Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2)[CH3:5].[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([NH2:35])=[CH:32][CH:33]=2)[CH:28]=[N:27]1>>[CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:35][C:31]1[CH:30]=[C:29]3[C:34](=[CH:33][CH:32]=1)[N:26]([CH2:25][C:21]1[S:20][CH:24]=[CH:23][N:22]=1)[N:27]=[CH:28]3)=[N:10][CH:11]=[N:12]2)[CH3:5]
Reactant: C[C@@H](Oc1cccc2nc[nH]c(=O)c12)C(=O)N(C)C
Reactant: Nc1ccc2c(cnn2Cc2nccs2)c1
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12)C(=O)N(C)C
Yield: 77.1 %

Procedure:
Using the same procedure as in Example 18, (2R)—N,N-dimethyl-2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]propanamide (150 mg, 0.57 mmol) and 1-(1,3-thiazol-2-ylmethyl)-1H-indazol-5-amine (138 mg, 0.6 mmol) were reacted to give the title compound as a white solid (208 mg, 77%); NMR Spectrum (CDCl3) 1.73 (d, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 5.43 (q, 1H), 5.92 (s, 2H), 6.82 (d, 1H), 7.26 (m, 1H), 7.50 (d, 2H), 7.61 (t, 1H), 7.75 (d, 1H), 7.87 (dd, 1H), 8.11 (s, 1H), 8.45 (s, 1H), 8.62 (s, 1H); Mass spectrum 474.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4](Cl)[N:3]=1.Cl.[F:26][C:27]1([F:35])[CH2:32][CH2:31][CH2:30][C@@H:29]([NH2:33])[C@H:28]1[NH2:34].CCN(C(C)C)C(C)C>C(#N)C>[NH2:34][C@H:28]1[C:27]([F:35])([F:26])[CH2:32][CH2:31][CH2:30][C@H:29]1[NH:33][C:4]1[N:3]=[C:2]([Cl:1])[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]=1[F:23]
Reactant: COc1ccc(CN2Cc3c(F)c(Cl)nc(Cl)c3C2=O)c(OC)c1
Reactant: N[C@@H]1CCCC(F)(F)[C@@H]1N
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC(F)(F)[C@@H]4N)nc(Cl)c3C2=O)c(OC)c1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
A mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (100 mg, 0.269 mmol) and cis-3,3-difluorocyclohexane-1,2-diamine hydrochloride (75 mg, 0.404 mmol) and DIPEA (118 μL, 0.674 mmol) in acetonitrile (449 μL) was stirred at 100° C. for 3 d. The reaction mixture was concentrated to a brown oil and reconstituted in DMF (1 mL). The residue was purified by preparative HPLC, the appropriate fraction was collected, and excess acetonitrile was evaporated. The residue was treated with saturated aq sodium carbonate and extracted with EtOAc (3×20 mL). The organic layers were combined, dried over sodium sulfate, and concentrated to give the title compound as a colorless residue (13.7 mg, 10%). [M+H] calc'd for C22H24ClF3N4O3, 485; found, 485.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:22])[NH:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])C.C(O)C.[OH-].[K+].Cl>O>[C:16]1([C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7](=[O:22])[C:6]=2[C:4]([OH:5])=[O:3])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2ccccc2[nH]c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1c(-c2ccccc2)c2ccccc2[nH]c1=O
Yield: 93.1 %

Procedure:
A mixture of 1,2-dihydro-4-phenyl-2-oxo-3-quinoline carboxylic acid ethyl ester (5 g, 17 mmol), ethanol (20 ml), water (40 ml) and potassium hydroxide (5 g, 89 mmol) was refluxed with heat for 1.5 hours. To the reaction mixture was added 60 ml of 2N-HCl to acidify the mixture to obtain a precipitated crystal by filtration. The crystal obtained was recrystallized from ethanol to give 4.2 g (yield: 92.9%) of the title compound.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10](Cl)=[CH:9][C:8]=1[NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].[C:21](=[O:23])=[O:22].[OH-].[Na+]>CCCCCC.O1CCCC1>[C:16]([C:15]1[O:20][C:9]2[C:10]([C:21]([OH:23])=[O:22])=[CH:11][CH:12]=[C:7]([Cl:6])[C:8]=2[N:14]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)ccc1Cl
Reactant: O=C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1nc2c(Cl)ccc(C(=O)O)c2o1
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
n-Butyl lithium (101.6 ml of a 2.5M solution in hexane) was added during 30 minutes to a stirred solution of 2,5-dichloro-1-(trimethylacetylamino)benzene (25.0 g) in dry tetrahydrofuran at -40° C. and the solution stirred at -20° C. for 1.5 hours and poured onto solid carbon dioxide in dry tetrahydrofuran. The mixture was allowed to reach room temperature, 2M sodium hydroxide solution added and extracted with ethylacetate. The aqueous solution was acidified (concentrated hydrochloric acid) and the precipitated solid collected and dried to give 2-t-butyl-4-chlorobenzoxazole-7-carboxylic acid (1 1.7 g) m.p. 209°-210° C.
Reaction SMILES: C(N(CC)CC)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:29]([NH:36][C@H:37]([C:45]([OH:47])=O)[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].[CH:48]1[C:56]2[C:55]3[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][C:54]=3[O:53][C:52]=2[CH:51]=[CH:50][C:49]=1[NH2:62]>>[CH2:38]([C@H:37]([NH:36][C:29](=[O:30])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[C:45](=[O:47])[NH:62][C:49]1[CH:50]=[CH:51][C:52]2[O:53][C:54]3[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57][C:55]=3[C:56]=2[CH:48]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 39 %

Procedure:
Following the procedure of Example 30, triethylamine (0.43 mL, 3.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.31 g, 1.6 mmol), N-hydroxybenzotriazole (0.22 g, 1.6 mmol), N-Boc-L-phenylalanine (0.36 g, 1.4 mmol), and 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.25 g, 1.2 mmol) provided tert-butyl [(1S)-1-benzyl-2-oxo-2-(7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylamino)ethyl]carbamate (0.21 g). MS (ESI) m/z 449 ([M+H]+); MS (ESI) m/z 447.3 ([M−H]−).
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[CH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18]1.OS(O)(=O)=O>O>[CH2:8]([NH:15][CH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClC1CCc2ccccc21
Reactant: NCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(CNC2CCc3ccccc32)cc1
Temperature: 90 °C
Yield: 72.5 %

Procedure:
A mixture of 272 ml of toluene and 199.5 g benzylamine was prepared and heated to 90° C. The chlorindan was added dropwise to the mixture over a 30 minute period. The reaction mixture was heated to 115° C. for ten hours. The reaction mixture was cooled to ambient temperature and 300 ml of water was added. The resulting heterogeneous mixture was then brought to pH2.2 by the addition of 33% H2SO4. The phases were separated and the organic layer discarded. The pH of the aqueous layer was adjusted to pH6.0 prior to extraction with 300 ml of toluene. A further 100 ml of toluene was then added and the aqueous phase discarded. The toluene was removed under vacuo from the combined organic layer leaving 104.3 g racemic N-benzyl-1-aminoindan base as an oil (72.5 % yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[NH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.O>CN(C)C=O>[N:16]1[CH:17]=[CH:18][C:13]([NH:12][C:9]([N:8]=[C:3]2[NH:4][C:5](=[O:7])[CH2:6][N:2]2[CH3:1])=[O:11])=[CH:14][CH:15]=1
Reactant: CN1CC(=O)NC1=NC(=O)O
Reactant: Nc1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CN1CC(=O)NC1=NC(=O)Nc1ccncc1

Procedure:
A mixture of 4.0 g (17 mM) of the phenyl ester of tetrahydro-1-methyl-4-oxo-1H-imidazol-2-ylidene carbamic acid 8 and 1.6 g (17 mM) of 4-aminopyridine in 25 ml of anhydrous dimethylformamide (DMF) was heated at 55° for 5 hrs. (hours), cooled, and poured with stirring into 250 ml of water. The precipitated solid was collected, washed with ethanol and ether, and air dried. Recrystallization from methanol gave 2.0 g of the above urea as a pale yellow solid, m.p. 218°-220° C. (dec.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)([CH3:23])[CH3:22].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:30]([C:27]3[CH:28]=[CH:29][C:24]([CH:21]([CH3:23])[CH3:22])=[CH:25][CH:26]=3)(=[O:32])=[O:31])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C2CCN(Cc3ccccc3)C2)cc1F
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(S(=O)(=O)Nc2ccc(C3CCN(Cc4ccccc4)C3)cc2F)cc1
Temperature: 25 °C
Yield: 25.4 %

Procedure:
4-(1-Benzyl-pyrrolidin-3-yl)-2-fluoro-phenylamine (400 mg, 1.48 mmol) and 4-isopropylphenylsulfonyl chloride (324 mg, 1.48 mmol) were dissolved in tetrahydrofuran (25 ml). Triethylamine (0.62 ml, 4.44 mmol) was added and the reaction mixture stirred over night at room temperature (10% conversion) and subsequently refluxed for 4 h (30% conversion). Small portions of 4-isopropyl-phenylsulfonyl chloride and triethylamine were added and the reaction mixture was stirred 15 min at 150° C. in the microwave (CEM). This procedure was repeated until complete conversion was observed. The solvent was evaporated under reduced pressure, the residue treated with ethyl acetate (50 ml) and extracted twice with slightly acidic water. The organic layer was dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to give an oil (170 mg, 21%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Cc1cccc(N)c1
Product: Cc1cccc(Nc2ncnc3cc(N)ncc23)c1
Temperature: 155 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (217 mg, 1.13 mmol) and m-toluidine (1.50 g, 14.0 mmol) is stirred at 155° C. for 30 min. The resulting product is chromatographed over silica gel (5% MeOH/CH2Cl2) to give 7-amino-4-(3-methylanilino)pyrido[4,3-d]pyrimidine (190 mg, 67%) as a pale yellow solid. 1H NMR (DMSO) δ 9.81 (1H, brs), 9.34 (1H, s), 8.38 (1H, s), 7.60 (2H, s), 7.26 (1H, dd, J=8.5, 7.6 Hz), 6.95 (1H, d, J=7.4 Hz), 6.63 (2H, brs), 6.44 (1H, s), 2.33 (3H, s).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[N:8]([CH2:20][C:21]([CH3:24])([OH:23])[CH3:22])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:4][CH2:5][CH3:6].[CH:25]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH2:26].O>O1CCCC1.[Cl-].[Na+].O>[CH2:3]([C:7]1[N:8]([CH2:20][C:21]([CH3:24])([O:23][CH2:26][CH2:25][S:27]([CH3:30])(=[O:29])=[O:28])[CH3:22])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Reactant: C=CS(C)(=O)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nc2cnc3ccccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 48.5 %

Procedure:
Sodium hydride (60% dispersion in oil, 55 mg, 1.38 mmol) was added to a stirred solution of 1-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (4.10 g, 13.8 mmol) in tetrahydrofuran (55 mL). After 5 minutes, methyl vinyl sulfone (2.90 g, 27.6 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. Water (50 mL) and a small amount of brine were added and the mixture was extracted with ethyl acetate (2×50 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford a solid that was purified by flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to provide 2.7 g of 2-butyl-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinoline as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:11]=1[C:12](O)=[O:13].CCCCCCC>CCOC(C)=O>[F:9][C:10]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:11]=1[C:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: Cc1ccc(O)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(OC(=O)c2cc(F)c(F)cc2F)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
The title compound can also be prepared according to the following method: 4-methylphenol (80.0 g, 739.8 mmol) was added to a suspension of 2,4,5-trifluorobenzoic acid (136.8 g, 776.8 mmol) and 1,1-carbonyldiimidazole (83-85% wt, 163.6 g, 849.7 mmol) in EtOAc (1.20 L) at 40° C. The reaction mixture was stirred at 40° C. for 2 hours, then cooled to 20° C. and washed with water (480 mL), a 0.5 M aqueous solution of sodium hydroxide (2×400 mL) and water (400 mL). The organics were concentrated in vacuo and azeotroped with heptane to give a yellow oil. Heptane (640 mL) was added and the mixture was stirred at room temperature for 16 hours. A seed was used to facilitate the formation of a precipitate. The resulting suspension was cooled to 10° C. and filtered. The residue was washed with cold heptane (80 mL) and dried to afford the title compound as an off white solid (147.5 g, 75%):
Reaction SMILES: CS([Cl:5])(=O)=O.C(N(CC)CC)C.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:38]=[CH:37][C:22]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:36]=[CH:35][C:32]([CH2:33]O)=[CH:31][CH:30]=2)=[O:24])=[CH:21][CH:20]=1>ClCCl>[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:38]=[CH:37][C:22]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:36]=[CH:35][C:32]([CH2:33][Cl:5])=[CH:31][CH:30]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCCCc1ccc(CO)cc1)c1ccc(-c2ccccn2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCc1ccc(CCl)cc1)c1ccc(-c2ccccn2)cc1
Reaction time: 16 h
Yield: 87.2 %

Procedure:
Methanesulfonyl chloride (294 mg) and triethylamine (0.37 ml) were successively added to a solution of 4-[3-(4-pyridine-2-ylbenzoylamino)propyl]benzylalcohol (0.74 g) in dichloromethane (20 ml). The mixture was allowed to stand at ambient temperature for 16 hours. The reaction mixture was concentrated. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and concentrated to afford crystals. The crystals were washed with a small amount of diisopropyl ether to afford the desired compound (0.68 g).
Reaction SMILES: C(O[CH:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)(=O)C.[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C1C=CC=CC=1>CCOCC>[N:24]1[CH:25]=[CH:26][C:21]([CH2:20][NH:19][CH:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[O:12][C:13]3[C:18]2=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:22][CH:23]=1
Reactant: NCc1ccncc1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Solvent: c1ccccc1
Solvent: CCOCC
Product: c1ccc2c(c1)Oc1ccccc1C2NCc1ccncc1

Procedure:
A solution of 4.0 g. of 9-acetoxyxanthene and 2.0 g. of 4-aminomethylpyridine in 100 ml. of benzene is refluxed for 24 hours. The reaction mixture is stripped of solvent and the residue dissolved in ether. The ether solution is washed with cold 5% sodium carbonate and water and dried over potassium carbonate and chromatographed with alumina and eluting with ether/hexane. The eluate is extracted with ether/acetone and concentrated in vacuo to give 4-pyridylmethyl-9-xanthylamine having a m.p. of 83°-85° C.
Reaction SMILES: [Cl:1]Cl.[N+:3]([C:6]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:7]=1[NH2:8])([O-:5])=[O:4].C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:9]1[CH:10]=[C:11]([O:13][C:14]([F:15])([F:16])[F:17])[CH:12]=[C:6]([N+:3]([O-:5])=[O:4])[C:7]=1[NH2:8]
Reactant: ClCl
Reactant: Nc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Nc1c(Cl)cc(OC(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Chlorine gas was passed through a solution of 2-nitro-4-trifluoromethoxy-aniline (14.5 g) in carbon tetrachloride (175 ml). As the mixture was stirred it became solid and more carbon tetrachloride (50 ml) was added. Chlorine gas was passed through the reaction mixture until thin layer chromatography (silica gel, using petroleum ether (boiling range 60°-80° C.) containing ethyl acetate (30% by volume) as eluent) demonstrated the absence of starting material. Evaporation of the solvent under reduced pressure gave a dark orange solid, which on trituration with petroleum ether (boiling range 60°-80° C.) gave a 2-chloro-4-trifluoromethoxy-6-nitro-aniline as an orange solid.
Reaction SMILES: C[N:2](C)/[CH:3]=[N:4]/[C:5]([C:7]1[CH:12]=[CH:11][N:10]2[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:24])[CH:17]=3)=[CH:14][N:15]=[C:9]2[CH:8]=1)=O.O.[NH2:33]N>C(O)(=O)C>[N:2]1[N:33]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]3[C:13]([C:16]4[CH:17]=[C:18]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:24])[CH:19]=[CH:20][CH:21]=4)=[CH:14][N:15]=[C:9]3[CH:8]=2)[NH:4][CH:3]=1
Reactant: NN
Reactant: CN(C)/C=N/C(=O)c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Solvent: CC(=O)O
Solvent: O
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4nnc[nH]4)ccn23)c1
Temperature: 90 °C
Yield: 74.7 %

Procedure:
To a stirred solution of 3-{3-[3-(2,2,2-Trifluoro-ethyl)-ureido]-phenyl}-imidazo[1,2-a]pyridine-7-carboxylic acid 1-dimethylamino-meth-(E)-ylideneamide (17 mg, 0.04 mmol) in acetic acid (0.5 ml) was added hydrazine hydrate (5 μl, 0.1 mmol). The reaction mixture was heated at 90° C. for 30 min before being cooled to room temperature. The volatiles were removed in vacuo and the residue azeotroped with toluene. Trituration of the residue with Et2O afforded a pink solid (12 mg). MS: [M+H]+ 402.
Reaction SMILES: [N:1]#[C:2][NH2:3].N1C=CC=CC=1.OS(C(F)(F)F)(=O)=O.[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][S:25](Cl)(=[O:27])=[O:26])=[CH:20][CH:19]=1>C(#N)C>[C:2]([NH:3][S:25]([CH2:24][C:21]1[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=1)(=[O:27])=[O:26])#[N:1]
Reactant: N#CN
Reactant: O=S(=O)(Cl)Cc1ccncc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Solvent: c1ccncc1
Product: N#CNS(=O)(=O)Cc1ccncc1
Temperature: -20 °C
Reaction time: 3 h
Yield: 66.1 %

Procedure:
Anhydrous cyanamide (32 g, 0.76 mol) was dissolved in acetonitrile (600 ml) in a 2 l, 3-necked flask equipped with a mechanical stirrer, drying tube, and two dropping funnels. The solution was cooled in a 1:1 ethanol-water bath that was maintained at -20° C. by the addition of dry ice. Solutions of pyridine (57 g, 0.72 mol) in acetonitrile (70 ml) and of 4-pyridylmethanesulfonyl chloride triflate (130 g, 0.38 mol) in acetonitrile (200 ml) were added simultaneously at such a rate that the additions of both solutions were completed in 3 hrs. The resulting suspension was stirred at -10° C. for 1 hr and then filtered and the solids washed with cold acetonitrile (50 ml). The solid portion was recrystallized by adding it to ice-cold water (100 ml). The product was filtered off and washed with ice-water (100 ml) to give a light yellow solid (49.5 g). The mother liquors were refrigerated overnight to give additional product (5 g, 73% total yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:17]N1C(=O)CCC1=O.C([O-])(=O)C.[K+]>CN(C)C=O>[Br:17][C:9]1[O:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=2[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ncnc2occ(-c3ccccc3)c12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2oc(Br)c(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
To 4-amino-5-phenylfuro-[2,3-d]pyrimidine (2.3 g, 10.8 mmol) dissolved in dimethylformamide (100 mL) was added N-bromosuccinimide (2.0 g, 11.2 mmol) and potassium acetate (1.1 g, 11.2 mmol). The resulting solution was stirred overnight at room temperature. The mixture was then partitioned between ethyl acetate (150 mL) and water (150 mL). The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (25% acetone/hexane) to give the product as a pale solid (2.0 g, 64%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([OH:14])[CH:10]=[C:11]([CH3:13])[CH:12]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.C(N(CC)CC)C.[CH:26]([Si:29](OS(C(F)(F)F)(=O)=O)([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])([CH3:28])[CH3:27]>C(Cl)Cl>[C:15]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:8]=[C:9]([O:14][Si:29]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:26]([CH3:28])[CH3:27])[CH:10]=[C:11]([CH3:13])[CH:12]=2)[N:5]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1cc(O)cc(-n2nc(C(C)(C)C)cc2N)c1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-n2nc(C(C)(C)C)cc2N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.3 %

Procedure:
To a solution of Intermediate 54a (430 mg, 1.75 mmol) in DCM (10 mL) and triethylamine (0.36 mL, 2.63 mmol) was added triisopropylsilyltrifluoromethanesulphonate (0.52 mL, 1.93 mmol). Mixture stirred for 1 h at RT, diluted with DCM, washed with sat. sodium hydrogen carbonate solution then brine, dried, and concentrated in vacuo. The residue was purified by FCC, using 0-25% EtOAc in cyclohexane, to give impure title compound (740 mg), contaminated with the ˜25% bis-silyl impurity. 1H NMR (300 MHz, CDCl3): inter alia 1.03-1.15 (18H, m), 1.18-1.35 (12H, m), 2.32 (3H, s), 3.74 (2H, br s), 5.49 (1H, s), 6.60-6.66 (1H, m), 6.85-6.89 (1H, m), 6.95-7.00 (1H, m).
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:2]([CH3:4])[CH3:3])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 22 h
Yield: 98.6 %

Procedure:
2-Bromopropane (4.51 mL, 5.90 g, 48 mmol) was added to a mixture of 4-benzyloxy-2-nitrophenol (J.Biol.Chem., 1985, 260, 3440, 2.94 g, 12 mmol) and potassium carbonate (9.95 g, 72 mmol) in dimethylformamide (20 mL) and the mixture was stirred at 50° C. for 22 h. The mixture was cooled, diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic fractions were washed with aqueous sodium hydroxide (1M, 4×100 mL) and brine (100 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as an orange oil (3.40 g, 99%). 1H NMR (360 MHz, CDCl3) δ 7.41-7.33 (6H, m), 7.12 (1H, dd, J 9.1, 3.1 Hz), 7.02 (1H, d, J 9.1 Hz), 5.05 (2H, s), 4.52 (1H, hept, J 6.1 Hz), and 1.35 (6H, d, J 6.1 Hz).