Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:38]3[CH:37]=[N:36][C:35]([Cl:34])=[CH:40][CH:39]=3)[C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(Cl)nc1)N1CCC(N2CCCCC2)CC1
Yield: 57 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 168), 2-chloropyridine-5-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a brown oil (57%).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:13]2[C:12]3[CH2:14][CH2:15][CH2:16][CH2:17][C:11]=3[C:10](=[O:18])[O:9][C:8]=2[CH:7]=[C:6]([CH3:19])[CH:5]=1.[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>CS(C)=O.O>[CH3:19][C:6]1[CH:5]=[C:4]([O:3][CH2:20][CH:22]2[CH2:23][O:24]2)[C:13]2[C:12]3[CH2:14][CH2:15][CH2:16][CH2:17][C:11]=3[C:10](=[O:18])[O:9][C:8]=2[CH:7]=1
Reactant: Cc1cc(O)c2c3c(c(=O)oc2c1)CCCC3
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(OCC2CO2)c2c3c(c(=O)oc2c1)CCCC3
Reaction time: 0.08 h

Procedure:
To a stirred solution of NaOH (4.0 g, 0.1 m) in dimethylsulfoxide (DMSO) (250 ml) and water (250 ml), was added 7,8,9,10-tetrahydro-1-hydroxy-3-methyl-6-oxo-6H-dibenzo[b,d]pyran (20.0 g, 0.87 m) and the mixture stirred for 5 minutes, then treated with epichlorohydrin (50 ml). After 5 hours the mixture was cooled in an ice bath for 30 minutes and the precipitated solid collection by filtration, washed with water and dried to give 7,8,9,10-tetrahydro-3-methyl-1-(oxiranylmethoxy)-6-oxo-6H-dibenzo[b,d]pyran as a white solid, mp. 164°-165° C. An analytical sample recrystallized from methanol melted at 165°-166° C.
Reaction SMILES: C1COCC1.[NH:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Cl.C1C=CC2N(O)N=NC=2C=1.[NH:32]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@H:33]([C:43](O)=[O:44])[CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[NH:32]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@H:33]([C:43]([N:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])=[O:44])[CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
THF (100 ml, H-Pro-OBzl.HCl (31.5 g, 0.13 M) and HOBT (17.5 g, 0.13 M) were added to BOC-Ser(Bzl)-OH (35.4 g, 0.12 M), and then DMF (50 ml) was added thereto to prepare a solution. WSCI (24.8 ml) was added dropwise and stirred at 0° C. for one hour and then at room temperature overnight. The solvent was distilled off in vacuo and benzene was added to the residue, which was then washed three times with 5% sodium bicarbonate solution, three times with 1 N HCl and three times with water, in that order. After drying with anhydrous sodium sulfate, the solution was dried in vacuo to obtain the substance [17] as an oil material (58 g, yield: 100%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:30][C:29]=1[O:40][CH3:41]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:30][C:29]=4[O:40][CH3:41])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CCCC(=O)Cc1ccc(OCCCBr)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCC(=O)Cc1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(OC)c1
Yield: 68.7 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10 mmol), K2CO3 (3 g), 1-[4-(3-bromopropoxy)-3-methoxyphenyl]pentanone (3.7 g, 11.3 mmol) in acetonitrile (140 ml) was heated at reflux for 4 hours. At the end of the reaction, the mixture was cooled and filtered. The flitrate was concentrated to an oil. Purification was performed by flash chromatography over a silica gel column (SiO2, 55 g; eluted with 1% methanol in dichloromethane, 600 ml; 3% methanol: 97% dichloromethane, 400 ml). The fractions containing pure product were pooled and concentrated to a solid (4.3 g, 91%). Recrystallization from ethanol (10 ml) gave a powdery solid of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-pentanone (3.22 g), m.p.=79°-80° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][Si](C)(C)C)[N:4]=1.C1C=CC(O[C:22](Cl)=[S:23])=CC=1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10]=[C:22]=[S:23])[N:4]=1
Reactant: COc1nc(C)nc(N[Si](C)(C)C)n1
Reactant: S=C(Cl)Oc1ccccc1
Solvent: Cc1ccccc1C
Product: COc1nc(C)nc(N=C=S)n1
Temperature: 140 °C
Reaction time: 6.5 h
Yield: 23.3 %

Procedure:
To 50 ml of xylene are added 15.0 g of 4-methoxy-6- methyl-2-trimethylsilylamino-1,3,5-triazine and 12.2 g of phenyl chlorothionocarbonate. The mixture is stirred at about 140° C. for 6.5 hours. After cooling the reaction mixture to room temperature, insoluble matters are filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent, ethyl acetate:toluene=1:3) to yield 3.0 g of the title compound as an oil.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4](/[CH:7]=[CH:8]/[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:5][CH:6]=1.[CH:17](=[O:20])[CH2:18][CH3:19].C(N(CC)CC)C>[Br-].C([N+]1C(C)=C(CCO)SC=1)C.C(O)C>[C:11]1([C:9](=[O:10])[CH2:8][CH:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:17](=[O:20])[CH2:18][CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(/C=C/c1ccccc1)c1ccccc1
Reactant: CCC=O
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCC(=O)C(CC(=O)c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
A mixture of (E)-1,3-diphenyl-propenone (1.042 g; 5.00 mmol), propionaldehyde (0.40 mL; 5.6 mmol), 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (126 mg; 0.500 mmol) and triethyl-amine (0.42 mL; 3.0 mmol) in absolute ethanol (3.0 mL) was degassed then heated at 70° C. for 25 h. After an additional 1.5 h at 80° C., the organic volatiles were removed on a rotary evaporator. EtOAc (25 mL) was added and the solution washed with water (3×5 mL) and satd NaCl (2×5 mL); then dried (MgSO4), filtered through silica and washed through with EtOAc. Crude product was adsorbed onto silica (2.0 g) then purified by MPLC (40 g of silica using a 0→20% EtOAc in hexanes gradient). Pure product was obtained as a clear, pale tan liquid (760 mg; 57%). 1H NMR (CDCl3) δ 7.96 (m, 2H), 7.56 (m, 1H), 7.45 (m, 2H), 7.38-7.26 (m, 5H), 4.43 (dd, J=3.4, 10.2 Hz, 1H), 4.05 (dd, J=10.4, 18.0 Hz, 1H), 3.14 (dd, J=3.8, 18.2 Hz, 1H), 2.65 (m, 1H), 2.53 (m, 1H), 1.02 (t(app), J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:14]=[CH:13][C:10](C#N)=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].C[Mg]Br.C([O:20][CH2:21][CH3:22])C>C1(C)C=CC=CC=1>[CH2:1]([N:3]([CH2:6][C:7]1[CH:14]=[CH:13][C:10]([C:21](=[O:20])[CH3:22])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCOCC
Reactant: CCN(CC)Cc1ccc(C#N)cc1
Agent: C[Mg]Br
Solvent: Cc1ccccc1
Product: CCN(CC)Cc1ccc(C(C)=O)cc1
Temperature: 0 °C

Procedure:
A solution of 12.1 g of 4-[diethylaminomethyl]benzonitrile in 40 ml of toluene was added to a solution of methylmagnesium bromide (43 ml of a 3 M solution in diethyl ether) in 40 ml of toluene, and the mixture was heated to reflux. Completion of the reaction was followed by pouring into ice-water, extracting with methyl tert-butyl ether, adjusting the aqueous phase to pH 11-12 by adding NaOH, and renewed extracting with methyl tert-butyl ether. The organic phase was dried and the solvent was evaporated. 12.1 g of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:31])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:30])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25](OC)=[CH:24][CH:23]=2)[CH2:14][CH2:13]1.[Cl:32]C1C=CC=CC=1CCl.COC1C=CC(CCl)=CC=1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:31])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:30])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:32])[CH2:14][CH2:13]1
Reactant: COc1ccc(CCC(O)CN2CCN(CC(=O)Nc3c(C)cccc3C)CC2)cc1
Reactant: ClCc1ccccc1Cl
Agent: COc1ccc(CCl)cc1
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)CCc2ccccc2Cl)CC1

Procedure:
Compound 18 was prepared in a manner similar to that of compound 16 substituting 2-chlorobenzyl chloride for 4-methoxybenzyl chloride. (M+1)=430.2
Reaction SMILES: [CH3:1][C:2]1([CH:15]2[CH2:19][CH2:18][O:17][C:16]2=[O:20])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[CH3:21][NH2:22]>O1CCCC1.[Cl-].[Na+].O>[CH3:21][NH:22][C:16](=[O:20])[CH:15]([CH2:19][CH2:18][OH:17])[C:2]1([CH3:1])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CC1(C2CCOC2=O)OCCc2c1[nH]c1ccccc21
Reactant: CN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)C(CCO)C1(C)OCCc2c1[nH]c1ccccc21

Procedure:
A solution of 4,5-dihydro-3-(1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indole-1-yl)-2(3H)-furanone (described in Example 1, 20 g, 0.074 mole) in tetrahydrofuran (200 ml) and 40% aqueous methylamine-(200 ml)-is refluxed for 24 hr. The reaction mixture is diluted with brine and extracted with diethyl ether. The organic extracts are washed with brine, dried over magnesium sulfate and evaporated. The residue is subjected to chromatography on silica gel using acetone-benzene (1:2). The eluates are evaporated and crystallized from diethyl ether-hexane to obtain isomer A (6.9 g) of the title compound, mp 169°-171° C. The eluant for the column is changed to acetone-benzene (1:1) and the eluates are evaporated followed by trituration of the residue to obtain isomer B (7.5 g) of the title compound, mp 194°-196° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[C:6]([CH3:8])=O)[CH3:2].[C:20]1(=[O:39])[N:24]([CH2:25][CH2:26][O:27][C:28](=[O:33])/[CH:29]=[C:30](\[NH2:32])/[CH3:31])[C:23](=[O:34])[C:22]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:21]12>C(O)C>[CH3:8][C:6]1[NH:32][C:30]([CH3:31])=[C:29]([C:28]([O:27][CH2:26][CH2:25][N:24]2[C:23](=[O:34])[C:22]3=[CH:35][CH:36]=[CH:37][CH:38]=[C:21]3[C:20]2=[O:39])=[O:33])[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[C:5]=1[C:4]([O:3][CH2:1][CH3:2])=[O:19]
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: C/C(N)=C/C(=O)OCCN1C(=O)c2ccccc2C1=O
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2C(=O)c3ccccc3C2=O)C1c1cccc([N+](=O)[O-])c1
Yield: 89 %

Procedure:
Prepared by a method analogous to that of Example 1(a) from 15.80 g (60 mmol) of 2-(3-nitrobenzylidene)-acetoacetic acid ethyl ester and 16.46 g (60 mmol) of 3-amino-crotonic acid-(2-phthalimidoethyl)ester in ethanol. 27.75 g (89%) of yellow crystals melting at 194°-195° C. are obtained.
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([OH:46])=O)=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.[N:50]1[CH:55]=[CH:54][N:53]=[CH:52][C:51]=1[CH2:56][NH2:57]>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH:57][CH2:56][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][N:50]=4)=[O:46])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:48][CH:49]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1cnccn1
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cnccn1
Yield: 42 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with pyrazin-2-ylmethanamine, the title compound was obtained as a colorless solid in 42% yield: mp 185-187° C.; 1H NMR (300 MHz, CDCl3) δ 8.65 (s, 1H), 8.53-8.51 (m, 2H), 7.30-7.25 (m, 2H), 7.07-7.01 (m, 2H), 6.83 (br s, 1H), 4.76 (d, J=6.0 Hz, 2H), 4.46 (s, 2H), 4.09 (t, J=9.0 Hz, 2 H), 3.46 (t, J=9.0 Hz, 2H), 2.63 (s, 3H): MS (ES+) m/z 427.2 (M+1).
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=3)=[C:16]([CH3:29])[N:15]([CH:30]([CH3:32])[CH3:31])[N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[C:33](Cl)(=[O:36])[CH2:34][CH3:35].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>CC1C=C(C)C=C(C)N=1>[CH:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:17]2[C:13]([O:12][C@@H:1]3[O:9][C@H:8]([CH2:10][O:11][C:33](=[O:36])[CH2:34][CH3:35])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]3[OH:3])=[N:14][N:15]([CH:30]([CH3:32])[CH3:31])[C:16]=2[CH3:29])=[CH:20][CH:21]=1)([CH3:27])[CH3:28]
Reactant: CCC(=O)Cl
Reactant: Cc1c(Cc2ccc(OC(C)C)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: CCC(=O)OC[C@H]1O[C@@H](Oc2nn(C(C)C)c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 65.8 %

Procedure:
To a solution of 3-(β-D-glucopyranosyloxy)-4-[(4-iso-propoxyphenyl)methyl]-1-isopropyl-5-methylpyrazole (0.10 g) in 2,4,6-trimethylpyridine (1 mL) was added propionyl chloride (0.072 g) at 0° C., and the mixture was stirred for hours. To the reaction mixture were added citric acid monohydrate (3.3 g) and water, and the resulting mixture was purified by ODS solid phase extraction (washing solvent: distilled water, eluent: methanol). Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) afforded 4-[(4-isopropoxyphenyl)methyl]-1-isopropyl-5-methyl-3-(6-O-propionyl-β-D-glucopyranosyloxy)pyrazole (0.074 g)
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:25][O:26][C:27](=[O:38])[CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH2:37]>>[CH3:25][O:26][C:27](=[O:38])[CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: COC(=O)CCCc1ccccc1N
Product: COC(=O)CCCc1ccccc1Nc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12

Procedure:
Heat 259.8 mg (0.771 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and 228 mg of 4-(2-aminophenyl)butanoic acid methyl ester (85% strength, approx. 1.0 mmol) to 150° C. overnight. After cooling, concentrate under reduced pressure, add dichloromethane to the residue and purify the crude product by chromatography on silica gel (eluent: dichloromethane/ethyl acetate 50:1→10:1). The product thus obtained is purified further by preparative RP-HPLC. 33.1 mg (8.7% of theory) of the target product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[NH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:15]=1.O.O.Cl[Sn]Cl>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]1[NH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:15]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(-c2ncc(-c3ccccc3)[nH]2)c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(Cl)c(-c2ncc(-c3ccccc3)[nH]2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(2-chloro-5-nitrophenyl)-5-phenyl-1H-imidazole (27 g, 90.3 mmol) in EtOH (200 ml) is added SnCl2.2H2O (71 g, 316 mmol). The mixture is refluxed for 2 hours, cooled to room temperature and then concentrated. Ethyl acetate (200 ml) and NaOH (25 g in 100 ml water) are added to the residue and the mixture is stirred for 10 minutes at room temperature. The solid is removed by filtering through celite pad. The filtrate is separated and the organic layer is further washed with brine, dried over anhydrous MgSO4 and concentrated. The crude product is purified by silica gel flash chromatography, eluted with 40% ethyl acetate in dichloromethane to afford 4-Chloro-3-(5-phenyl-1H-imidazol-2-yl) aniline as a brown solid. LC-MS m/z: 270.1 (M+1).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C@H:17]([C:21]([OH:23])=O)[CH:18]([CH3:20])[CH3:19])(=[O:15])=[O:14])=[CH:9][CH:8]=1)[CH:2]=[C:3]=[CH:4][CH3:5].[OH:24][N:25]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.NO>CN(C)C=O>[OH:24][NH:25][C:21](=[O:23])[CH:17]([NH:16][S:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:1][CH:2]=[C:3]=[CH:4][CH3:5])=[CH:8][CH:9]=1)(=[O:15])=[O:14])[CH:18]([CH3:20])[CH3:19]
Reactant: CC=C=CCOc1ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC=C=CCOc1ccc(S(=O)(=O)NC(C(=O)NO)C(C)C)cc1
Yield: 47.8 %

Procedure:
The procedure of Example 13 was followed using the product from Example 18 (230 mg, 0.67 mmol), 1-hydroxybenzotriazol (80 mg, 0.59 mmol), 1-[3-(dimethylamino)-propyl]-3-ethylcarbodimide hydrochloride (132 mg, 0.69 mmol), N-methylmorpholine (0.81 mmol, 0.74 mmol), and hydroxylamine (0.150 ml, 2.45 mmol) in dimethylformamide (5 ml) to give 100 mg (42%) of the product.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([O:8][C@H:9]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([C:21]([O:23][CH3:24])=[O:22])[CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[CH2:25](Br)[CH:26]=[CH2:27].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[CH2:27]([O:1][C:2]1[N:7]=[C:6]([O:8][C@H:9]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C@H:11]([C:21]([O:23][CH3:24])=[O:22])[CH2:10]2)[CH:5]=[CH:4][CH:3]=1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2cccc(O)n2)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: C=CCOc1cccc(O[C@@H]2C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C2)n1
Temperature: 60 °C
Yield: 82 %

Procedure:
A 500 mL round bottom flask under nitrogen was charged with the product of Step 4 (4.95 g, 14.63 mmol), tetrahydrofuran (200 ml), allyl bromide (2.53 ml, 29.3 mmol), and cesium carbonate (4.77 g, 14.63 mmol). Heated in a 60° C. oil bath for 18 hours. HPLC/MS o.k. Cooled. Evaporated. Added 2.5% potassium bisulfate. Extracted three times with ethyl acetate, washed combined organic portions with brine, dried with anhydrous magnesium sulfate, filtered and rotary evaporated filtrate. Subjected to flash column chromatography eluting with 70 hexane/30 ethyl acetate. Evaporation of fractions containing product gave the title compound as a pale oil. (4.56 g, 12.05 mmol, 82% yield). LCMS (ES+) m/z 379.3 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[SH:7][CH2:8][CH2:9][OH:10].[CH3:11][C:12]1[CH:13]=[C:14]([C:29]2[S:33][C:32]([N:34]3[CH2:40][CH2:39][CH2:38][NH:37][C:36](=[O:41])[CH2:35]3)=[N:31][CH:30]=2)[CH:15]=[C:16]([NH:18][C:19]2[N:24]=[C:23](S(C)(=O)=O)[CH:22]=[CH:21][N:20]=2)[CH:17]=1>CN(C=O)C.C(OCC)(=O)C>[OH:10][CH2:9][CH2:8][S:7][C:21]1[CH:22]=[CH:23][N:24]=[C:19]([NH:18][C:16]2[CH:15]=[C:14]([C:29]3[S:33][C:32]([N:34]4[CH2:40][CH2:39][CH2:38][NH:37][C:36](=[O:41])[CH2:35]4)=[N:31][CH:30]=3)[CH:13]=[C:12]([CH3:11])[CH:17]=2)[N:20]=1
Reactant: Cc1cc(Nc2nccc(S(C)(=O)=O)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Reactant: OCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(SCCO)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Reaction time: 0.25 h
Yield: 27.7 %

Procedure:
Potassium carbonate (9.95 mg, 0.072 mmol) was added to a solution of 2-mercaptoethanol (18.34 μL, 0.262 mmol) stirring in DMF (327 μL) at room temperature in an oven-dried vial. Stirred for 15 minutes, then added 4-[5-(3-methyl-5-{[4-(methylsulfonyl)-2-pyrimidinyl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (30 mg, 0.065 mmol). Stirred at room temperature for 30 minutes, diluted with ethyl acetate (10 mL), and washed with 1:1 water:brine (10 mL). The organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purified by CombiFlash (100:0 to 0:20 dichloromethane:methanol) to afford 4-{5-[3-({4-[(2-hydroxyethyl)sulfanyl]pyrimidin-2-yl}amino)-5-methylphenyl]-1,3-thiazol-2-yl}-1,4-diazepan-2-one (8.4 mg, 0.018 mmol, 28.1% yield) as a yellow solid. MS APCI: [M+H]+ m/z 457.1. 1H NMR (500 MHz, DMSO) δ 9.52 (s, 1H), 8.14 (d, J=5.3 Hz, 1H), 7.58 (d, J=12.2 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 6.92 (s, 1H), 6.75 (d, J=5.4 Hz, 1H), 4.97 (t, J=5.4 Hz, 1H), 4.16 (s, 2H), 3.79 (s, 2H), 3.64 (dd, J=6.3 Hz, 11.9 Hz, 2H), 3.29 (s, 1H), 3.21 (s, 2H), 3.15 (d, J=5.2 Hz, 1H), 2.27 (s, 3H), 1.78 (s, 2H). rhSYK activity=+++.
Reaction SMILES: [H-].[Na+].[OH:3][NH:4][C:5](=[NH:7])[CH3:6].C(O[C:11]([C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=2)[CH:17]=1)=O)C>C1COCC1>[Br:24][C:20]1[CH:19]=[C:18]([N:16]2[CH:17]=[C:13]([C:11]3[O:3][N:4]=[C:5]([CH3:6])[N:7]=3)[N:14]=[CH:15]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(=N)NO
Reactant: CCOC(=O)c1cn(-c2cccc(Br)c2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(-c2cn(-c3cccc(Br)c3)cn2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
To a suspension of NaH (1.30 g, 32.64 mmol, 60% in mineral oil) in THF (15 mL) under nitrogen atmosphere was added N-hydroxy-acetamidine (2.62 g, 35.4 mmol) and stirred for 1 h at room temperature. The bromo ester 3 (8 g, 27.2 mmol) in THF (2 mL) was added and refluxed for 12 h. The reaction mixture was quenched by adding brine, extracted with ethylacetate (100 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure and purified by flash chromatography using 25% ethylacetate in hexane as mobile phase to furnish 4 (2.8 g, 35%) as pale yellow solid, mp=200.1-202.4° C.