Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[C:12]([C:15]1[N:19]2[N:20]=[C:21]([C:24](=O)[CH3:25])[CH:22]=[CH:23][C:18]2=[N:17][CH:16]=1)([OH:14])[CH3:13].Cl.[NH2:28][NH:29][C:30]([NH2:32])=[O:31].C(N(CC)CC)C>CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[C:12]([C:15]1[N:19]2[N:20]=[C:21](/[C:24](=[N:28]/[NH:29][C:30]([NH2:32])=[O:31])/[CH3:25])[CH:22]=[CH:23][C:18]2=[N:17][CH:16]=1)([OH:14])[CH3:13]
Reactant: CC(=O)c1ccc2ncc(C(C)(O)c3cc4cccnc4cc3F)n2n1
Reactant: NNC(N)=O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C/C(=N\NC(N)=O)c1ccc2ncc(C(C)(O)c3cc4cccnc4cc3F)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
To a solution of 1-(3-(1-(7-fluoroquinolin-6-yl)-1-hydroxyethyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (35 mg, 0.09 mmol) in methanol (20 mL) was added semicarbazide hydrochloride (20 mg, 0.18 mmol). Triethyl amine was added dropwise to adjust the pH to 5-6. The reaction mixture was stirred at room temperature overnight. The solution was concentrated in reduced pressure and the residue was purified by column chromatography (3%-50% MeOH in CH2Cl2) to afford 23 mg (yield: 62%) title compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.47 (s, 1H), 8.87 (d, 1H), 8.52 (m, 2H), 8.06 (d, 1H), 7.92 (d, 1H), 7.85 (s, 1H), 7.54 (m, 2H), 6.62 (b, 2H), 6.24 (s, 1H), 2.13 (s, 3H), 1.53 (s, 3H). LCMS (method A): [MH]+=408, tR=4.03 min.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][C@H:10]([CH3:13])[CH2:11][OH:12].F[C:15]1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24].C1C=CC=CC=1>C1(C)C=CC=CC=1>[F:21][C:20]1[C:19]([F:22])=[CH:18][CH:17]=[C:16]([N+:23]([O-:25])=[O:24])[C:15]=1[O:12][CH2:11][C@H:10]([O:9][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][O:3]1)[CH3:13]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: C[C@H](CO)OC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: C[C@H](COc1c([N+](=O)[O-])ccc(F)c1F)OC1CCCCO1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To an ice-cooled suspension of 720 mg of sodium hydride (60%) in 12 ml of anhydrous toluene was added dropwise a solution of 2.88 g of 2-O-tetrahydropyranyl-(R)-propane-1,2-diol (IIIR, Rc=THP) in 12 ml of anhydrous toluene, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 10 minutes. The mixture was added dropwise to a solution of 2.66 g of 2,3,4-trifluoronitrobenzene in 12 ml of anhydrous toluene with stirring under cooling with ice. The mixture was stirred at an external temperature of 5° C. for 24 hours. To the mixture were added ice-water and benzene, and the resulting mixture was shaken. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to yield 2,3-difluoro-6-nitro-{[(R)-2-(tetrahydropyran-2-yl)oxypropyl]oxy}benzene (IR, Xa=Xb=F, Rc=THP) in quantitative yield. This compound was dissolved in 38 ml of anhydrous ethanol and to this was added 450 mg of pyridinium tosylate. The mixture was heated under refluxing for 1 hour. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate. This solution was washed successively with 1 N hydrochloric acid, a 5% sodium bicarbonate aqueous solution and water, then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography to yield 3.20 g of the oily titled compound.
Reaction SMILES: C([Li])(C)(C)C.[Br:6][C:7]1[C:11]([Br:12])=[CH:10][O:9][CH:8]=1.CN(N[CH:17]=[O:18])C.Cl>C1COCC1>[Br:12][C:11]1[C:7]([CH:17]=[O:18])=[CH:8][O:9][CH:10]=1.[Br:6][C:7]1[C:11]([Br:12])=[CH:10][O:9][C:8]=1[CH:17]=[O:18]
Reactant: Brc1cocc1Br
Reactant: CN(C)NC=O
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=Cc1cocc1Br
Product: O=Cc1occ(Br)c1Br
Temperature: -70 °C
Yield: 69.1 %

Procedure:
t-Butyl lithium (1.7M in hexane) (29.23 ml, 49.7 mmol) was added dropwise to 3,4-dibromofuran (11.23 g, 49.7 mmol) in THF (120 ml) maintaining the temperature below -65° C. After 1 h at -70° C. dimethylaminoformamide (7.70 ml, 99.4 mmol) was added dropwise. After 2 h at -70° C. the solution was warmed to room temperature, acidified with 6N hydrochloric acid and the solution extracted with ethyl acetate. Drying (Na2SO4), evaporation to dryness under reduced pressure and purification by flash chromatography using hexane/dichloromethane (1:1) as eluent gave a mixture (3:1) of 3-bromofuran-4-carboxaldehyde and 3,4-dibromofuran-2-carboxaldehyde (4.36 g). This mixture (4.36 g) was treated with sodium borohydride (0.54 g, 14.25 mmol) in aqueous ethanol (4:1) (50ml) at 5° C. After 2 h at 5° C. the mixture was acidified with 6N hydrochloric acid and the solution extracted with ethyl acetate. Drying (Na2SO4), evaporation to dryness under reduced pressure and purification by flash chromatography using dichloromethane/hexane (4:1) as eluent gave the title compound (1.55 g, 18% ) as an amorphous yellow solid; δH (CDCl3) 1.74 (1H, br, s, OH), 4.54 (2H, s, CH2), 7.40-7.47 (2H, m, 2 and 5-H); δC (CDCl3) 55.4 (CH2), 100.7 (C-3), 125.4 (C-4), 141.1, 141.5; m/z 178 (M+, 97%), 176 (100%); (Found: M+, 175.9476. C5H5O2Br requires M, 175.9473).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[F:7][C:8]([F:22])([F:21])[C:9]1[CH:20]=[CH:19][C:12]2[S:13][C:14]([C:16](O)=[O:17])=[CH:15][C:11]=2[CH:10]=1>C(O)C>[F:21][C:8]([F:7])([F:22])[C:9]1[CH:20]=[CH:19][C:12]2[S:13][C:14]([C:16]([O:5][CH2:1][CH3:2])=[O:17])=[CH:15][C:11]=2[CH:10]=1
Reactant: O=C(O)c1cc2cc(C(F)(F)F)ccc2s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCO
Product: CCOC(=O)c1cc2cc(C(F)(F)F)ccc2s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.1 %

Procedure:
Then, 254 mg of oxalyl chloride was added to a mixture of 400 mg of 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid and 20 ml of ethanol while ice-cooling, and the mixture was stirred for 6 hours under reflux. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. To the residue was added chloroform, and then the organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 330 mg of ethyl 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate (the present compound 5).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:16]1[C:21]([CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25][CH3:26])=[O:24])=[C:20]([CH3:30])[N:19]=[C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:17]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[CH3:30][C:20]1[C:21]([CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25][CH3:26])=[O:24])=[C:16]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[N:17]=[C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:19]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1N1CCN(C)CC1
Temperature: 100 °C
Yield: 62.7 %

Procedure:
1-methylpiperazine (0.111 mL, 1.00 mmol) and triethylamine (0.277 mL; 2.00 mmol) were added to a solution of methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol) in tetrahydrofuran (1.5 mL). the reaction vessel was heated at 100° C. for 18 h. The mixture was diluted with a saturated solution of sodium hydrogen carbonate and was extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (60-100%) in heptane furnished 0.120 g (63%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH3:23][O:24][CH2:25][C:26]([C:29]1[CH:33]=[C:32]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[O:31][N:30]=1)([CH3:28])[CH3:27].COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(NC(NC2ON=C(C(C)C)C=2)=O)C=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:35]([NH:34][C:32]2[O:31][N:30]=[C:29]([C:26]([CH3:28])([CH3:27])[CH2:25][O:24][CH3:23])[CH:33]=2)=[O:36])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: COCC(C)(C)c1cc(NC(=O)Oc2ccccc2)on1
Agent: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Product: COCC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OC)c(OC)cc34)c2)on1
Yield: 54 %

Procedure:
3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (40 mg, 0.13 mmol) and phenyl 3-(1-methoxy-2-methylpropan-2-yl)isoxazol-5-ylcarbamate from the previous step (50 mg, 0.18 mmol) were reacted according to the method described for 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B. Purification via preparative silica gel thin layer chromatography eluting with 10% methanol in dichloromethane afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(1-methoxy-2-methylpropan-2-yl)isoxazol-5-yl)urea as a pale yellow solid (35 mg, 54%). 1H NMR (300 MHz, DMSO-d6) δ 10.17 (brs, 1H), 9.05 (brs, 1H), 8.56 (s, 1H), 7.56 (s, 2H), 7.38-7.44 (m, 2H), 7.30 (m, 1H), 7.00 (m, 1H), 6.03 (s, 1H), 3.98-4.00 (2×s, 6H), 3.34 (s, 3H), 3.22 (s, 2H), 1.20 (s, 6H); LC-MS (ESI) m/z 494 (M+H)+.
Reaction SMILES: O=C1CCN(CC2C=CC=CC=2)[C@H]1CC1CC(=O)CC(=O)C1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:35]([O:37][C:38]1[CH2:39][C@@H:40]([CH2:45][C@H:46]2[N:50]([CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:49](=[O:58])[CH2:48][CH2:47]2)[CH2:41][C:42](=[O:44])[CH:43]=1)[CH3:36]>C(O)C.C1(C)C=CC=CC=1>[CH2:35]([O:37][C:38]1[CH2:39][C@H:40]([CH2:45][C@H:46]2[N:50]([CH2:51][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[C:49](=[O:58])[CH2:48][CH2:47]2)[CH2:41][C:42](=[O:44])[CH:43]=1)[CH3:36]
Reactant: CCOC1=CC(=O)C[C@H](C[C@@H]2CCC(=O)N2Cc2ccccc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CC(=O)CC(C[C@H]2C(=O)CCN2Cc2ccccc2)C1
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC1=CC(=O)C[C@@H](C[C@@H]2CCC(=O)N2Cc2ccccc2)C1
Yield: 57 %

Procedure:
A solution of (S)-5-[[oxo-1-(phenylmethyl)-2-pyrrolidinyl]methyl]-1,3-cyclohexanedione (60 g, 0.20 mol) and p-toluenesulfonic acid monohydrate (3.8 g, 0.02 mol) in 600 mL of ethanol and 1200 mL of toluene was stirred and refluxed for 1.5 h. The solvent was removed on a rotary evaporator and the residue dissolved in methylene chloride. The methylene chloride solution was washed with saturated sodium bicarbonate solution, brine, and dried over Na2SO4. The solvent was removed on a rotary evaporator to give 57.6 g of a crude oil. The crude product was chromatographed on silica gel (800 g) eluting with 2-4% methanol in ethyl acetate to give a 1:1 mixture of diastereomeric products: (5S,1R)-5-[(3-ethoxy-5-oxo-3-cyclohexen-1-yl)methyl]-1-(phenylmethyl)-2-pyrrolidinone and (5s,1S)-5-[(3-ethoxy-5-oxo-3-cyclohexen-1-yl)methyl]-1-(phenylmethyl)-2-pyrrolidinone (37.5 g, 57% yield). A total of 25.5 g of mixture (from this and a similar preparation) was chromatographed using a Waters Prep 500 high pressure liquid chromatograph, eluting with 1:24:25 methanol:ethyl acetate:hexane, and recovering and rechromatographing the mixed fractions. A total of 24.3 g (25.0% yield) of the more polar diastereomer, (5S,1R)-5-[(3-ethoxy-5-oxo-3-cyclohexen-1-yl)methyl]-1-(phenylmethyl)-2-pyrrolidinone, and a total of 23.9 g (24.6% yield) of the less polar diastereomer, (5S,1S)-5-[(3-ethoxy-5-oxo-3-cyclohexen-1-yl)methyl]-1-(phenylmethyl)-2-pyrrolidinone was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C[NH:23][CH2:24][CH2:25][NH:26][CH3:27].[CH3:28]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([NH:23][CH2:24][CH2:25][N:26]([CH3:27])[CH3:28])=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CNCCNC
Reactant: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)O)c3)nc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1cc(F)cc(-c2ccc3ncnc(N)c3n2)c1

Procedure:
Following the same reaction and purification procedure, the acid 3 (100 mg, 0.35 mmol) was reacted with N,N′-dimethylethane-1,2-diamine (CAS 5752-40-9) (0.08 mL, 0.7 mmol), HATU (165 mg, 0.42 mmol) and DIPEA (0.30 mL, 1.8 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-(2-(dimethylamino)ethyl)-5-fluorobenzamide 12. LC/MS (ESI+): m/z 355 (M+H). 1H NMR (400 MHz, DMSO) δ 8.69 (t, J=5.5 Hz, 1H), 8.62 (d, J=8.8 Hz, 1H), 8.57 (dd, J=19.4, 10.5 Hz, 2H), 8.44 (s, 1H), 8.27 (d, J=8.8 Hz, 1H), 8.20 (d, J=8.8 Hz, 1H), 8.05 (s, 1H), 7.73 (d, J=9.3 Hz, 1H), 3.43 (dd, J=12.8, 6.6 Hz, 2H), 2.46 (t, J=6.9 Hz, 2H), 2.21 (s, 6H).
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][NH2:16].O>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:16][CH2:15][CH:14]([O:17][CH3:18])[O:13][CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: COC(CN)OC
Solvent: O
Solvent: Cc1ccccc1
Product: COC(CN=Cc1ccc(C(C)C)cc1)OC
Yield: 83.6 %

Procedure:
A mixture of 4-isopropyl benzaldehyde (25 g, 183 mmol) and aminoacetaldehyde dimethylacetal (28.9 g, 275 mmol) in toluene (250 ml) was refluxed with azeotropic removal of water for 13 hours. The solvent was removed under vacuum to afford the titled compound as viscous oil (36 g, 83%). TLC-Chloroform/methanol: (95/5): Rf=0.75. 1H-NMR (CDCl3, 400 MHz) δ 1.28 (6H, d), 2.95 (1H, m), 3.44 (6H, s), 3.78 (2H, d), 4.68 (1H, t), 7.28 (2H, d), 7.68 (2H, d), 8.27 (1H, s).
Reaction SMILES: [OH:1]C1C=CC=CN=1.CC(C)([O-])C.[K+].ClC1N=N[C:18]([O:21][C:22]2[C:27]([CH3:28])=[C:26]([CH3:29])[CH:25]=[C:24]([CH3:30])[C:23]=2[CH:31](SCC)[CH3:32])=C(OC)C=1>CS(C)=O>[CH3:18][O:21][C:22]1[C:27]([CH3:28])=[C:26]([CH3:29])[CH:25]=[C:24]([CH3:30])[C:23]=1[C:31](=[O:1])[CH3:32]
Reactant: CCSC(C)c1c(C)cc(C)c(C)c1Oc1nnc(Cl)cc1OC
Reactant: Oc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1c(C)c(C)cc(C)c1C(C)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In dimethylsulfoxide (1 mL) was dissolved 34.0 mg (0.358 mmol) of 2-hydroxypyridine, 41.0 mg (0.366 mmol) of potassium tert-butoxide was added to the solution at room temperature, and the resulting mixture was stirred at room temperature for 20 minutes. To the mixture was added a dimethylsulfoxide (1 mL) solution containing 26.7 mg (0.0728 mmol) of 6-chloro-3-{2-[1-(ethylsulfanyl)ethyl]-3,5,6-trimethylphenoxy}-4-methoxypyridazine obtained in (1), and the resulting mixture was stirred at 60° C. After completion of the reaction, the reaction mixture was allowed to stand for cooling, and poured into water. After making the mixture acidic by adding hydrochloric acid to the mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, and washed successively with water and brine. After drying over anhydrous magnesium sulfate, the solvent was removed. The obtained residue was purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, developed by ethyl acetate) to obtain 6.6 mg (0.019 mmol, Yield: 26%) of 6-chloro-3-{2-[1-(ethylsulfanyl)ethyl]-3,5,6-trimethylphenoxy}-4-pyridazinol (Compound No. 2606).
Reaction SMILES: BrCCO.C12(C(Cl)=O)CC3CC(CC(C3)C1)C2.C(N(CC)CC)C.Br[CH2:26][CH2:27][O:28][C:29]([C:31]12[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]3)[CH2:32]1)[CH2:38]2)=[O:30].[F:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([C:55]2[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=2)=[C:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[CH:44][CH:43]=1>C(Cl)Cl>[F:61][C:58]1[CH:59]=[CH:60][C:55]([C:48]([C:45]2[CH:44]=[CH:43][C:42]([F:41])=[CH:47][CH:46]=2)=[C:49]2[CH2:54][CH2:53][N:52]([CH2:26][CH2:27][O:28][C:29]([C:31]34[CH2:40][CH:35]5[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]5)[CH2:32]3)[CH2:38]4)=[O:30])[CH2:51][CH2:50]2)=[CH:56][CH:57]=1
Reactant: O=C(OCCBr)C12CC3CC(CC(C3)C1)C2
Reactant: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1
Agent: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: OCCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-bromoethanol (4.9 g., 0.04 mol) in 50 mL of methylene chloride, adamantane-1-carboxylic acid chloride (5.6 g., 0.02 mol) and triethylamine (4 g., 0.04 mol) were added. The reaction mixture was stirred at room temperature overnight and the methylene chloride was washed with water, dried over anhydrous Na2SO4 and removed under reduced pressure to afford 12 g. of the intermediate adamantane-1-carboxylic acid bromoethyl ester. The title compound was prepared by stirring 4-[bis(4-fluorophenyl)-methylene]piperidine (2 g., 0.07 mol), adamantane-1-carboxylic acid bromoethyl ester (2.0 g., 0.007 mol) and triethylamine (1 g., 0.01 mol) in 50 mL of CH2Cl2 for 24 hours. The methylene chloride was washed with water, dried (anhydrous Na2SO4) and removed under reduced pressure. The remaining residue was subjected to preparative HPLC over silica gel using ethylacetate as the eluent and the desired product (TLC Rf = 0.75 in 30% ethanol/ethylacetate system) was separated and converted to the hydrochloride salt with ethanolic HCl; mp. 249°-254° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4].CCN(C(C)C)C(C)C.[CH3:28][O:29][CH2:30]Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:9][C:10]=1[O:11][CH2:28][O:29][CH3:30])=[O:4]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOC1=C(C(=O)OC)CN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butylester 3-methyl ester (10 mmol, 2.71 g) and DIEA (1 mL) in DCM was added methoxymethyl chloride (1.3 mL) drop-wise and continued stirring for 16 h at room temperature. Volatiles were removed under reduced pressure, the resultant residue was taken up in ethyl acetate (50 mL), washed with water (25 mL), dried the organic layer, filtered and concentrated under reduced pressure. The resultant residue was purified by flash column chromatography using mixture of hexanes and ethyl acetate to provide 4-methoxymethoxy-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[CH:26][C:20]=1[CH:21]=[CH:22][C:23](O)=O>>[CH2:13]([N:4]1[C:3](=[O:16])[C:2]2[NH:1][C:23](/[CH:22]=[CH:21]/[C:20]3[CH:26]=[C:27]([O:32][CH3:33])[C:28]([O:30][CH3:31])=[CH:29][C:19]=3[O:18][CH3:17])=[N:8][C:7]=2[N:6]([CH2:9][CH2:10][CH3:11])[C:5]1=[O:12])[CH2:14][CH3:15]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: COc1cc(OC)c(OC)cc1C=CC(=O)O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cc(OC)c(OC)cc3OC)nc2n(CCC)c1=O
Yield: 22.9 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 2.00 g (8.85 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.32 g (9.73 mmol) of 2,4,5-trimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from 2-propanol/water to give 870 mg (yield 23%) of Compound 23 as a pale yellow powder.
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][C:7]2[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:6]=2[C:5]1=[O:23])[CH:2]=[CH2:3].C12BC(CCC1)CCC2.C1C[O:36]CC1>>[OH:36][CH2:3][CH2:2][CH2:1][N:4]1[CH2:10][CH:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][C:7]2[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:6]=2[C:5]1=[O:23]
Reactant: C1CCOC1
Reactant: C=CCN1CC(Cc2ccccc2)Oc2ccc(I)cc2C1=O
Agent: B1C2CCCC1CCC2
Product: O=C1c2cc(I)ccc2OC(Cc2ccccc2)CN1CCCO
Reaction time: 1 h
Yield: 77 %

Procedure:
To a magnetically stirred solution of 2-allyl-4-benzyl-8-iodo-2,3,4,5-tetrahydro-1H-5-oxa-2-benzazepin-1-one (0.9234 grams, 2.2 mmol) in 4 mL THF at room temperature under an atmosphere of nitrogen was added 6.0 mL of a 0.5M solution of 9-borabicylo[3.3.1]nonane in THF (3 mmol) and the mixture stirred for 1 hour. The reaction was quenched with 6 mL of a solution of 2 grams of sodium hydroxide and 22 mL of a 1:1 mixture of ethanol and water. To the resulting solution was added 7 mL of a 30% solution hydrogen peroxide in water. After 30 minutes the mixture was partitioned between diethyl ether and water. The organic layer was washed with 10% citric acid and brine, dried over sodium sulfate, concentrated in vacuo, and purified by column chromatography (SiO2, using 1:5 ethyl acetate/methylene chloride as the eluting solvent, Rf (product)=0.22) to yield 0.74 grams (77%) of 2-(3-hydroxypropyl)-4-benzyl-8-iodo-2,3,4,5-tetrahydro-1H-5-oxa-2-benzazepin-1-one. 1H NMR (CDCl3, dTMS) 8.08 (1H, d, 4JHH =2 Hz, C9-H), 7.71 (1H, dd, 4JHH =2 Hz, 3JHH =8 Hz, C7-H), 7.4 -7.2 (5H, m, C6H5), 6.78 (1H, d, 3JHH =8 Hz, C6-H), 4.64 (1H, m, ArOCH), 3.70 (2H, m, CH2OH), 3.58 (2H, bt, 3JHH =5 Hz, NCH2CH2), 3.39 (1H, dd, 2JHH =15 Hz, 3JHH =8 Hz, C3-H), 3.24 (1H, dd, 2JHH =15 Hz, 3JHH =3 Hz, C3-H), 3.1 (1H, dd, 2JHH =14 Hz, 3JHH =7 Hz, CHHPh), 2.76 (1H, dd, 2JHH =14 Hz, 3JHH =7 Hz, CHHPh), 1.68 (2H, m, CH2CH2OH). 13C NMR (CDCl3) 168.3, 152.6, 141.6, 139.4, 136.2, 132.1, 131.9, 129.2, 129.0, 128.8, 128.4, 127.0, 124.7, 86.8, 85.7, 58.0, 49.9, 44.5, 38.8, 30.3. IR (NaCl, cm-1) 3422 (b), 1636, 1463, 1436, 1217, 1064.
Reaction SMILES: [CH3:1][C:2]([C:13]1[NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[N:14]=1)([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)[CH3:3].[H-].[Na+].I[CH2:25][CH2:26][CH3:27].O1C[CH2:31][CH2:30][CH2:29]1>>[CH3:3][C:2]([C:4]1[N:5]([CH2:29][CH2:30][CH3:31])[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)([C:13]1[N:14]([CH2:25][CH2:26][CH3:27])[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[CH3:1]
Reactant: CCCI
Reactant: CC(C)(c1nc2ccccc2[nH]1)c1nc2ccccc2[nH]1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CCCn1c(C(C)(C)c2nc3ccccc3n2CCC)nc2ccccc21
Reaction time: 0.33 h

Procedure:
To a flask were added 1.4 g 2,2′-propane-2,2-diylbis(1H-benzimidazole) and 30 ml tetrahydrofuran and the mixture was cooled to 10 C under nitrogen. 0.61 g Sodium hydride were added in portions and the reaction mixture was stirred for 20 minutes. 2.6 g 1-iodopropane were added and the mixture was stirred at 22 C for 3.5 hours. The mixture was quenched slowly with 30 ml water and stirred 16 hours. After cooling to 5 C, the solid was filtered and washed with water and purified by silica gel chromatography using 25% ethyl acetate in hexane to 50% ethyl acetate in hexane. 1.4 g of off-white solid was obtained.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8]>>[CH2:7]([NH:9][C:10]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[O:11])[CH3:8]
Reactant: CCN=C=O
Reactant: CC(C)(N)CO
Product: CCNC(=O)NC(C)(C)CO
Yield: 94 %

Procedure:
Prepared as in Example 206d from 2-amino-2-methylpropan-1-ol and ethyl isocyanate in 94% yield. MS 161 (MH+).