Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.[CH3:14][O:15][C:16]1[CH:36]=[CH:35][C:19]([CH2:20][N:21]2[CH:25]=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:23]=[N:22]2)=[CH:18][CH:17]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1.O.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]>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][N:21]2[CH:25]=[C:24]([C:2]3[N:3]=[C:4]([O:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[S:5][CH:6]=3)[CH:23]=[N:22]2)=[CH:35][CH:36]=1
Reactant: COc1ccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)cc1
Reactant: Brc1csc(Oc2ccccn2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc(-c3csc(Oc4ccccn4)n3)cn2)cc1
Temperature: 150 °C
Reaction time: 1 h
Yield: 14.7 %

Procedure:
According to Scheme 3, Step 3: A mixture of 2-(4-bromothiazol-2-yloxy)pyridine (1.56 mmol, 400 mg), 1-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.87 mmol, 587 mg), PdCl2(dppf) (0.16 mmol, 127 mg) and N-ethyl-N-isopropylpropan-2-amine (3.11 mmol, 0.53 mL) in dioxane/water (1:1, 10 mL) was stirred at 150° C. for 1 hour under microwave conditions. The reaction mixture was filtered through a pad of celite and was washed with DCM. The organic phase was washed with water, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude mixture was purified by flash chromatography over silica gel using cyclohexane/EtOAc (90:10 to 70:30) as eluent to yield 2-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-2-yloxy)pyridine (0.23 mmol, 83 mg, 9%) as an oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9]Br)[C:4]=1[F:11].C[O:13][P:14]([O:17][CH3:18])[O:15][CH3:16]>C1(C)C=CC=CC=1>[CH3:16][O:15][P:14]([CH2:2][C:3]1[C:4]([F:11])=[C:5]([CH2:9][P:14](=[O:13])([O:17][CH3:18])[O:15][CH3:16])[CH:6]=[CH:7][CH:8]=1)(=[O:13])[O:17][CH3:18]
Reactant: COP(OC)OC
Reactant: Fc1c(CBr)cccc1CBr
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1cccc(CP(=O)(OC)OC)c1F)OC

Procedure:
A solution of 2,6-bis(bromomethyl)-1-fluorobenzene (2.82 g, 0.010 mole) and trimethylphosphite (5.0 mL, 0.042 mole) in toluene (25 mL) is heated at reflux temperature for 24 hours, after which the solvent and excess trimethylphosphite are removed under reduced pressure. The solid residue is crystallized from ethyl acetate-hexane, giving 3.12 g (0.0089 mole, 89%) of of the title compound, mp 116.5°-117.5° C. Recrystallization gives 2.64 g, mp 117°-118° C.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl>CN(C=O)C.C1COCC1>[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19][O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: Oc1cccnc1
Reactant: C[Si](C)(C)CCOCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCOc1cccnc1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
Add potassium tert-butoxide (2.69 g, 24 mmol) to a 0° C. solution of 3-hydroxy-pyridine (1.90 g, 20 mmol) in DMF (30 mL) and THF (30 mL) stirring under N2. Add 2-(trimethylsilyl)ethoxy-methyl chloride (3.72 mL, 21 mmol) dropwise and allow to warm slowly to RT overnight. Add water to quench, stir for 5 minutes and concentrate. Dissolve in 20% i-PrOH/CHCl3, wash with saturated NaHCO3 solution (2×) and brine. Dry the combined organic layers over MgSO4 and concentrate. Purify the residue by flash chromatography on silica gel eluting with 0-50% EtOAc/hexanes to afford the title compound (3.14 g, 70%) as yellow liquid. MS(IS) 226 (M+1). TLC: Rf=0.43 (50% EtOAc/hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[NH:5][C:6]2=[O:11].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]N)=[CH:16][CH:15]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[N:5]([CH2:18][C:17]1[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=1)[C:6]2=[O:11]
Reactant: NCc1ccc(F)cc1
Reactant: O=C1NC(=O)c2c(Cl)cccc21
Solvent: CC(=O)O
Product: O=C1c2cccc(Cl)c2C(=O)N1Cc1ccc(F)cc1
Temperature: 150 °C
Yield: 88.8 %

Procedure:
A mixture of 4-chloro-isoindole-1,3-dione (2.75 g, 15 mmol) and 4-fluorobenzylamine (1.88 g, 15 mmol) in glacial acetic acid (10 mL) was heated at 150° C. in microwave for 30 mins. After cooled to room temperature, the reaction mixture was poured into ice water and the white precipitates were collected. Recrystallization with EtOH provided the title compound (3.86 g, 89%).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH:19]([OH:20])[C:18]3[S:21][CH2:22][CH:23]([O:26][CH3:27])[CH2:24][S:25][C:17]=3[C:16]2=[O:28])=[N:13][CH:14]=1.Cl.Cl[C:31]([N:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)=[O:32].N1C=CC=CC=1>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH:16]([O:28][C:31]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[O:32])[C:17]3[S:25][CH2:24][CH:23]([O:26][CH3:27])[CH2:22][S:21][C:18]=3[C:19]2=[O:20])=[N:13][CH:14]=1
Reactant: COC1CSC2=C(SC1)C(O)N(c1ccc(Cl)cn1)C2=O
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1CSC2=C(SC1)C(OC(=O)N1CCN(C)CC1)N(c1ccc(Cl)cn1)C2=O
Temperature: 45 °C
Yield: 31.7 %

Procedure:
Triethylamine (42 cc) is added, at about 15° C., to a suspension of 7-(5-chloropyrid-2-yl)-6-hydroxy-3-methoxy-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (7.4 g) and 1-chlorocarbonyl-4-methylpiperazine hydrochloride (43.0 g) in anhydrous methylene chloride (215 cc), and anhydrous pyridine (90 cc) is then added to the resulting mixture. The reaction mixture is heated for 10 hours at 45° C. After cooling, the mixture is diluted by adding methylene chloride (250 cc). The organic phase is washed three times with an N aqueous sodium hydroxide solution (total 300 cc) and three times with distilled water (total 750 cc), dried over anhydrous sodium sulphate and evaporated. The residue is dissolved in boiling ethanol (50 cc). After cooling the solution for 20 hours at 2° C., the resulting crystals are filtered off, washed three times with ice-cooled ethanol (total 30 cc) and dried under reduced pressure (20 mm Hg). The resulting product (5.1 g; m.p. 197° C.) is dissolved in boiling ethanol (80 cc). After filtering the boiling solution and then cooling the filtrate for 16 hours at 2° C., the resulting crystals are filtered off, washed with ice-cooled ethanol (8 cc) and dried under reduced pressure (0.2 mm Hg) at 55° C. 7-(5-Chloropyrid-2-yl)-3-methoxy-6-(4-methylpiperazin-1-yl)carbonyloxy-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]-pyrrole (3.2 g), which melts at 199° C., is obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5]CC)=O.[CH:8](O)([CH2:10][CH3:11])[CH3:9]>C1(C)C=CC=CC=1>[CH2:9]([C@@:2]1([CH3:9])[NH:1][C:3](=[O:5])[CH2:2][NH:1][C:3]1=[O:5])[C:8]1[CH:11]=[CH:10][CH:8]=[CH:11][CH:10]=1
Reactant: CCOC(=O)CN
Reactant: CCC(C)O
Solvent: Cc1ccccc1
Product: C[C@]1(Cc2ccccc2)NC(=O)CNC1=O
Reaction time: 21 h
Yield: 100 %

Procedure:
A solution of α-methyl-(R)-phenylalanyl)glycine, ethyl ester (0.63 g, 2.4 mmol) in sec-butanol (14 ml) and toluene (7 ml) was stirred at reflux. After 21 h, the solvent was removed in vacuo and the residue azeotroped with toluene (3×) to afford the product (0.51 g, 100% yield) as a white solid. MS (ESI) 219 (M+H). This was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:12]=[CH:13][N:14]=[C:15]([O:16][CH2:17][CH3:18])[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1.Cl[C:20]1[C:29]2[CH:30]=[CH:31][N:32]=[C:33]([Cl:34])[C:28]=2[C:27]2[C:22](=[CH:23][CH:24]=[N:25][CH:26]=2)[N:21]=1.[Cl:35][C:36]1[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[C:37]=1[NH2:38].CC(C)([O-])C.[Na+]>C1COCC1>[Cl:35][C:36]1[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[C:37]=1[NH:38][C:2]1[C:11]2[CH:12]=[CH:13][N:14]=[C:15]([O:16][CH2:17][CH3:18])[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1.[Cl:34][C:33]1[C:28]2[C:27]3[C:22](=[CH:23][CH:24]=[N:25][CH:26]=3)[N:21]=[C:20]([NH:38][C:37]3[C:39]([F:44])=[CH:40][C:41]([F:43])=[CH:42][C:36]=3[Cl:35])[C:29]=2[CH:30]=[CH:31][N:32]=1
Reactant: Clc1nc2ccncc2c2c(Cl)nccc12
Reactant: CCOc1nccc2c(Cl)nc3ccncc3c12
Reactant: Nc1c(F)cc(F)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1nccc2c(Nc3c(F)cc(F)cc3Cl)nc3ccncc3c12
Product: Fc1cc(F)c(Nc2nc3ccncc3c3c(Cl)nccc23)c(Cl)c1
Temperature: 85 °C

Procedure:
To a solution of 1.5:1 mixture of 6-chloro-10-ethoxypyrido[4,3-c]-1,6-naphthyridine and 6,10-dichloropyrido[4,3-c]-1,6-naphthyridine (1.5 g) in THF (25 mL) was added 2-chloro-4,6 difluoro aniline (945 mg, 5.78 mmol) and sodium tert-butoxide (1.65 g, 17 mmol). The solution was heated to 85° C. for 40 min then cooled to room temperature and extracted with EtOAc and brine. The organic layers were dried with MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified on silica gel (100% hexanes to 100% EtOAc, gradient elution) which provided N-(2-chloro-4,6-difluorophenyl)-10-ethoxypyrido[4,3-c]-1,6-naphthyridin-6-amine and 10-chloro-N-(2-chloro-4,6-difluorophenyl)pyrido[4,3-c]-1,6-naphthyridin-6-amine.
Reaction SMILES: [Na].Cl.[N:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O>C(O)C>[F:12][C:13]1[CH:14]=[C:15](/[CH:16]=[C:9](\[C:6]2[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=2)/[C:10]#[N:11])[CH:18]=[CH:19][CH:20]=1
Reactant: N#CCc1ccncc1
Reactant: O=Cc1cccc(F)c1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: N#C/C(=C/c1cccc(F)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.3 %

Procedure:
Sodium (3.0 g, 130 mmol) was dissolved in ethanol (150 mL), 4-pyridylacetonitrile hydrochloride (10 g, 65 mmol) was added thereto, and then the mixture was stirred at room temperature. After 10 minutes, 3-fluorobenzaldehyde (8 g, 65 mmol) was added thereto, followed by stirring as it was for 30 minutes. The resulting precipitates were collected by filtration and washed with a small portion of water, to give the title compound (8.2 g, 56%) as a colorless solid.
Reaction SMILES: O.NN.[CH2:4]([N:11]=[C:12]=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N:14]12CCN(CC1)CC2.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:4]([NH:11][C:12]([NH2:14])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C=NCc1ccccc1
Reactant: C1CN2CCN1CC2
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: NC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound obtained in Example 190, (1) (87 mg) was dissolved in toluene (2 ml), and benzyl isocyanate (14 μl) was added to the solution. 1,4-Diazabicyclo-[2,2,2]octane (4.7 μl) was added to the mixture under ice cooling, and the resulting mixture was warmed to room temperature and stirred for 2 hours. Ethyl acetate and saturated aqueous sodium hydrogencarbonate were added to the reaction mixture, the layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer chromatography (chloroform:methanol:28% aqueous ammonia=20:1:0.1) to obtain a benzylurea compound (62 mg). (2) By using the compound obtained in (1) mentioned above (62 mg) as a starting material, a deprotected compound (55 mg) was obtained in the same manner as that of Example 2, (2). (3) By using the compound obtained in (2) mentioned above (55 mg) as a starting material, the compound shown in Table 5 (20 mg) was obtained in the same manner as that of Example 11.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[C:9](=[O:16])[NH:10][C:11](SC)=[N:12][CH:13]=2)=[CH:3][CH:2]=1.[Br:17][C:18]1[C:19]([CH2:24][S:25][CH2:26][CH2:27][NH2:28])=[N:20][CH:21]=[CH:22][CH:23]=1>>[Br:17][C:18]1[C:19]([CH2:24][S:25][CH2:26][CH2:27][NH:28][C:11]2[NH:10][C:9](=[O:16])[C:8]([CH2:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:13][N:12]=2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: CSc1ncc(Cc2ccncc2)c(=O)[nH]1
Reactant: NCCSCc1ncccc1Br
Product: O=c1[nH]c(NCCSCc2ncccc2Br)ncc1Cc1ccncc1

Procedure:
5-(4-Pyridylmethyl)-2-methylthio-4-pyrimidone (1.1 g) was reacted with 2-(3-bromo-2-pyridylmethylthio)ethylamine (1.15 g) according to the procedure of Example 2. The reaction mixture was triturated under hot water to give 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(4-pyridylmethyl)-4-pyrimidone. This product was acidified with dilute ethanolic hydrogen chloride, evaporated to dryness and the residue recrystallised from ethanol to give the title compound m.p. 211°-215° (decomp). (Found: C, 42.65; H, 3.9; N, 13.9; S, 6.3; C18H18Br N5OS.2HCl requires: C, 42.8; H, 4.0; N, 13.9; S, 6.35%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C1N2CN3CN(C2)CN1C3.[C:21](O)(=[O:23])C>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:21]=[O:23]
Reactant: CC(=O)O
Reactant: Clc1cnc2[nH]ccc2c1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1c[nH]c2ncc(Cl)cc12
Temperature: 25 °C

Procedure:
To a solution of 5-chloro-7-azaindole (0.50 g, 3.3 mmol) in acetic acid (5.0 mL), hexamethylenetetramine (0.69 g, 4.9 mmol) was added at ambient temperature. The mixture was refluxed for 8 h. Cooled to ambient temperature, the reaction mixture was diluted with water, extracted with ethyl acetate for 2 times. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel(hexane/ethyl acetate) to afford 5-chloro-7-azaindole-3-carboxaldehyde as solid (0.13 g, y. 22%).
Reaction SMILES: OC1[CH2:6][CH2:5][CH:4]([CH:7]=[CH:8][CH:9]([OH:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23].[N+](=[CH2:28])=[N-].[B-](F)(F)(F)[O+:30]([CH3:32])[CH3:31]>C(OCC)C>[CH3:31][O:30][CH:32]1[CH2:6][CH2:5][CH:4]([CH:7]=[CH:8][CH:9]([O:15][CH3:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23]
Reactant: C=[N+]=[N-]
Reactant: CCCCCC(O)C=CC1CCC(O)C1CCCCCCC(=O)OC
Reactant: C[O+](C)[B-](F)(F)F
Solvent: CCOCC
Product: CCCCCC(C=CC1CCC(OC)C1CCCCCCC(=O)OC)OC
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
A solution of methyl 7-[2-hydroxy-5-(3-hydroxy-1-octenyl)cyclopentyl]heptanoate (0.6 g.) [prepared as described in Example 5] in dry diethyl ether (30 ml.) was cooled to -40°C. Freshly prepared dry diazomethane in diethyl ether, cooled to -40°C., was added to the solution of methyl ester immediately after the addition of boron trifluoride dimethyl etherate (3 ml.). Diazomethane solution was added until the yellow colour persisted. After 15 minutes at -40°C. and standing at ambient temperature overnight the solution was filtered from precipitated polymethylenes, washed with sodium bicarbonate solution and water, dried over anhydrous sodium sulphate and evaporated in vacuo. The last traces of solvent were removed by pumping under high vacuum to give methyl 7-[2-methoxy-5-(3-methoxy-1-octenyl)cyclopentyl]heptanoate (0.42 g., 65%). (Found: C, 72.4; H, 10.3. C23H42O4 requires C, 72.3; H,11.0%) νmax 1730 cm-1, 1100 cm-1 and 990 cm-1 (liquid film).
Reaction SMILES: [CH:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]([CH2:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)[C:9]([C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)=[O:10])=[CH:5][CH:4]=1)=O.C[Si](C)(C)CCOCN1C=CN=C1C=O.[CH2:39]([N:42]([CH2:48][CH2:49][CH3:50])[CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])[CH2:40][CH3:41]>>[CH2:48]([N:42]([CH2:39][CH2:40][CH3:41])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][CH2:1][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]([CH2:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)[C:9]([C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)=[O:10])=[CH:5][CH:4]=1)[CH2:49][CH3:50]
Reactant: CCCN(CCC)CCCCN
Reactant: O=Cc1ccc(CN(Cc2ncc[nH]2)C(=O)c2ncc[nH]2)cc1
Agent: C[Si](C)(C)CCOCn1ccnc1C=O
Product: CCCN(CCC)CCCCNCc1ccc(CN(Cc2ncc[nH]2)C(=O)c2ncc[nH]2)cc1

Procedure:
The same procedure as a series of reactions of Example 1 was carried out, except that the compound 18 was used in place of 1-({[2-(trimethylsilyl)ethyloxy]methyl}-1H-imidazole-2-carboaldehyde and N,N-dipropyl-1,4-butanediamine was used in place of {[4-(methyloxy)phenyl]methyl}amine, to obtain the title compound having the following physical properties.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:10])([CH3:9])[C:4]1[O:5][CH:6]=[CH:7][CH:8]=1.[I-:11].[Na+]>C(#N)C>[I:11][CH2:2][Si:3]([CH3:10])([CH3:9])[C:4]1[O:5][CH:6]=[CH:7][CH:8]=1
Reactant: [I-]
Reactant: C[Si](C)(CCl)c1ccco1
Agent: [Na+]
Solvent: CC#N
Product: C[Si](C)(CI)c1ccco1

Procedure:
Combine chloromethyl(dimethyl)furylsilane (4.4 g, 23.1 mmol) obtained from Example 2, step (a) with acetonitrile (100 mL). Add sodium iodide (3.5 g, 23.1 mmol) and stir overnight under nitrogen. Filter the mixture and remove ~40 mL of solvent via distillation.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH3:18][C:19]([CH3:35])(C)[C:20](=[O:33])[C:21](=[CH:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:22]([OH:24])=[O:23].[C:36](O)(=O)C>C1COCC1.O>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH:25]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:11]2=[O:17])[CH:21]([C:20](=[O:33])[CH:19]([CH3:35])[CH3:18])[C:22]([O:24][CH3:36])=[O:23])=[CH:27][CH:28]=1
Reactant: CC(C)(C)C(=O)C(=Cc1ccc(F)cc1)C(=O)O
Reactant: CC(=O)O
Reactant: O=C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)C(C)C)C(c1ccc(F)cc1)C1CCCCC1=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A NaHMDS solution in THF (112 mL, 1.0 M) was diluted with 50 mL of dry THF and cooled to −78° C. A solution of cyclohexanone (10.6 mL, 102 mmol) in 50 mL of dry THF was added dropwise over 10 min. After the addition, the mixture was allowed to warm to room temperature and stirred at 0° C. for 15 min before it was cooled to −78° C. again. A pre-cooled solution of methyl 2-[(4-fluorophenyl)methylene]-4-methyl-3-oxo-pentanoic acid (30.7 g, 123 mmol) in 30 mL of dry THF at −78° C. was added quickly via a cannula. The reaction mixture was stirred at −78° C. for 3 h and quenched with acetic acid (30 mL, 524 mmol) in 30 mL of THF. After warming to room temperature the reaction was diluted with 50 mL of water and extracted with ethyl acetate (3×100 mL). The organic fractions were combined, washed with saturated aqueous sodium chloride solution (100 mL), dried over magnesium sulfate, filtered and concentrated in vacuum to provide methyl 4-fluoro-α-(1-oxo-2-methylpropyl)-β-(2-oxocyclohexyl)benzenepropanoate a pale yellow oil: LCMS (method 5) tR=2.1 min; (ESI, pos. ion spectrum) m/z 349 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH:8]=[CH:7][CH2:6][CH2:5]1.[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11].[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[C:22]1([N:28]2[CH2:33][CH2:32][N:31]([C:10]([NH:1][CH2:2][CH2:3][N:4]3[CH2:5][CH:6]=[CH:7][CH2:8][CH2:9]3)=[O:11])[CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCN1CC=CCC1
Solvent: C1CCOC1
Product: O=C(NCCN1CC=CCC1)N1CCN(c2ccccc2)CC1

Procedure:
Following the procedure of Example 5, N-(2-aminoethyl)-1,2,3,6-tetrahydropyridine and 1,1'-carbonyldiimidazole are reacted together in tetrahydrofuran and the product thereof is reacted further with 1-phenylpiperazine to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:25]5[C:26](Br)=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:25]5[C:26]([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5-c5ccccc5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-(2-bromo-pyridin-3-yl)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and phenylboronic acid following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 9): tR=1.15 min; Mass spectrum (ESI+): m/z=496 [M+H]+.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[Br:9]Br.C(Cl)(Cl)Cl.CO>C(OC)(C)(C)C>[Br:9][C:7]1[CH:8]=[C:1]([OH:2])[CH:3]=[CH:4][C:5]=1[OH:6]
Reactant: BrBr
Reactant: Oc1ccc(O)cc1
Solvent: COC(C)(C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Oc1ccc(O)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of hydroquinone Q-1 (10 g, 90.90 mmol) in MTBE (methyl tert-butyl ether) (100 mL) at −5° C. was added bromine (17.4 g, 90.90 mmol). The reaction mixture was stirred at 0° C. for 30 min. Solvent was removed in vacuo and the crude product was purified by column chromatography (SiO2, 2% MeOH—CHCl3) to afford compound Q-2 (13 g, 75%) as a solid. TLC Rf=0.6 (CHCl3-MeOH, 9:1); 1H NMR (CDCl3) δ 6.94 (app d, 1H), 6.88 (d, J=8.7 Hz, 1H), 6.72 (dd, J=8.7, 2.8 Hz, 1H), 5.19 (s, 2H) (Synlett 2000, 11, 1561-1564).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:21]=3)=[O:19])[CH:14]=[CH:13][C:12]=2[Cl:32])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[Cl:32][C:12]1[CH:13]=[CH:14][C:15]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH:21]=2)=[O:19])=[CH:16][C:11]=1[NH:10][C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:37]2[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]2)[CH:7]=1)=[O:9]
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccnc(Cl)c2)c1)c1ccnc(N2CCOCC2)c1
Reactant: CN1CCNCC1
Product: CN1CCN(c2cc(C(=O)Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3Cl)ccn2)CC1
Yield: 69 %

Procedure:
Using an analogous procedure to that described in Example 21, 2-chloro-N-[2chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-4-carboxamide was reacted with N-methylpiperazine to give the title compound in 69% yield; NMR Spectrum: (DMSOd6) 2.21 (s, 3H), 2.4 (m, 4H), 3.53 (m, 8H), 3.71 (m, 4H), 7.09 (m, 2H), 7.25 (d, 2H), 7.53 (d, 1H), 7.71 (d, 1H), 8.02 (s, 1H), 8.26 (t, 1H), 10.19 (s, 1H), 10.48 (s, 1H); Mass Spectrum: M+H+ 536.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[N:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][CH:28]=[C:29]([C:31](O)=[O:32])[N:30]=2)=[CH:22][CH:21]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:31]([C:29]1[N:30]=[C:26]([C:23]2[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=2)[S:27][CH:28]=1)=[O:32]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1csc(-c2ccncc2)n1
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1csc(-c2ccncc2)n1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 2-pyridin-4-yl-thiazole-4-carboxylic acid. MS: 448.2 (M+H).