenyl-1,2(S)-butanediol and 30 mg of 4-dimethylaminopyridine in a mixture of 30 ml of dichloromethane and 5 ml of pyridine. The resulting solution was stirred at room temperature for 48 hours. The solvents were removed under reduced pressure and the oily residue was partitioned between water and ethyl acetate. The aqueous phase was back-extracted twice with ethyl acetate. The organic phases were combined, washed with 10% aqueous sulphuric acid and with sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated to dryness. Purification of the crude product by flash chromatography on silica gel using n-hexane/ethyl acetate (3:1) for the elution gave 1.37 g of 3(S)-azido-4-phenyl-1-(p-toluenesulphonyloxy)-2(S)-butanol in the form of a viscous oil: MS: m/e 362 [M+H]+.
Reaction SMILES: Br/[CH:2]=[CH:3]/[C:4]([CH3:16])([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)[CH3:5].CC(C)([O-])C.[K+].O>C(O)(C)(C)C>[CH3:16][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:15])[F:14])=[CH:8][CH:7]=1)([CH3:5])[C:3]#[CH:2]
Reactant: CC(C)(/C=C/Br)c1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: C#CC(C)(C)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere, a stirred solution of 40.9 grams (0.14 mole) of cis/trans-1-bromo-3-methyl-3-(4-trifluoromethylphenyl)-1-butene and 47.0 grams (0.42 mole) of potassium tert-butoxide in 300 mL of tert.butanol was heated at reflux for about three hours. After this time the reaction mixture was allowed to cool to ambient temperature as it stirred for about 18 hours. The reaction mixture was then poured into 300 mL of water and extracted with one 200 mL portion of diethyl ether. The extract was dried with magnesium sulfate, filtered, and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel using petroleum ether as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 25.2 grams of 3-methyl-3-(4-trifluoromethylphenyl)-1-butyne. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.[C:16]([CH2:18][C:19](OCC)=O)#[N:17]>>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[C:19]([CH2:18][C:16]#[N:17])[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1
Reactant: Nc1cnc(Br)cc1Nc1ccccc1
Reactant: CCOC(=O)CC#N
Product: N#CCc1nc2cnc(Br)cc2n1-c1ccccc1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
The product from Step 4 (2.1 g, 7.95 mmol) and ethyl cyanoacetate (3.6 g, 31 mmol) were heated together at 195° C. in a sealed tube for 54 minutes. After cooling to room temperature, the product crystallized and the crystals were collected and washed with ethanol to give the title compound (0.87 g, 35%). MS (ES+) m/e 313/315 [M+H]+.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH:7]([CH:9]1[C:13]2([CH2:15][CH2:14]2)[NH:12][C:11](=[O:16])[CH2:10]1)=C>CO.O.[Os](=O)(=O)(=O)=O>[O:16]=[C:11]1[CH2:10][CH:9]([CH:7]=[O:2])[C:13]2([CH2:15][CH2:14]2)[NH:12]1
Reactant: C=CC1CC(=O)NC12CC2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=CC1CC(=O)NC12CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Osmium tetroxide (55 mg, 0.22 mmol) and sodium periodate (1.4 g, 6.6 mmol) were added in portions to a solution of 7-ethenyl-4-azaspiro[2.4]heptan-5-one (0.50 g, 3.3 mmol) in methanol (8 mL) and water (12 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered and the filtrate was dried under reduced pressure to afford 5-oxo-4-azaspiro[2.4]heptane-7-carbaldehyde. The material was used in the next step without purification. MS ESI calc'd. for C7H10NO2 [M+H]+ 140. found 140.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](Cl)=[O:12])[C:6]=1[CH3:14])(=[O:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(C)=O>Cl[Pd]Cl.O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:12])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:6]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1C
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Oc1cccc(C(=O)c2ccccc2)c1C
Yield: 64.3 %

Procedure:
A mixture of 3-(chlorocarbonyl)-2-methylphenyl acetate (10.0 g, 47.0 mmole), PdCl2 (83.4 mg, 0.470 mmole), Na2CO3 (8.13 g, 76.7 mmole) and phenyl boronic acid (6.02 g, 49.4 mmole) in a 3:1 acetone:H2O mixture (300 mL) was stirred at room temperature for 5 days. The acetone was removed in vacuo and the aqueous mixture was extracted with EtOAc (2×200 mL). The combined extracts were washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo to give 7.68 g (64% yield) of the product as a white crystalline solid: E1HRMS m/z 254.0939 (M+, C16H14O3, Calc'd 254.0943).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH2:19][O:20][CH2:21][CH3:22]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH2:19][O:20][CH2:21][CH3:22])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCOCCBr
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 94.9 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg) in N,N-dimethylformamide (4.5 mL) was added cesium carbonate (1324 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. 1-Bromo-2-ethoxyethane (1016 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 14 hrs. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (120 mL×3). The organic layer was washed with saturated brine (100 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=85/15→20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (697 mg) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[CH2:12]([O:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH3:13].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:12]([O:14][C:15](=[O:19])[CH:16]=[C:17]([O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[CH3:18])[CH3:13]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CC#CC(=O)OCC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C=C(C)Oc1cccc(C(F)(F)F)c1
Temperature: 130 °C
Yield: 53.3 %

Procedure:
A mixture of 3-trifluoromethyl-phenol (1.09 mL, 8.96 mmol) and ethyl-2-butynoate (2.0 g, 17.83 mmol) in tetrahydrofuran (14 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.4 mL, 9.37 mmol). The reaction was then heated at 130° C. for 2 h. At this time, the reaction was concentrated in vacuo. The residue dissolved in dichloromethane (100 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a 1N aqueous sodium hydroxide solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were then dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 1-10% ethyl acetate/hexanes) afforded 3-(3-trifluoromethyl-phenoxy)-but-2-enoic acid ethyl ester (1.31 g, 53%) as a clear, colorless oil: HR-ES-MS m/z calculated for C13H13O3F3 [M+H]+ 275.0890, observed 275.0889; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (t, J=7.1 Hz, 3H), 2.45 (s, 3H), 4.01 (q, J=7.1 Hz, 2H), 4.68 (s, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.57 (br. s., 1H), 7.66-7.75 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:19]2[C:18](=O)[CH2:17][CH2:16][CH2:15][C:14]=2[NH:13][CH:12]=1)=[O:10].N1C=CC=CC=1.Cl.[O:28]([NH2:30])[CH3:29]>CCO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:19]2[C:18](=[N:30][O:28][CH3:29])[CH2:17][CH2:16][CH2:15][C:14]=2[NH:13][CH:12]=1)=[O:10]
Reactant: O=C(Nc1ccccc1F)c1c[nH]c2c1C(=O)CCC2
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C1CCCc2[nH]cc(C(=O)Nc3ccccc3F)c21
Temperature: 120 °C
Yield: 72.7 %

Procedure:
4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (2-fluoro-phenyl)-amide (0.73 mmol), pyridine (2.2 mmol), EtOH (10 ml) and methoxylamine hydrochloride (2.2 mmol) are combined in a sealed tube and heated at 120° C. for 16 hours. The reaction mixture is cooled to room temperature, the solvent is removed in vacuo and the residue is treated with 10 ml of H2O for 5 minutes. The resulting solid is collected by vacuum filtration to yield 160 mg (72%) of 4-methoxyimino-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (2-fluoro-phenyl)-amide as a white solid. 1H NMR (DMSO-d6) δ1.80-1.86 (m, 2H), 2.62-2.73 (m, 4H), 3.81 (s, 3H), 7.10-7.29 (m, 3H), 7.48 (d, 1H), 8.01 (t, 1H), 11.70 (s, 1H), 11.81 (s, 1H).
Reaction SMILES: [CH2:1]([NH:7][C:8]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[C:25](=O)([O:27]CC)[NH2:26]>C(Cl)(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[CH2:1]([N:7]1[C:8]2[C:9](=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:26][C:25]1=[O:27])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1NCC1CCCO1
Reactant: CCOC(N)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: O=c1nc(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1CC1CCCO1
Temperature: 190 °C

Procedure:
A mixture of 1.63 g of 2-tetrahydrofurfurylamino-5-nitrobenzophenone, 3.0 g of ethyl carbamate and 0.2 g of zinc chloride was heated at 190° C. (oil bath temperature) for 2 hours. After cooling, the reaction mixture was dissolved in chloroform and the insoluble material was filtered off. The chloroform solution was washed successively with dilute hydrochloric acid and water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was washed with ether. The insoluble product was collected by filtration and dried to give 1-tetrahydrofurfuryl-4-phenyl-6-nitro-2(1H)-quinazolinone, m.p. 150°-152° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:10]1([CH3:15])[O:14][CH2:13][CH2:12][O:11]1)[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5].[F:16][C:17]1[CH:27]=[CH:26][CH:25]=[C:19]2[C:20]([O:22][C:23](=O)[C:18]=12)=[O:21]>C(Cl)(Cl)Cl>[F:16][C:17]1[CH:27]=[CH:26][CH:25]=[C:19]2[C:18]=1[C:23](=[O:22])[N:1]([CH2:2][CH:3]([C:10]1([CH3:15])[O:11][CH2:12][CH2:13][O:14]1)[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])[C:20]2=[O:21]
Reactant: C=CCOC(=O)C(CN)C1(C)OCCO1
Reactant: O=C1OC(=O)c2c(F)cccc21
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)C(CN1C(=O)c2cccc(F)c2C1=O)C1(C)OCCO1
Temperature: 80 °C
Yield: 51.9 %

Procedure:
Allyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (400 mg, 1.86 mmol) was dissolved in 10 mL of chloroform, and 3-fluorophthalic anhydride (401 mg, 2.42 mol) was added to the obtained solution. The resulting mixture was then refluxed at 80° C. for 3 days after adding. After the reaction was completed, the solvent was evaporated by distilling under a reduced pressure. The residue was purified by performing column chromatography (eluent: n-hexane/ethyl acetate=3/1) to obtain the desired product as a white solid (351 mg, 52%). Rf=0.29 (eluent: n-hexane/ethyl acetate=2/1)
Reaction SMILES: Br[C:2]1[C:3]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:30])=[N:4][O:5][C:6]=1[C:7]1[CH:8]=[N:9][N:10]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11]=1[C:12]([F:15])([F:14])[F:13].[O:31]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[Cl:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[C:3]1[C:2]([C:33]2[CH:34]=[CH:35][O:31][CH:32]=2)=[C:6]([C:7]2[CH:8]=[N:9][N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:11]=2[C:12]([F:15])([F:14])[F:13])[O:5][N:4]=1
Reactant: Fc1cccc(-n2ncc(-c3onc(-c4c(F)cccc4Cl)c3Br)c2C(F)(F)F)c1
Reactant: OB(O)c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: Fc1cccc(-n2ncc(-c3onc(-c4c(F)cccc4Cl)c3-c3ccoc3)c2C(F)(F)F)c1
Temperature: 100 °C
Yield: 16.9 %

Procedure:
The tube was charged with 4-bromo-3-(2-chloro-6-fluorophenyl)-5-(1-(3-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole (30 mg, 0.06 mmol), tetrakis(triphenylphosphine)palladium(0) (0.010 g), 1.5 mL 1,2-Dimethoxyethane and was purged with argon. Then furan-3-ylboronic acid (0.012 g, 0.1 mmol) and an aqueous solution of cesium carbonate (0.05 g in 0.2 mL) were added. The reaction mixture was heated under microwave irradiation to 100° C. for 2 h. The solvent was evaporated and the product was isolated by column chromatography (hexane:ethyl acetate 25: I) to obtain 5 mg (17%) of a yellowish solid of example I-13. As a major side reaction, hydrodebromination was observed.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CSc1ccc(C2=C(Br)CCC2)cc1
Product: CSc1ccc(C2=C(c3ccc(C(F)(F)F)cc3)CCC2)cc1
Yield: 80.6 %

Procedure:
Following the synthetic procedure outlined in Step 3 of Example 1, 240 mg (0.89 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methylthio)benzene (Example 1, Step 2) was reacted with 360 mg (1.8 mmol) of 4-trifluoromethylphenylboronic acid (Step 1). Purification by silica gel chromatography (MPLC) with hexane gave 240 mg (81%) of 1-[2-(4-trifluoromethylphenyl)cyclopenten-1-yl]-4-(methylthio)benzene as a colorless solid: mp 60.0°-61.5° C.; NMR (CDCl3) δ2.06 (m, J=7 Hz, 2H), 2.46 (s, 3H), 2.89 (t, J=7 Hz, 4H), 7.06 (d, J=6 Hz, 2H), 7.10 (d, J=6 Hz, 2H), 7.27 (d, J=8 Hz, 2H), 7.46 (d, J=8 Hz, 2H).
Reaction SMILES: N1C=CC=CC=1S[C:8](=[O:17])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH:18]1([Mg]Br)[CH2:22][CH2:21][CH2:20][CH2:19]1.CCOCC>C1COCC1>[CH:11]1([CH2:10][CH2:9][C:8]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: Br[Mg]C1CCCC1
Reactant: O=C(CCC1CCCCC1)Sc1ccccn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(CCC1CCCCC1)C1CCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
3-Cyclohexyl-thiopropionic acid S-pyridin-2-yl ester (1.43 g, 5.74 mmol) from Step 1 above was dissolved in dry THF (28 mL) and cooled to −78° C. A solution of cyclopentylmagnesium bromide in Et2O (2.0 M, 3.01 mL, 6.02 mmol) was added dropwise. After stirring 1 h, the cooling bath was removed. The reaction mixture was quenched with 1N HCl and extracted with EtOAc (100 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (1% EtOAc in hexanes) to give the product (0.99 g, 83%) as clear oil. 1H NMR (CDCl3) δ: 0.82-1.84 (m, 21H), 2.42-2.47 (m, 2H), 2.82-2.92 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:12][CH2:13][N:14]([CH2:22][CH2:23]Cl)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[H-].[Na+]>CS(C)=O.ClCCl>[C:9]([C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:23][CH2:22][N:14]([C:15]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:21])[CH2:13][CH2:12]1)#[N:10]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CCc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(F)c2)CC1
Temperature: 18 °C
Reaction time: 2 h

Procedure:
A mixture of 3-fluorophenylacetonitrile (200 mg, 1.48 mmol) and tert-butyl bis(2-chloroethyl)carbamate (358 mg, 1.48 mmol) was dissolved in 14.8 mL of anhydrous DMSO. The reaction was purged with a stream of nitrogen and cooled to 18° C. To this reaction was added sodium hydride (358 mg, 1.48 mmol), which was then warmed to ambient temperature and stirred for 2 hours. The reaction was warmed to 50° C. and stirred for 17 hours. The mixture was diluted with dichloromethane (40 mL), washed with water (3×40 mL), and partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate, filtered, concentrated, and subjected to silica gel chromatography eluting with 0-20% EtOAc in hexanes. Collection of product containing fractions and removal of solvent yielded tert-butyl 4-cyano-4-(3-fluorophenyl)piperidine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH:13]3[O:18][CH2:17][CH2:16][NH:15][CH2:14]3)[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[C:22]([NH2:27])[N:21]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:19][C:20]1[CH:25]=[C:24]([N:15]2[CH2:16][CH2:17][O:18][CH:13]([C:10]3[NH:11][CH:12]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:9]=3)[CH2:14]2)[N:23]=[C:22]([NH2:27])[N:21]=1
Reactant: Clc1cccc(-c2c[nH]c(C3CNCCO3)n2)c1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1nc(Cl)cc(N2CCOC(c3nc(-c4cccc(Cl)c4)c[nH]3)C2)n1
Yield: 140.6 %

Procedure:
A solution of 2-[4-(3-chlorophenyl)-1H-imidazol-2-yl]morpholine (600 mg, 2.0 mmol), 4,6-dichloro-2-pyrimidinamine (328 mg, 2.0 mmol) and Hunig's base (0.870 mL, 5.00 mmol) in ethanol (80 mL) was heated overnight at 85° C. The reaction mixture was filtered and concentrated to afford the crude title compound (1.1 g) as a brown oil. LC-MS (ES) m/z=391 [M+H]+.