Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:14][C:15]4[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[C:23]([OH:28])(=O)[C:24](O)=[O:25]>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][C:20]([NH:22][C:23](=[O:28])[C:24]([NH:22][C:20]5[CH:19]=[CH:18][C:16]6[NH:17][C:13]([C:10]7[CH:11]=[CH:12][C:7]([N:4]8[CH2:3][CH2:2][O:1][CH2:6][CH2:5]8)=[CH:8][CH:9]=7)=[N:14][C:15]=6[CH:21]=5)=[O:25])=[CH:21][C:15]=4[N:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2nc(-c3ccc(N4CCOCC4)cc3)[nH]c2c1
Reactant: O=C(O)C(=O)O
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1)C(=O)Nc1ccc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1

Procedure:
Compound 434 was prepared according to the procedure similar to that described in Scheme V from 2-(4-morpholinophenyl)-5-aminobenzimidazole and oxalic acid. [M+H]+ calcd for C36H34N8O4: 643.27; found: 643.09.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[OH:15].[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>[CH2:18]([O:15][C:9]1[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=1[O:7][CH3:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(C)ccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
A dimethylformamide (15 ml) solution of 2-methoxy-4-methylphenol (6.91 g) was dropwise added to a dimethylformamide (20 ml) suspension of sodium hydride (2.4 g) under cooling with ice, followed by stirring for 30 minutes. A dimethylformamide (15 ml) solution of benzyl bromide (9.41 g) was dropwise added thereto, and tetrabutylammonium bromide in a catalytic amount was added thereto, followed by stirring at the same temperature for 30 minutes. The temperature was raised to room temperature and stirring was further carried out for one night. The reaction solution was poured into water (250 ml), and extraction with ethyl acetate (100 ml) was carried out three times. The ethyl acetate phase was washed with water (100 ml) three times and then washed with an aqueous sodium chloride solution (100 ml). After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 11.4 g of 4-benzyloxy-3-methoxytoluene (m.p. 38-39° C.) quantitatively, and its structure was confirmed by nuclear magnetic resonance spectrum.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([CH2:9][CH2:10][CH3:11])[CH2:4][C:5](=[O:8])[NH:6][N:7]=1.BrBr>CC(O)=O>[CH3:1][C:2]1[C:3]([CH2:9][CH2:10][CH3:11])=[CH:4][C:5](=[O:8])[NH:6][N:7]=1
Reactant: CCCC1CC(=O)NN=C1C
Agent: BrBr
Solvent: CC(=O)O
Product: CCCc1cc(=O)[nH]nc1C
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a solution of 6-methyl-5-propyl-4,5-dihydropyridazin-3-one (16.7 g, 108 mmol) in HOAc (200 ml) heated to 85° C. is added Br2 (5.5 ml, 108 mmol) dropwise. After the addition, the mixture is stirred at 85° C. for 1 hour. The solvent is removed in vacuo and the residue is dissolved in EtOAc (250 ml) and washed with NaHCO3 (200 ml), followed by Na2S2O3 saturated solution (50 ml) and brine (200 ml). The organic phase is dried (Na2SO4) and evaporated. The resulting 6-methyl-5-propyl-pyridazin-3-one is obtained as a yellow solid, which is used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[I:16]I.Cl>CO.O.[Cl-].[Na+].O.II>[I:16][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([OH:8])=[C:6]([CH3:9])[CH:5]=1
Reactant: Cc1ccnc(C)c1O
Reactant: II
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: Cc1cc(I)nc(C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
A mixture of 2,4-dimethyl-3-hydroxypyridine (3.00 g, 24.36 mmol) and Na2CO3 (5.16 g, 48.7 mmol) in MeOH (40 mL) and water (24 mL) was treated with iodine (6.18 g, 24.36 mmol) and stirred at RT for 1 h. Additional iodine (0.4 g) was added, the mixture stirred at RT for 3 h, then acidified to pH=5 with 3M HCl. The mixture was treated with brine, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford 6-iodo-2,4-dimethylpyridin-3-ol (5.1 g, 84%). MS (ESI) m/z: 250.0 (M+H+).
Reaction SMILES: [SH:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[CH:3]=1.[C:12](O)(=[O:17])[CH2:13][C:14](O)=[O:15].C(OC(=O)C)(=O)C>C(O)(=O)C>[OH:17][C:12]1[C:3]2[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[N:7]([CH3:8])[C:2]=2[S:1][C:14](=[O:15])[CH:13]=1
Reactant: Cn1c(S)cc(=O)n(C)c1=O
Reactant: O=C(O)CC(=O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cn1c(=O)c2c(O)cc(=O)sc2n(C)c1=O
Temperature: 25 °C

Procedure:
A mixture of Step 2 intermediate (12.75 g, 74.127 mmol), malonic acid (9.30 g, 88.953 mmol), acetic acid (7.41 ml) and acetic anhydride (16.8 ml) was heated to 80° C. under nitrogen atmosphere for 2 h. The reaction mixture was cooled to room temperature and quenched with water (50 ml). Precipitated solid was filtered, washed with water (2×50 ml) and dried well to obtain 14.4 g of the product as brown solid; 1H NMR (300 MHz, DMSO-d6) δ 3.28 (s, 3H), 3.48 (s, 3H), 5.73 (s, 1H), 13.76 (br s, 1H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:11]3[N:12]=[CH:13][C:14]([C:15]#[N:16])=[C:10]3[NH:9][C:8]=2[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][C:18]=2[O:27][CH3:28])[CH2:5][CH2:4][CH2:3][CH2:2]1.CS(C)=[O:31]>>[NH2:9][C:10]1[N:11](/[C:7](=[N:6]/[CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)/[C:8]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][C:18]=2[O:27][CH3:28])=[O:31])[N:12]=[CH:13][C:14]=1[C:15]#[N:16]
Reactant: COc1cc(OC)c(-c2[nH]c3c(C#N)cnn3c2NC2CCCC2)cc1OC
Reactant: CS(C)=O
Product: COc1cc(OC)c(C(=O)/C(=N\C2CCCC2)n2ncc(C#N)c2N)cc1OC
Reaction time: 720 h
Yield: 10 %

Procedure:
A mixture of 3-(cyclopentylamino)-2-(2,4,5-trimethoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile (153 mg, 0.401 mmol) and DMSO (20 mL) was heated gently to dissolve all the solids. The resulting brown solution was stored for 30 days at RT. As a result, some solids were precipitated which was collected by filtration and the filtrate was diluted with water (˜100 mL). The resulting solids were collected by filtration and washed with diethyl ether. These solids were again purified by HPLC using acetonitrile and ammonium acetate as eluent to obtain 16.5 mg (10% yield) of (E)-5-amino-1-(1-(cyclopentylimino)-2-(2,4,5-trimethoxyphenyl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.40-1.85 (br m, 8H), 3.65 (s, 3H), 3.67 (p, 1H), 3.79 (s, 3H), 3.91 (s, 3H), 6.72 (s, 1H), 7.35 (s, 1H), 7.63 (s, 1H), 8.06 (br s, 2H). LC/MS calcd. for C20H23N5O4 (m/e) 397.433, obsd. 398.3 (M+H, ES+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N:17]4[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[N:12]=3)[C:4]=2[CH:3]=1.[CH3:24][N:25]1[C:30](=[O:31])[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1.C([O-])(=O)C.[K+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[N:17]1([C:13]2[N:12]=[C:11]([N:10]3[C:4]4[CH:3]=[C:2]([C:28]5[CH:27]=[N:26][N:25]([CH3:24])[C:30](=[O:31])[CH:29]=5)[N:7]=[CH:6][C:5]=4[CH:8]=[N:9]3)[CH:16]=[CH:15][CH:14]=2)[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: Cn1ncc(B2OC(C)(C)C(C)(C)O2)cc1=O
Reactant: Clc1cc2c(cn1)cnn2-c1cccc(N2CCCNCC2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: ClCCl
Product: Cn1ncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCNCC3)n2)cc1=O
Temperature: 150 °C
Yield: 8.5 %

Procedure:
A mixture of 6-chloro-1-[6-(1,4-diazepan-1-yl)-2-pyridyl]pyrazolo[4,3-c]pyridine (0.3190 mmol; 104.9 mg), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3-one (0.4786 mmol; 113.0 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.03190 mmol; 26.6 mg), potassium acetate (0.4786 mmol; 0.48 mL) and sodium carbonate (0.4786 mmol; 0.48 mL) in Acetonitrile (10 mL) in a pressure tube was heated under microwave at 150° C. for 15 min. The mixture was filtered through Celite. The filtrated was concentrated. The residue was purified on silica eluted with 10% MeOH in DCM with 1% NH4OH. The product obtained (29 mg, purity>90%) was further purified by reverse phase HPLC to afford 148 as an off-white solid (10.9 mg, 8.5%). 1H NMR (400 MHz, DMSO) δ 9.39-9.31 (s, 1H), 9.08-9.01 (s, 1H), 8.72-8.65 (s, 1H), 8.56-8.51 (d, J=2.1 Hz, 1H), 8.31-8.22 (s, 1H), 7.76-7.69 (t, J=8.1 Hz, 1H), 7.42-7.38 (d, J=2.1 Hz, 1H), 7.22-7.18 (d, J=7.7 Hz, 1H), 6.69-6.62 (d, J=8.5 Hz, 1H), 3.87-3.79 (m, 4H), 3.74-3.72 (s, 3H), 3.05-3.00 (m, 2H), 2.83-2.77 (m, 2H), 1.94-1.87 (m, 2H); MS (ESI) m/z: 403.2 [M+H]+.
Reaction SMILES: N1C=CC=CC=1.[CH:7]1([C:10](Cl)=[O:11])[CH2:9][CH2:8]1.[NH2:13][C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([Cl:38])[C:21]=2[N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]2)[NH:16][CH:15]=1.[Li+].[OH-]>CN1C(=O)CCC1.CC#N.O.C(Cl)Cl.O>[Cl:38][C:20]1[C:21]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:24]2)=[C:22]2[C:14]([NH:13][C:10]([CH:7]3[CH2:9][CH2:8]3)=[O:11])=[CH:15][NH:16][C:17]2=[N:18][CH:19]=1
Reactant: O=C(Cl)C1CC1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(N)c23)C1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC#N
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
Pyridine (1 mL) and cyclopropanecarbonyl chloride (0.413 g, 3.95 mmol) were added to (R)-tert-butyl 1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate (0.300 g, 0.790 mmol) in NMP (2 mL), and the reaction was stirred at room temperature for 1 hour. 3M aqueous LiOH (3 mL) was then added, and the reaction was stirred for 10 minutes. Water (10 mL) and DCM (10 mL) were then added, and the organic fraction was separated, dried, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 5-95% CH3CN/water) to give (R)-tert-butyl 1-(5-chloro-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate (0.170 g, 48% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][F:28].O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:25][CH2:26][CH2:27][F:28])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: FCCCBr
Reactant: Oc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: FCCCOc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 86.6 %

Procedure:
290 mg (corresponding to 1.0 mmol) of 6-bromo-2-(4′-hydroxyphenyl)imidazo[1,2-a]pyridine that was sufficiently dried to remove moisture was dissolved in 10 mL of N,N-dimethylformamide, and 413 mg (corresponding to 3.0 mmol) of potassium carbonate was added thereto. 138 μL (corresponding to 1.5 mmol) of 1-bromo-3-fluoropropane was added to the resulting solution, and then the solution was stirred at room temperature for 20.5 hours. After the completion of the reaction, the reaction solution was poured into water and extracted three times with chloroform. The combined chloroform layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered and concentrated. The resulting crude product was purified by recycle preparative HPLC (HPLC apparatus: LC-908 (under trade name; manufactured by Japan Analytical Industry Co., Ltd.); column: two of JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), to obtain 302 mg (corresponding to 0.866 mmol) of 6-bromo-2-[4′-(3″-fluoropropoxy)phenyl]imidazo[1,2-a]pyridine (FIG. 7, Step 3).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([OH:28])=[C:20]([NH:23][C:24]([O:26]C)=O)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:29]1[CH2:34][CH:33]=[C:32]([C:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[NH:37][CH:36]=2)[CH2:31][CH2:30]1>CS(C)=O>[NH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:35]([C:32]2[CH2:33][CH2:34][N:29]([CH2:12][CH:13]3[O:18][C:17]4[C:16](=[CH:22][CH:21]=[C:20]5[NH:23][C:24](=[O:26])[O:28][C:19]5=4)[O:15][CH2:14]3)[CH2:30][CH:31]=2)=[CH:36]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: COC(=O)Nc1ccc2c(c1O)O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Solvent: CS(C)=O
Product: O=c1[nH]c2ccc3c(c2o1)OC(CN1CC=C(c2c[nH]c4ccccc24)CC1)CO3
Temperature: 60 °C

Procedure:
0.85 g (2.08 mmole) of {(2R)-8-hydroxy-7-[(methoxycarbonyl)amino]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate and 1.13 g (5.70 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole were combined in DMSO (40 mL) and heated at 60° C. under nitrogen for 6 hours. After completion, the reaction was cooled to room temperature and partitioned between 300 mL each of ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuum to a viscous oil. The crude oil was dissolved in methylene chloride and was heated at reflux in the presence of carbonyl diimidazole (1.02 g) for 4 hours. The reaction was allowed to cool to room temperature and the solvent was removed in vacuum. The residue was column chromatographed on silica gel using first 20% hexane/methylene chloride, then methylene chloride and finally 2% methanol/methylene chloride as eluant. The product fractions were combined and concentrated in vacuum to give 0.080 g of the (S)-enantiomer of the title compound as a light yellow solid, m.p. 202° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]([NH:50][CH2:51][CH2:52][O:53][CH3:54])([CH3:49])[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:50]([CH:47]([CH3:49])[CH3:48])[CH2:51][CH2:52][O:53][CH3:54])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCNC(C)C
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(CCOC)C(C)C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with N-isopropyl-N-(2-methoxy-ethyl)amine (TCI-US) to give the title compound. HR-MS (ES, m/z) calculated for C42H55Cl2N5O4 [(M+H)+] 764.3704, observed 764.3703.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([NH:12][C:13]([NH:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:11][C:5]2=[N:4][CH:3]=1.[NH2:18][C:19]1[C:20]([CH3:25])=[CH:21][CH:22]=[CH:23][CH:24]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1>[CH2:16]([NH:15][C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:5]2[C:6]([N:8]=1)=[N:7][C:2]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25])=[CH:3][N:4]=2)=[O:14])[CH3:17]
Reactant: Cc1ccccc1N
Reactant: CCNC(=O)Nc1ccc2ncc(Cl)nc2n1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1ccc2ncc(Nc3ccccc3C)nc2n1
Temperature: 100 °C

Procedure:
55 mg 1-(3-chlor-pyrido[2,3-b]pyrazine-6-yl)-3-ethyl-urea (0.22 mmol), 60 mg o-toluidine (0.56 mmol), 33 mg sodium-tert.-butylate(0.33 mmol), 29 mg tris(dibenzalacetone)palladium(0) (0.03 mmol) and 78 mg 2-(dicyclohexylphosphanyl)biphenyl (0.22 mmol) were presented in 1.5 ml predried toluene in a microwave reaction vessel under nitrogen as protective gas. The reaction mass was heated in the microwave at 100° C. (100 watt) for 30 minutes. Then the volatile components were removed in vacuum and the raw product was cleaned using column chromatography on silica gel (solvent dichloromethane/methanol). A yellow solid was obtained.
Reaction SMILES: O=[C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:3]1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:2]1[S:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1sc(=O)[nH]c1-c1ccccc1
Product: CCOC(=O)c1sc(Cl)nc1-c1ccccc1
Temperature: 0 °C
Yield: 68 %

Procedure:
To a solution of 20.0 g (0.105 mole) of ethyl β-amino-cinnamate in 40 ml. of chlorobenzene under ice cooling was added a solution of 11.6 g (0.112 mole) of chorocarbonylsulfenyl chloride in 10 ml. of chlorobenzene. The reaction mixture was heated at 110° C. for 2 hours, cooled to triturated with petroleum ether. The precipitate was heated with hot benzene, cooled and filtered to give 14.4 g (55%) of ethyl 2,3-dihydro-2-oxo-4-phenyl-5-thiazolecarboxylate as yellow needles. A mixture of 3.0 g (0.012 mole) of ethyl 2,3-dihydro-2-oxo-4-phenyl-5-thiazolecarboxylate and 14 ml. of phosphorus oxychloride was held at reflux for 24 hours and cooled. The reaction mixture was poured into ice water. The solid precipitate was extracted into ether. The ether solution was dried and concentrated under reduced pressure. The residue was recrystallized from hexane to give 2.2 g (68%) of ethyl 2-chloro-4-phenyl-5-thiazolecarboxylate, m.p. 56°-57° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29]([C:32](=O)[CH2:33][CH3:34])[S:30][CH:31]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br-].[C:37]([CH2:40][CH2:41][CH2:42][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:39])=[O:38].CC(C)([O-])C.[K+]>>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29](/[C:32](/[CH2:33][CH3:34])=[CH:42]/[CH2:41][CH2:40][C:37]([OH:39])=[O:38])[S:30][CH:31]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC(=O)c1cc(CCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)cs1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Product: CC/C(=C\CCC(=O)O)c1cc(CCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)cs1

Procedure:
In a manner similar to that of Example 6(i), by reaction of 3 g (5.6 mmol) of 1-{4-[2-(3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl)ethyl]-2-thienyl}-1-propanone with 3.6 g (8.4 mmol) of (3-carboxy-propyl)triphenylphosphonium bromide and 1.9 g (17 mmol) of potassium tert-butoxide, the desired product is obtained in the form of a yellow oil (m=1.7 g, Y=50%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)CCC.Cl[C:21]1[S:22][CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27]>>[N+:26]([C:25]1[CH:24]=[CH:23][S:22][C:21]=1[C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccsc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Product: O=[N+]([O-])c1ccsc1-c1cnccn1

Procedure:
The title compound was prepared from 2-(tributylstannyl)pyrazine and 2-chloro-3-nitrothiophene using protocol E and was purified by flash chromatograpy (hexane:ethyl acetate). Method [7] Retention time 2.38 min by HPLC (MH+ 208).
Reaction SMILES: C[CH:2]([C:39]([O-:41])=[O:40])[N:3]([C:12](=[O:38])[CH:13]([CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)[NH:14][C:15]([O:17][CH:18]1[CH:25]2[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:27][CH:19]1[CH2:20]3)[CH2:24]2)=[O:16])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O1CCOC[CH2:43]1>O>[NH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]([CH2:28][C:13]([CH3:43])([NH:14][C:15]([O:17][CH:18]2[CH:19]3[CH2:20][CH:21]4[CH2:22][CH:23]([CH2:24][CH:25]2[CH2:26]4)[CH2:27]3)=[O:16])[C:12]([N:3]([CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][C:39]([OH:41])=[O:40])=[O:38])=[CH:30]1
Reactant: CC(C(=O)[O-])N(CCc1ccccc1)C(=O)C(Cc1c[nH]c2ccccc12)NC(=O)OC1C2CC3CC(C2)CC1C3
Reactant: C1COCCO1
Solvent: O
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)N(CCc1ccccc1)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl N-[α-methyl-N-[(tricyclo[3.3.1.13,7 ]dec-2-yloxycarbonyl)-DL-tryptophyl]-N-(2-phenylethyl)glycinate (285 mg, 0.5 mmol) in dioxane (10 mL) and water (5 mL) was added lithium hydroxide-1-hydrate (42 mg, 1.0 mmol) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated, acidified with dilute HCl, and extracted with ethyl acetate (2×50 mL). After drying over magnesium sulfate and concentration, flash column chromatography yielded the title compound which was crystallized from ethyl acetate and hexane to give 80 mg (29%) of white solid, mp 100°-105° C. IR (KBr) 3388 2908, 2855 1710 cm-1 ; NMR (250 MHz DMSO, 70° C.) 1.30 (3H, s), 1.1-1.58 (2H, m), 1.58-2.18 (12H, m), 2.56-2.92 (2H, m), 2.92-3.6 (4H, m), 3.6-4.26 (4H, m), 4.76 (1H, br s), 6.82-7.38 (9H, m), 7.45 (1H, d, J 7.7 Hz), 10.70 (1H, br s).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:16]=2)[C:13](=[O:27])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:28])[N:6]=1)[CH2:3][CH3:4].Cl[C:30]1[CH:35]=[CH:34][N:33]=[C:32]2[NH:36][CH:37]=[N:38][C:31]=12.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:38]1[C:31]2[C:32](=[N:33][CH:34]=[CH:35][C:30]=2[NH:1][C@H:2]([C:5]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([F:26])([F:24])[F:25])[CH:16]=3)[C:13](=[O:27])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[F:28])[N:6]=2)[CH2:3][CH3:4])[NH:36][CH:37]=1
Reactant: Clc1ccnc2[nH]cnc12
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CC[C@H](Nc1ccnc2[nH]cnc12)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
Under nitrogen, to (S)-2-(1-aminopropyl)-5-fluoro-3-(3-(2,2,2-trifluoroethoxy)phenyl)quinazolin-4(3H)-one (40 mg, 0.10 mmol, 1.0 equiv) in t-BuOH (0.5 mL) at 23° C. is added 7-chloro-3H-imidazo[4,5-b]pyridine (23 mg, 0.15 mmol, 1.5 equiv) and diisopropylethylamine (63 μL, 0.36 mmol, 4.0 equiv). After stirring for 48 hr at 120° C. in a sealed tube, the reaction mixture is concentrated in vacuo and the residue is purified by preparative TLC eluting with CH2Cl2/MeOH to afford the title compound (Compound 12A).