Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-]1C2C(=CC=CC=2)C=CC=1.[Li+].[CH2:12]([N:19]1[C@@H:24]2[C@H:25](S(C3C=CC=CC=3)(=O)=O)[CH2:26][C@@:20]1([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:21]([OH:36])[CH2:22][CH2:23]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH2:12]([N:19]1[C@@H:24]2[CH2:25][CH2:26][C@@:20]1([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:21]([OH:36])[CH2:22][CH2:23]2)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@@]2(c3ccccc3)[C@H](O)CC[C@@H]1N2Cc1ccccc1
Agent: [Li+]
Agent: [c-]1cccc2ccccc12
Solvent: C1CCOC1
Product: O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1
Temperature: 25 °C
Yield: 84.5 %

Procedure:
Lithium naphthalenide (200 ml, 0.6M in teterahydrofuran) was added dropwise into a −78° C. solution of (1R*,2R*,5S*,6R*)-8-benzyl-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octan-2-ol (Description 4; 25 g, 57.7 mmol) in THF (350 ml). The mixture was quenched by addition of saturated ammonium chloride and warmed to room temperature The reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic layer was washed (×2) with water then dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5, 15 and 40% ethyl acetate/iso-hexanes to yield the title compound (14.3 g, 84.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C1([O:25][C:26]([C:28]2[CH:29]=[N:30][N:31]([CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH:32]=2)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:26]([C:28]3[CH:29]=[N:30][N:31]([CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH:32]=3)=[O:25])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CN(C)CCn1cc(C(=O)Oc2ccccc2)cn1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3cnn(CCN(C)C)c3)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 1-(2-dimethylamino-ethyl)-1H-pyrazole-4-carboxylic acid phenyl ester, the title compound was obtained as white crystals 54% yield). MS: m/e=431(M+H+), mp 203-205° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][NH:17][CH2:16][C@:14]2([C:19]2[CH:20]=[C:21]([NH:25][C:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=3)=[O:27])[CH:22]=[CH:23][CH:24]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[F:42][C:43]1[CH:44]=[N:45][C:46](Cl)=[N:47][CH:48]=1.C(N(C(C)C)CC)(C)C>CS(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>[C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:46]3[N:47]=[CH:48][C:43]([F:42])=[CH:44][N:45]=3)[CH2:16][C@:14]2([C:19]2[CH:20]=[C:21]([NH:25][C:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=3)=[O:27])[CH:22]=[CH:23][CH:24]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1=N[C@@]2(c3cccc(NC(=O)c4ccc(F)cn4)c3)CNC[C@H]2CS1)c1ccccc1
Reactant: Fc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1=N[C@@]2(c3cccc(NC(=O)c4ccc(F)cn4)c3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Temperature: 50 °C
Yield: 41 %

Procedure:
A solution of N-[3-[(4aR,7aS)-2-benzamido-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-7a-yl]phenyl]-5-fluoro-pyridine-2-carboxamide; 2,2,2-trifluoroacetic acid (150 mg, 254 μmol), 5-fluoro-2-chloropyrimidine (68 mg, 51 μmol) and diisopropylethylamine (98 μL, 56 μmol) is heated in dimethyl sulfoxide (5 mL) overnight at 40° C. Additional 5-fluoro-2-chloropyrimidine (68 mg, 51 μmol) and diisopropylethylamine (98 μL, 56 μmol) is added and the mixture is heated overnight at 50° C. Additional 5-fluoro-2-chloropyrimidine (68 mg, 51 μmol) and diisopropylethylamine (98 μL, 56 μmol) is added and the mixture is heated overnight at 50° C. for a third night. The reaction is cooled, diluted with saturated aqueous sodium carbonate (50 mL) to give a slurry that is filtered and dried in a vacuum oven at 50° C. for 4 hours to give the title compound (60 mg, 41%). ES/MS (m/e): 449 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:8]2[O:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10](=[O:19])[C:9]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Ni]>[C:1]([C:5]1[CH:6]=[C:7]([C:21]([CH3:22])([CH3:24])[CH3:23])[C:8]2[O:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][C:10](=[O:19])[C:9]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(=O)c2cc(C(C)(C)C)cc(C(C)(C)C)c2o1
Agent: [Ni]
Product: CCOC(=O)C1CC(=O)c2cc(C(C)(C)C)cc(C(C)(C)C)c2O1

Procedure:
A solution of 12.0 parts of 6,8-di-t-butyl-4-oxo-4H-1benzopyran-2-carboxylic acid, ethyl ester in 150 parts of ethanoo was hydrogenated, using Raney Nickel as catalyst, until one equivalent of hydrogen had been absorbed. The catalyst was removed by filtration and the ethanol was evaporated to give a residue which was chromatographed on silica gel. Careful elution with a 1:1 mixture of chloroform and light petroleum (b.p. 60°-80° C) gave 3.73 parts of 6,8-di-t-butyl-2,3-dihydro-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester, m.p. 61°-63° C, as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH3:17].[CH2:18]([N:20]([CH2:24][CH3:25])[C:21](Cl)=[O:22])[CH3:19].N1C=CC=CC=1>C(#N)C.C(Cl)Cl>[CH2:18]([N:20]([CH2:24][CH3:25])[C:21]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH3:17])=[O:22])[CH3:19]
Reactant: CCN(CC)C(=O)Cl
Reactant: Cc1c(O)c(=O)ccn1C
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN(CC)C(=O)Oc1c(C)n(C)ccc1=O
Reaction time: 1 h

Procedure:
With stirring, 0.56 ml of triethylamine is added at room temperature to a suspension of 0.556 g of 3-hydroxy-1,2-dimethyl-4(1H)-pyridinone in 40 ml of acetonitrile and 40 ml of methylene chloride, followed by the addition of 0.76 ml of diethylcarbamoyl chloride. The suspension still remains intact after 60 minutes and thin-layer chromatography shows that no reaction has taken place. Then 20 ml of pyridine are added to the mixture, which turns yellowish in colour. After a further 60 minutes the onset of reaction can be observed. This reaction is brought to completion by stirring for 16 hours. The volatile constituents are removed by evaporation under reduced pressure. The residue is dried under a high vacuum, then dissolved in methanol, and the solution is treated with activated carbon, filtered and concentrated by evaporation. The filtrate is taken up in 100 ml of ethyl acetate, whereupon a product crystallises. A furthher crystalline product can be obtained by working up the mother liquor. The two products are combined and dissolved in methylene chloride. The solution is washed twice with water and the organic phase is concentrated by evaporation. The residue is crystallised from ethyl acetate, affording 3-(diethylaminocarbonyloxy)-1,2-dimethyl-4(1H)-pyridinone with a melting point of 135°-137° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[CH3:11][N:12]1[C:16]([C:17]#[N:18])=[CH:15][CH:14]=[C:13]1B(O)O.[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([C:13]3[N:12]([CH3:11])[C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: Brc1ccc2c(c1)CCN2
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 5 h
Yield: 35.8 %

Procedure:
5-Bromoindoline (0.59 g, 3.0 mmol), 1-methyl-5-cyano-2-pyrroleboronic acid (0.54 g, 3.6 mmol), potassium fluoride (KF—0.57 g, 9.9 mmol), and Pd2(dba)3 (72 mg, 0.075 mmol) were added to a round bottom flask under nitrogen. The flask was sealed and purged with nitrogen for 5 minutes. Tetrahydrofuran (THF—7.5 mL) was added and the mixture was purged with nitrogen for an additional 5 minutes. A solution of tri-t-butylphosphine (10% wt in hexanes, 0.45 mL, 0.15 mmol) was added via syringe and the mixture was stirred vigorously at 25° C. for 5 hours. The mixture was diluted with ethyl acetate, filtered through a plug of silica gel, washed through with additional ethyl acetate and concentrated to give a crude brown/black semi-solid. Purification was performed using Isco chromatography (the Redisep® column, silica, gradient 10-60% ethyl acetate in hexane). Further purification via Isco chromatography (the Redisep® column, silica, gradient 50% hexane:45% methylene chloride:5% ethyl acetate) afforded 5-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (0.24 g) as a white solid. HPLC purity 100.0% at 210-370 nm, 8.5 min.; the Xterra® column RP18, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes. HRMS: calcd for C14H13N3+H+, 224.11822; found (ESI, [M+H]+), 224.1188;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]([OH:15])=O)[CH2:11][S:10][CH:9]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1([CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]([N:34]2[CH2:35][CH2:36][N:31]([CH2:30][CH2:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:32][CH2:33]2)=[O:15])[CH2:11][S:10][CH:9]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C(C(=O)O)CSC1c1cccnc1
Reactant: c1ccc(CCCN2CCNCC2)cc1
Product: CC(C)(C)OC(=O)N1C(C(=O)N2CCN(CCCc3ccccc3)CC2)CSC1c1cccnc1
Yield: 57.6 %

Procedure:
3-tert-Butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid (650 mg) and 1-(3-phenylpropyl)piperazine (400 mg) were used as the starting materials and treated in the same manner as in Example 54. Without conversion to the hydrochloride, the product was purified by silica gel column chromatography (eluent ethyl acetate) Thus was obtained 1-[3-(tert-butoxycarbonyl)-2-(3 pyridyl)thiazolidin-4-ylcarbonyl]-4-(3-phenylpropyl)piperazine (560 mg) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][O:34][CH2:35][CH2:36][CH2:37]N.C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:37][CH2:36][CH2:35][O:34][CH3:33])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Reactant: COCCCN
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCCCNC(=O)Nc1cn(-c2cccc(F)c2)cc1C(=O)N[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Yield: 71 %

Procedure:
Following general method 6, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and 3-methoxy-propylamine afforded the crude desired product. Column chromatography (silica, 12 g column, ISCO, 0-60% ethyl acetate in DCM) afforded the title compound as a glass (100 mg, 71%). LCMS (method B): RT=3.67 min, M+H+=518.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][C@H:7]1[CH2:11][O:10][C:9](=[O:12])[C@@H:8]1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=1.[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31].[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:28][N:29]([CH3:33])[C:30](=[O:31])[O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C@@H:8]2[C@@H:7]([CH2:6][C:5]3[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:11][O:10][C:9]2=[O:12])=[CH:15][C:16]=1[O:21][CH3:22]
Reactant: COc1cc(C[C@H]2C(=O)OC[C@@H]2Cc2ccc(OC)c(OC)c2)ccc1O
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COc1ccc(C[C@H]2COC(=O)[C@@H]2Cc2ccc(OC(=O)N(C)C)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of (3R,4R)-4-(3,4-dimethoxybenzyl)-3-(4-hydroxy-3-methoxybenzyl)dihydrofuran-2(3H)-one (150 mg, 0.40 mmol, 1.0 eq) in DCM (15 mL) was added TEA (81 mg, 0.81 mmol, 2.0 eq) and DMAP (98 mg, 0.81 mmol, 2.0 eq), followed by N,N-dimethylcarbamoyl chloride (65 mg, 0.60 mmol, 1.5 eq). The mixture was stirred at rt for overnight, then sat. aq. NH4Cl (30 mL) was added. The reaction mixture was extracted with DCM (30 mL×3). The combined organic layers were dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=1/1, v/v) to afford 4-(((3R,4R)-4-(3,4-dimethoxybenzyl)-2-oxotetrahydrofuran-3-yl)methyl)-2-methoxyphenyl dimethylcarbamate (110 mg, 61.6%). LRMS (M+H+) m/z calculated 444.2, found 443.9. 1H NMR (CDCl3, 400 MHz) δ 6.97 (d, 1H), 6.73-6.78 (m, 2H), 6.64-6.70 (m, 1H), 6.50-6.55 (m, 2H), 4.12-4.17 (m, 1H), 3.82-3.90 (m, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.77 (s, 3H), 3.11 (s, 3H), 3.00 (s, 3H), 2.97 (d, 2H), 2.49-2.69 (m, 4H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]1[C:12]2[CH2:13][CH2:14][C:15]3[C:16]4([CH3:27])[CH:25]([CH3:26])[CH:9]1[CH2:10][C:11]=2[C:22]=3[C:21](=O)[C:20](=O)[NH:19][CH:18]=[CH:17]4>O1CCCC1>[CH3:7][N:8]1[C:12]2[CH2:13][CH2:14][C:15]3[C:16]4([CH3:27])[CH:25]([CH3:26])[CH:9]1[CH2:10][C:11]=2[C:22]=3[CH:21]=[CH:20][NH:19][CH:18]=[CH:17]4
Reactant: CC1C2CC3=C(CCC4=C3C(=O)C(=O)NC=CC41C)N2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1C2CC3=C(CCC4=C3C=CNC=CC41C)N2C
Temperature: 0 °C
Yield: 35.5 %

Procedure:
To a stirred slurry of 11.35 g of lithium aluminum hydride and 700 ml of tetrahydrofuran, cooled to 0° C. under nitrogen, was added, via cannula, a solution of 8.50 g of 1,2,3,4,5,6-hexahydro-3,6,12-trimethyl-2,6-methanopyrrolo[2,3-j][3]benzazocine-10,11(9H)-dione. The reaction mixture was refluxed for 3 hours, cooled to 0° C., and quenched with 10% aqueous tetrahydrofuran. The aqueous mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by means of flash chromatography (silica gel; 2% triethylamine/0-3% methanol/ethyl acetate) to yield 2.70 g (35%) of 1,2,3,4,5,6-hexahydro-3,6,12-trimethyl-2,6-methano-9H-pyrrolo[2,3-j][3]benzazocine.
Reaction SMILES: [PH4+].[Li][CH2:3][CH2:4][CH2:5][CH3:6].[CH:7]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)=O>O1CCCC1>[CH3:6][C:5]1[C:13]([CH2:12]/[CH:17]=[CH:7]/[C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:3][C:4]2[CH2:5][CH2:6][C:9]([CH3:18])([CH3:7])[CH2:10][CH2:11][C:3]=2[CH:4]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: [Li]CCCC
Agent: [PH4+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C/Cc2cc3c(cc2C)CCC(C)(C)CC3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In analogy to Example 1B (1st paragraph), from 6,7,8,9-tetrahydro-α,3,7,7-tetramethyl-5H-benzocycloheptene-2-methanol, there is obtained the corresponding phosphonium salt. 5.30 g of the phosphonium salt are suspended in 35 ml of tetrahydrofuran and deprotonized at 0° with 9.0 ml of 1.4M nBuLi (hexane) After 30 minutes, 2 30 g of methyl 4-formylbenzoate are added thereto and the mixture is stirred at room temperature for an additional 2 hours. The mixture is poured on to ice-water, extracted with Et2O, washed with water, dried and evaporated. Chromatography on silica gel (low-boiling petroleum ether/AcOEt=93/3), followed by crystallization from n-hexane, yields 560 mg of methyl p-[(E)-(6,7,8,9-tetrahydro-3,7,7-trimethyl-5H-benzocyclohepten-2-yl) propenyl]benzoate of m.p. 59°-60°.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([Cl:28])[CH:22]=1)=[O:17])C>>[Cl:28][C:23]1[CH:22]=[C:21]([CH:19]2[CH2:20][CH:18]2[C:16]([OH:17])=[O:15])[CH:26]=[CH:25][C:24]=1[O:27][CH2:2][C:3]1[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(Cl)c1
Reactant: CC(C)Sc1ncccc1CCl
Product: CC(C)Sc1ncccc1COc1ccc(C2CC2C(=O)O)cc1Cl
Yield: 69.5 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-pyridine (33 mg, 0.16 mmol) obtained in Step C of Preparation Example 1 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (43 mg, 0.17 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (42 mg, 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:10][C:9]2([C:17](=O)[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[NH2:33][NH2:34]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:34][N:33]=[C:17]([CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH2:20]3)[C:9]2([OH:10])[C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)C2(c3ccncc3)OC2c2ccc(F)cc2)CC1
Reactant: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CC2=NNC(c3ccc(F)cc3)C2(O)c2ccncc2)CC1
Temperature: 25 °C
Yield: 53.9 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[2-[3-(4-fluorophenyl)-2-(4-pyridinyl)oxiranyl]-2-oxoethyl]-1-piperidinecarboxylate prepared in step 4 of this Example (3.45 g, 7.8409 mmol) in ethanol (15 mL), anhydrous hydrazine (0.50 mL, 15.6818 mmol) was added. The reaction was heated to reflux overnight. The reaction solution was cooled to room temperature and ethanol was removed under reduced pressure. The resulting residue was taken into ethyl acetate, washed with water and brine, and dried over MgSO4. After filtration the solvent was removed under reduced pressure. The crude residue was purified by chromatography (silica gel, 2:1-1:1-1:2 hexane/ethyl acetate) to give 1,1-dimethylethyl 4-[[5-(4-fluorophenyl)-4,5-dihydro-4-hydroxy-4-(4-pyridinyl)-1H-pyrazol-3-yl]methyl]-1-piperidinecarboxylate (1.9187 g, 53.9%). This intermediate (1.8611 g, 4.0993 mmol) was dissolved in dry methylene chloride (40 mL) and treated with Martin sulfurane dehydrating reagent (4.13 g, 6.1490 mmol). The reaction solution was stirred at room temperature under N2 overnight, then diluted with ethyl acetate, washed with 1N sodium hydroxide solution, water and brine, dried over MgSO4. After filtration the solvents were removed. The resulting crude product mixture was purified by flash chromatoghaphy (silica gel, 2:1-1:1-1:2 Hexane/ethyl acetate) to give 1,1-dimethylethyl 4-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]methyl]-1-piperidinecarboxylate (0.6964 g, 39%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[NH2:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[C:16]([Cl:21])[N:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[NH2:13][C:14]1[N:19]=[C:18]([O:1][C:2]2[CH:11]=[C:10]([CH3:12])[C:5]3[NH:6][C:7](=[O:9])[O:8][C:4]=3[CH:3]=2)[CH:17]=[C:16]([Cl:21])[N:15]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Cc1cc(O)cc2oc(=O)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(Cl)nc(N)n2)cc2oc(=O)[nH]c12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
0.20 g (1.15 mmol) 6-hydroxy-4-methylbenzo[d]oxazol-2(3H)-one and 0.19 g (1.16 mmol) 2-amino-4,6-dichloropyrimidine in 3.0 mL DMF were combined with 0.22 g (1.59 mmol) potassium carbonate and stirred overnight at 60° C. Then water was added and the precipitate formed was suction filtered, washed and dried. The substance was purified by preparative HPLC-MS. The fractions containing product were combined and evaporated down i.vac.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[O:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][CH:33]([C:36]([OH:39])([CH3:38])[CH3:37])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:41]1[N:46]2[CH:47]=[CH:48][N:49]=[C:45]2[CH:44]=[CH:43][CH:42]=1>O1CCOCC1.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.C1C=C(C([O-])=O)SC=1.[Cu+]>[N:49]1[CH:48]=[CH:47][N:46]2[C:41]([C:11]3[N:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[C:8]4[O:28][C:27]([CH2:29][N:30]5[CH2:31][CH2:32][CH:33]([C:36]([OH:39])([CH3:38])[CH3:37])[CH2:34][CH2:35]5)=[CH:26][C:9]=4[N:10]=3)=[CH:42][CH:43]=[CH:44][C:45]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2oc(CN3CCC(C(C)(C)O)CC3)cc2n1
Reactant: Brc1cccc2nccn12
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: CC(C)(O)C1CCN(Cc2cc3nc(-c4cccc5nccn45)nc(N4CCOCC4)c3o2)CC1
Yield: 42 %

Procedure:
A mixture of 2-[1-(4-morpholin-4-yl-2-tributylstannanylfuro[3,2-d]pyrimidin-6-ylmethyl)piperidin-4-yl]propan-2-ol (147 mg, 0.23 mmol), 5-bromoimidazo[1,2-a]pyridine (46 mg, 0.23 mmol), tetrakis(triphenylphosphine)palladium (22 mg, 8 mol %) and CuTC (9 mg, 20 mol %) in 1,4-dioxane (2.5 mL) was purged with argon gas then subjected to microwave irradiation at 140° C. for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g), which was washed with MeOH/DCM before the desired product was eluted with 2 M NH3 in MeOH/DCM. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:NH3/MeOH (2 M); gradient from 100:0 to 96:4)), followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to afford 249 as a white foam (46 mg, 42%). LCMS (Method G): RT=3.47 min, M+H+=477. 1H NMR (CDCl3, 400 MHz) 9.14 (s, 1 H); 6 7.87 (dd, J=8.5, 1.19 Hz, 2H); 7.76 (d, J=8.9 Hz, 1 H); 7.73 (d, J=1.3 Hz, 1 H); 7.30 (m, 1 H); 6.79 (s, 1 H); 4.11 (t, J=4.7 Hz, 4 H); 3.90 (t, J=4.7 Hz, 4 H); 3.75 (s, 2 H); 3.08 (d, J=11.0 Hz, 2 H); 2.12 (t, J=11.0 Hz, 2 H); 1.78 (m, 2 H); 1.52-1.38 (m, 3 H); 1.31 (m, 1 H) and 1.19 (s, 6 H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:27][C:14]1[C:13]([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:30]4[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=4)[CH:3]=3)[NH:8][CH:9]=2)=[O:12])=[C:18]([F:19])[CH:17]=[CH:16][C:15]=1[NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Temperature: 160 °C

Procedure:
To propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-0773, prepared as described in Example 1, 65.0 mg, 0.14 mmol) in acetonitrile (4.0 mL) was added pyridine-3-boronic acid (609, 25.0 mg, 0.20 mmol), tetrakis (triphenylphosphine)palladium(0) (11 mg, 1.0% mmol) and aqueous potassium carbonate (1.0 M, 2.0 mL). The reaction was heated to 160° C. for 10 minutes in a CEM Discover microwave instrument. The reaction was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtrated and concentrated. The desired compound was isolated by silica gel column chromatography (methylene chloride/methanol 5%) to give a white solid (P-0088, 30 mg, 46.9%). MS(ESI) [M+H+]+=457.2.