Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:15][CH2:16][CH2:17][CH3:18])[C:3]([NH:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][N:7]=1)=[O:4].[CH3:19]I>>[CH3:1][N:2]([CH2:15][CH2:16][CH2:17][CH3:18])[C:3]([N:5]([CH3:19])[C:6]1[CH:10]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[O:8][N:7]=1)=[O:4]
Reactant: CI
Reactant: CCCCN(C)C(=O)Nc1cc(C(C)(C)C)on1
Product: CCCCN(C)C(=O)N(C)c1cc(C(C)(C)C)on1

Procedure:
The reaction is effected as in Example 171 by using 1-methyl-1-butyl-3-(5-t-butyl-3-isoxazolyl)urea and methyl iodide to give 1,3-dimethyl-1-butyl-3-(5-t-butyl-3-isoxazolyl)urea as an oil boiling at 130° to 135° C. (bath temperature)/0.25 mm Hg.
Reaction SMILES: ClCCl.[CH3:4][O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([O:17]C)[CH:11]=2)=[O:7].B(Br)(Br)Br>O>[CH3:4][O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([OH:17])[CH:11]=2)=[O:7]
Reactant: COC(=O)c1cc2ccc(OC)cc2[nH]1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc2ccc(O)cc2[nH]1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 84.7 %

Procedure:
To a dichloromethane (10 mL) solution of 6-methoxy-1H-indole-2-carboxylic acid methyl ester (500 mg, 2.44 mmol) was added boron tribromide (12.2 mL, 12.2 mmol) at −78° C., which was stirred for 50 minutes at 0° C. under nitrogen atmosphere. To the reaction solution was added water at 0° C. followed by extraction with ethyl acetate. The organic layer was washed with sat. NaCl followed by drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (395 mg, 85%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(#N)C.CC(N(C)C)=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:6]2[C:5]([O:9][CH3:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cnc(Cl)nc1Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cnc(Cl)nc1NC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A solution of 2,4-dichloro-5-methoxy-pyrimidine (0.80 g, 4.47 mmol, 1.0 equiv; commercially available from Specs Research Laboratory, The Netherlands), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.34 g, 6.70 mmol, 1.5 equiv) and triethylamine (0.93 mL, 0.68 g, 6.70 mmol, 1.5 equiv) in acetonitrile (9 mL) and DMAc (2 mL) was heated by microwave irradiation to 120° C. for 20 min. The reaction mixture was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 1.43 g (93%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.28-1.49 (m, 2H), 1.40 (s, 9H), 1.93-1.98 (m, 2H), 2.85-2.92 (m, 2H), 3.80 (s, 3H), 3.97-4.02 (m, 2H), 4.06-4.12 (m, 1H), 5.22 (d, J=8.0 Hz, 1H), 7.46 (s, 1H). MS (ISP): 343.3 [M+H]+.
Reaction SMILES: C(OC([O:11][C:12]1[C:21]2[C:16](=[C:17]([CH2:33][N:34]([C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])[CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:18]([O:22]C(OCC3C=CC=CC=3)=O)=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[CH2:51][N:52]([C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:60])[CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1)=O)C1C=CC=CC=1.C[O-].[Na+]>CO>[OH:11][C:12]1[C:21]2[C:16](=[C:17]([CH2:33][N:34]([C:41]([O:43][CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)=[O:42])[CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[C:18]([OH:22])=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[CH2:51][N:52]([C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:60])[CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1
Reactant: O=C(OCc1ccccc1)Oc1ccc2c(OC(=O)OCc3ccccc3)c(CN(C(=O)OCc3ccccc3)C3CCCCC3)ccc2c1CN(C(=O)OCc1ccccc1)C1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(OCc1ccccc1)N(Cc1ccc2c(CN(C(=O)OCc3ccccc3)C3CCCCC3)c(O)ccc2c1O)C1CCCCC1

Procedure:
A solution of the crude product from Step B (2.0 g, 2.3 mmol) in methanol (50 ml) was treated with sodium methoxide (120 mg, 2.2 mmol) for 18 hours at room temperature. The mixture was evaporated, the residue taken up in diethyl ether, acetic acid (1 ml) added, the solution washed three times with water, saturated acueous sodium chloride solution, dried (sodium sulfate) and evaporated. The crude product was vacuum filtered through a column of silica gel (Merck β 7734) eluted with 2:1 hexane-ether; yield 1.5 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]([O:22]C)=O)[CH:17]=[C:16]([CH:24]=[CH2:25])[CH:15]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH3:26]>CO.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]([NH2:26])=[O:22])[CH:17]=[C:16]([CH:24]=[CH2:25])[CH:15]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: N
Reactant: C=Cc1cc(C(=O)OC)nc(-c2ccc(-c3ccc(F)cc3)cc2)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C=Cc1cc(C(N)=O)nc(-c2ccc(-c3ccc(F)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 6-(4′-fluoro-[1,1′-biphenyl]-4-yl)-4-vinylpicolinate (600 mg, 1.8 mmol) was dissolved in 10 mL of methanol in a pressure tube. Into the tube was condensed about 10 mL ammonia at −20° C. to −30° C. The pressure tube was tightly closed and the resulting solution was stirred at room temperature for overnight. TLC (silica gel, 10% methanol in chloroform) showed the reaction had gone to completion. The ammonia was removed by nitrogen purge and the methanol was removed under reduced pressure to obtain 300 mg of 6-(4′-fluoro-[1,1′-biphenyl]-4-yl)-4-vinylpicolinamide which was pure enough to take to next step without purification.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH2:24]([N:26]([CH2:43][CH3:44])[CH2:27][CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1)[CH3:25].C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C.O>[CH2:43]([N:26]([CH2:24][CH3:25])[CH2:27][CH2:28][N:29]1[CH:33]=[C:32]([C:2]2[CH:23]=[CH:22][C:5]3[C:6]4[N:7]([CH:11]=[C:12]([C:14]5[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=5)[N:13]=4)[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)[CH:31]=[N:30]1)[CH3:44]
Reactant: CCN(CC)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCN(CC)CCn1cc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)cn1
Reaction time: 0.17 h
Yield: 32.8 %

Procedure:
A 5 mL microwave vial was charged with 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (347 mg, 0.928 mmol), N,N-diethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanamine (340 mg, 1.16 mmol), 2 M potassium carbonate in water (0.9 mL, 2 mmol), and acetonitrile (1.52 g, 37.1 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium(II) chloride (45.4 mg, 0.056 mmol) was added prior to sealing the vial. The reaction was placed on the microwave at 140° C. for 10 minutes. The cooled reaction mixture was diluted with ethyl acetate and water and partitioned. The organic layer was washed with brine and, dried over sodium sulfate, concentrated in vacuo and purified by HPLC to give 222 (140 mg, 33% yield, M+1 461.6)
Reaction SMILES: [F-:1].[K+].COCCOCCOC.[F:12][C:13]([F:36])([C:32]([F:35])([F:34])[F:33])[C:14]([F:31])([F:30])[C:15]([F:29])([F:28])[C:16]([F:27])([F:26])[C:17]([F:25])([F:24])[C:18]([F:23])([F:22])[C:19]([F:21])=[O:20].S(F)(O[C:41]([F:48])([F:47])[C:42]([F:46])=[C:43]([F:45])[F:44])(=O)=O>O>[F:44][C:43]([F:45])=[C:42]([F:46])[C:41]([F:48])([F:47])[O:20][C:19]([F:1])([F:21])[C:18]([F:23])([F:22])[C:17]([F:25])([F:24])[C:16]([F:27])([F:26])[C:15]([F:28])([F:29])[C:14]([F:30])([F:31])[C:13]([F:36])([F:12])[C:32]([F:33])([F:34])[F:35]
Reactant: [F-]
Reactant: O=S(=O)(F)OC(F)(F)C(F)=C(F)F
Reactant: O=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Solvent: COCCOCCOC
Solvent: O
Product: FC(F)=C(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 5 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A mixture of potassium fluoride (5.80 g, 0.10 mol), diglyme (150 ml) and pentadecafluorooctanoyl fluoride (prepared by treating commercial perfluorooctanoic acid with sulfur tetrafluoride) (25.0 g, 0.06 mol) was stirred at 5° C. for 1 hour. Perfluoroallyl fluorosulfate (23.0 g, 0.10 mol) was added dropwise and the mixture was stirred at 5° C. for 4 hours, then at 25° C. for an additional 3 hours. The mixture was poured into water (1 l.), separated, and the lower layer was distilled from concentrated sulfuric acid to give perfluoro-3(octyloxy)propene (27.1 g, 0.048 mol, 80%) bp 69°-70° C. (20 mm Hg) whose structure was confirmed by: λmax 5.59 (CF=CF2) and 8-9 μm (CF C--O); 19F NMR-71.8 (d J=25.1 Hz, each member d J=13.4 Hz, t J=13.4 Hz, d J=7.7 Hz) 2F, OCF2C=C, -81.6 (t J=10.0 Hz) 3F, CF3, -83.8 (m) 2F, CF2CF2O, -92.3 (d J=53.6 Hz, each member d J=39.9 Hz, t J=7.7 Hz) 1F, cis-CF2CF=CF, -105.5 (d J=117.8 Hz, each member d J=53.5 Hz, t J=25.1 Hz) 1F, trans-CF2CF=CF, -122.2 (m) 6F, CF2, -122.9 (m) 2F, CF2, -125.7 (m) 2F, CF2, -126.5 (m) 2F, CF2, and -190.8 ppm (d J=117.8 Hz, each member d J=39.9 Hz, t 13.7 Hz, t 1.7 Hz) 1F, CF2CF=C.
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:13])[C@H:4]1[C:8]([CH3:10])([CH3:9])[O:7][C:6]([CH3:12])([CH3:11])[O:5]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>CCOCC>[CH3:11][C:6]1([CH3:12])[O:5][C@@H:4]([C:3]([Cl:13])=[N:2][O:1][S:15]([CH3:14])(=[O:17])=[O:16])[C:8]([CH3:9])([CH3:10])[O:7]1
Reactant: CC1(C)O[C@@H](C(Cl)=NO)C(C)(C)O1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC1(C)O[C@@H](C(Cl)=NOS(C)(=O)=O)C(C)(C)O1
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
(R)—N-hydroxy-2,2,5,5-tetramethyl-1,3-dioxolane-4-carbimidoyl chloride (12.4 g, 59.7 mmol) was dissolved in Et2O (200 mL) and cooled in an ice bath. Methanesulfonyl chloride (4.6 ml, 59.7 mmol) was added. Triethylamine (8.3 ml, 59.7 mmol) was added slowly and the reaction was stirred in an ice bath for 30 minutes. The reaction was filtered and concentrated. The residue was purified over silica gel (100% CH2Cl2) to afford (R)-2,2,5,5-tetramethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoyl chloride (11.3 g, 39.55 mmol, 66.22% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH2:14][CH2:13][C:8]3[N:9]([CH3:12])[N:10]=[CH:11][C:7]=3[C:4]=2[NH:5][N:6]=1.[H-].[Na+].I[CH3:18].[ClH:19]>CN(C)C=O.C(OCC)C>[ClH:19].[CH3:18][N:5]1[C:4]2[C:7]3[CH:11]=[N:10][N:9]([CH3:12])[C:8]=3[CH2:13][CH2:14][C:3]=2[C:2]([CH3:1])=[N:6]1
Reactant: Cc1n[nH]c2c1CCc1c-2cnn1C
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1nn(C)c2c1CCc1c-2cnn1C
Temperature: 0 °C
Yield: 20 %

Procedure:
A solution of 14.5 g of 1,4,5,6-tetrahydro-3,6-dimethylbenzo[1,2-c:3,4-c']dipyrazole in 50 ml of dimethylformamide was added to an ice-cold stirred suspension of 2.4 g of sodium hydride in 50 ml of dimethylformamide. The reaction was stirred at 0° C. for 20 minutes and then a solution of 6.3 ml of iodomethane in 15 ml of dimethylformamide was added dropwise. The mixture was allowed to come to room temperature and stirred for 2 hours. The solvent was evaporated under reduced pressure and the residue partitioned between dichloromethane and water. The aqueous layer was extracted exhaustively with dichloromethane and the combined dichloromethane extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was flash chromatographed (7.5% 2-propanol in dichloromethane) to give crude product. This crude mixture was dissolved in ethyl ether and acidified with ethereal hydrogen chloride. The cream color precipitate which formed was recrystallized from 2-butanol to give 1,4,5,6- tetrahydro-1,3,6-trimethylbenzo[1,2-c:3,4-c']dipyrazole monohydrochloride as light-yellow granules (20% yield) melting at about 252°-254° C.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][N:28]([CH3:32])[C:29](Cl)=[O:30]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:29](=[O:30])[N:28]([CH3:32])[CH3:27])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: CN(C)C(=O)Cl
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CN(C)C(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (24 mg, 24%), MS (ISP) m/z=400.4 [(M+H)+], mp 260° C., was prepared in accordance with the general method of example 47 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and dimethylcarbamic chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])/[CH:4]=[CH:5]/[O:6][CH3:7].[CH:9](OC)([O:12][CH3:13])[O:10][CH3:11].[C:16](=O)([O-])[O-:17].[Na+].[Na+]>>[CH3:1][O:2][C:3](=[O:8])[CH:4]([CH:9]([O:12][CH3:13])[O:10][CH3:11])[CH:5]([O:17][CH3:16])[O:6][CH3:7]
Reactant: O=C([O-])[O-]
Reactant: COC(OC)OC
Reactant: CO/C=C/C(=O)OC
Agent: [Na+]
Product: COC(=O)C(C(OC)OC)C(OC)OC
Temperature: 40 °C
Reaction time: 2 h
Yield: 123 %

Procedure:
To a stirred mixture of 17.7 g methyl-trans-3-methoxyacrylate and 32.3 g trimethyl ortho formate was added 1.0 g FeCl3. The mixture was heated to 40° C. for 24 hours, cooled to room temperature and 5.00 g anhydrous sodium carbonate were added. After stirring for 2 hours, the mixture was filtered and the filter-cake washed with trimethyl ortho formate. Fractional distillation gave 12.9 g colorless liquid (76.5% of theoretical based on converted methyl-trans-3-methoxyacrylate) of boiling point 100° C./4 mm Hg. A GC-analysis of the liquid revealed an assay of >99% (FID-detection).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[C:18](OC)[N:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)=[CH:6][CH:5]=1)([OH:3])=[O:2].P(Br)(Br)Br.[OH2:26].C[N:28]([CH:30]=O)C>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[C:18]([C:11]4[C:30]5[C:15](=[N:16][O:26][N:28]=5)[CH:14]=[CH:13][CH:12]=4)[N:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O
Reactant: CN(C)C=O
Reactant: COc1nc(-c2ccc(C(=O)O)cc2)cc2cccnc12
Agent: BrP(Br)Br
Product: O=C(O)c1ccc(-c2cc3cccnc3c(-c3cccc4nonc34)n2)cc1
Temperature: 100 °C

Procedure:
To a solution of 6-(4-carboxyphenyl)-8-methoxy-1,7-naphthyridine (250 mg, 0.892 mmol) in DMF (10 ml) is added PBr3 (0.63 ml, 6.63 mmol). The reaction mixture is heated to 100° C. for 30 min. Then, the suspension is poured into water (50 ml) and the solution washed with ethyl acetate (2×50 ml). The organic solvent is removed and the crude product stirred in ether. The suspension is filtered to yield the title compound (215 mg). Melting point 248-250, decomposition.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH2:9])=[O:8])=[O:4].[CH:10](=O)[CH3:11]>CO>[CH3:10][CH:11]1[NH:1][CH2:2][C:3](=[O:4])[N:5]1[CH2:6][C:7]([NH2:9])=[O:8]
Reactant: CC=O
Reactant: NCC(=O)NCC(N)=O
Solvent: CO
Product: CC1NCC(=O)N1CC(N)=O

Procedure:
A solution of glycylglycinamide (0.5 g) and acetaldehyde (0.4 ml) in methanol (5 ml) was stirred at room temperature for 8 hours. Evaporation of the solvent gave a residue which was chromatographed on a silica gel column (eluant dichloromethane/methanol 75:25). The selected fractions were collected, evaporated to give the title compound (Rf=0.3, dichloromethane/methanol 7:3, silica gel plates). Mass spectrum (E.I., 70 eV, 1.5 mA), m/z=142 (M+ -CH3), 99.
Reaction SMILES: [CH3:1][C:2](C)([CH3:30])[CH:3]([C:5]1[N:6]=[C:7]([CH3:29])[N:8]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=1)O.[CH:32]1C=CN=CC=1.[FH:38].[Si](C(O)C)(C)(C)C>C(Cl)Cl>[F:38][C:2]([CH3:1])([CH3:30])[CH:3]([C:5]1[N:6]=[C:7]([CH3:29])[N:8]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:9]=1)[CH3:32]
Reactant: Cc1nc(C(O)C(C)(C)C)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccncc1
Reactant: F
Agent: CC(O)[Si](C)(C)C
Solvent: ClCCl
Product: Cc1nc(C(C)C(C)(C)F)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,2-Dimethyl-1-(2-methyl-1-trityl-1H-imidazol-4-yl)propan-1-ol (200 mg, 0.49 mmol) in a minimal volume of methylene chloride was added to HF-pyridine (2 mL) at 0° C. After stirring at ambient temperature overnight, the reaction was added dropwise to TMS-ethanol and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. Organic phase was washed with brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 10-70% ethyl acetate/hexane afforded the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17]O)[C:12]=2[Cl:19])[CH2:7][CH2:6]1>C(Cl)(Cl)Cl>[ClH:3].[O:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][Cl:3])[C:12]=2[Cl:19])[CH2:7][CH2:6]1
Reactant: OCc1nccc(N2CCOCC2)c1Cl
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cl
Product: ClCc1nccc(N2CCOCC2)c1Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Thionyl chloride (3 ml) in chloroform (25 ml) was added dropwise to a solution of 4 -morpholino-3 -chloro-2 -hydroxymethylpyridine (3.09 g) in chloroform (25 ml) cooled in an ice/salt bath. Following the addition the ice bath was removed and the mixture stirred for a further 1.5 hours. The volume of the solution was reduced and ether added to give 4 -morpholino-3 -chloro-2 -chloromethylpyridine hydrochloride, 3.77 g, m.p. 200°-2°.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:24])[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19](SC)[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:25][O:26]C1C2N=C(C3N(C)C=NC=3C3C=CC=CC=3)SC=2N=CN=1.CN1C(C2SC3N=CN=C(SC)C=3N=2)=C(C2C=CC=CC=2)N=C1>>[Br:1][C:2]1[N:3]([CH3:24])[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([O:26][CH3:25])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: COc1ncnc2sc(-c3c(-c4ccccc4)ncn3C)nc12
Reactant: CSc1ncnc2sc(-c3c(-c4ccccc4)nc(Br)n3C)nc12
Agent: CSc1ncnc2sc(-c3c(-c4ccccc4)ncn3C)nc12
Product: COc1ncnc2sc(-c3c(-c4ccccc4)nc(Br)n3C)nc12

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 37 but using 7-Methoxy-2-(1-methyl-4-phenyl-1H-imidazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidine (Example 33) in place of 2-(1-methyl-4-phenyl-1H-imidazol-5-yl)-7-(methylthio)[1,3]thiazolo[5,4-d]pyrimidine (Intermediate 42). Light brown solid (0.47 g, 45%);
Reaction SMILES: [CH2:1]([C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[N:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[N+:26]([O-])([OH:28])=[O:27].O>S(=O)(=O)(O)O>[N+:26]([C:21]1[CH:20]=[C:19]([C:16]2[N:17]=[CH:18][C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:14][N:15]=2)[CH:24]=[CH:23][C:22]=1[OH:25])([O-:28])=[O:27]
Reactant: CCCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCCCCCCCc1cnc(-c2ccc(O)c([N+](=O)[O-])c2)nc1
Yield: 81.7 %

Procedure:
Step i) 2.00 g (5.87 mM) of 4-(5-dodecylpyrimidine-2-yl)phenol was dispersed in 20 ml of conc. sulfuric acid. To the dispersion, 0.50 ml of nitric acid (60%, density=1.38) was gradually added dropwise under cooling and stirring at 2°-8° C. After the addition, the mixture was stirred for 30 min. at about 5° C. After the reaction, the reaction mixture was poured into 150 ml of iced water to precipitate a crystal. The crystal was recovered by filtration, washed with water and recrystallized from ethanol to obtain 1.85 g of 2-nitro-4-(5-dodecylpyrimidine-2-yl)phenol (yield:81.7%).
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:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.ClC(Cl)(O[C:30](=[O:36])OC(Cl)(Cl)Cl)Cl.[C:38]([C:42]1[CH:54]=[CH:53][C:45]([CH2:46][N:47]2[CH2:51][CH2:50][CH:49]([NH2:52])[CH2:48]2)=[CH:44][CH:43]=1)([CH3:41])([CH3:40])[CH3:39].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[C:38]([C:42]1[CH:54]=[CH:53][C:45]([CH2:46][N:47]2[CH2:51][CH2:50][CH:49]([NH:52][C:30]([NH:20][C:19]3[CH:21]=[CH:22][C:16]([O:15][C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)=[CH:17][C:18]=3[N+:23]([O-:25])=[O:24])=[O:36])[CH2:48]2)=[CH:44][CH:43]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: CC(C)(C)c1ccc(CN2CCC(N)C2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NC4CCN(Cc5ccc(C(C)(C)C)cc5)C4)c([N+](=O)[O-])c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.7 %

Procedure:
Chloroform (13 ml) and triethylamine (2 ml) were added to 4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (100 mg) to prepare a solution. Triphosgene (96 mg) was added to the solution, and the mixture was stirred at room temperature for 30 min. 1-[4-(Tert-butyl)benzyl]-3-pyrrolidinamine (102 mg) was then added thereto, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/acetone for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (38 mg, yield 22%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:23]C1C=C2C(CCC2=NO)=CC=1.[Na].C(O)C>C1(C)C=CC=CC=1>[ClH:23].[NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([Cl:23])=[CH:7][CH:8]=2)[C:3]1=[O:11]
Reactant: ON=C1CCc2ccc(Cl)cc21
Reactant: NC1Cc2ccccc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cl
Product: NC1Cc2ccc(Cl)cc2C1=O

Procedure:
2-Amino-6-chloro-1-indanone hydrochloride is prepared in the same way as in Example 1 for the preparation of 2-amino-1-indanone, starting from 57.5 g of 6-chloro-1-indanone oxime p-toluenesulphonate, 3.94 g of sodium, 200 ml of absolute ethanol and 1 litre of anhydrous toluene. After 15 hours of reaction at 0° C., the precipitate formed is filtered off on Celite, the filtrate washed with water and then extracted with IN hydrochloric acid (2×500 ml) and the aqueous phase concentrated to dryness under reduced pressure. 10.5 g of expected product are obtained in the form of a brown-green solid, the melting point of which is above 260° C.