Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(#N)C.N>ClCCl.C1CCCCC1.CO>[N:20]1([CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:7](=[O:15])[C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:30]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: C1CCCN(CCC2CCCNC2)CC1
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ncccc21
Agent: N
Solvent: ClCCl
Solvent: C1CCCCC1
Solvent: CO
Product: O=C1Nc2ccccc2N(C(=O)N2CCCC(CCN3CCCCCC3)C2)c2ncccc21
Yield: 58 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 3-[2-(hexahydro-1H-1-azepinyl)ethyl]piperidine in a yield of 58% of theory. Colourless crystals, m.p. 152°-154° C. (acetonitrile), Rf 0.64 (Macherey-Nagel, Polygram® SIL G/UV254, pre-coated plastic sheets for TLC; eluant: dichloromethane/cyclohexane/methanol/conc. ammonia 68/15/15/2, v/v/v/v)
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][O:22][CH2:23][CH2:24]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:24][CH2:23][O:22][CH3:21])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: COc1cc2c(Cl)ccnc2cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COCCOc1cc2nccc(Cl)c2cc1OC
Temperature: 70 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
4-Chloro-6-methoxy-7-quinolinol (50 mg), potassium carbonate (40 mg), tetra-n-butylammonium iodide (9 mg), and 2-bromoethyl methyl ether (40 mg) were dissolved in N,N-dimethylformamide (10 ml). The solution was stirred at 70° C. overnight. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, followed by extraction with chloroform. The chloroform layer was dried over sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with hexane/acetone/dichloromethane (6/2/1) to give 47 mg (yield 74%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)[CH:21]=2)=[CH:4][C:5](=[O:19])[N:6]([CH2:8][CH2:9][C@@:10]([CH3:18])([S:14]([CH3:17])(=[O:16])=[O:15])[C:11]([OH:13])=O)[CH:7]=1.FC1C(C2C=CC(N3N=CC=N3)=CC=2)=CC(=O)N(CC[C@@](C)(S(C)(=O)=O)C([NH:44][O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)=O)C=1>>[F:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)[CH:21]=2)=[CH:4][C:5](=[O:19])[N:6]([CH2:8][CH2:9][C@@:10]([CH3:18])([S:14]([CH3:17])(=[O:16])=[O:15])[C:11]([NH:44][O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)=[O:13])[CH:7]=1
Reactant: C[C@@](CCn1cc(F)c(-c2ccc(-n3nccn3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reactant: C[C@@](CCn1cc(F)c(-c2cccc(Oc3nccs3)c2)cc1=O)(C(=O)O)S(C)(=O)=O
Product: C[C@@](CCn1cc(F)c(-c2cccc(Oc3nccs3)c2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Yield: 65.8 %

Procedure:
The title compound (115 mg, 65.8%) was prepared as an off-white solid from (2R)-4-{5-fluoro-2-oxo-4-[3-(1,3-thiazol-2-yloxy)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoic acid (144 mg, 0.31 mmol) using a procedure analogous to that described for (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, Example 26, Step D. MS (LCMS) m/z 566.2 (M−1).
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[CH2:3]2.[OH-].[K+].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1>CO>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[C:3]2[C:4](=[O:10])[CH:5]3[CH2:8][CH2:9][N:2]2[CH2:7][CH2:6]3)[CH:14]=1
Reactant: O=C1CN2CCC1CC2
Reactant: O=Cc1cccnc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1C(=Cc2cccnc2)N2CCC1CC2
Reaction time: 12 h
Yield: 89.2 %

Procedure:
3-Quinuclidinone hydrochloride (8.25 kg, 51.0 mol) and methanol (49.5 L) were added to a 100 L glass reaction flask, under an nitrogen atmosphere, equipped with a mechanical stirrer, temperature probe, and condenser. Potassium hydroxide (5.55 kg, 99.0 mol) was added via a powder funnel over an approximately 30 min period, resulting in a rise in reaction temperature from 50° C. to 56° C. Over an approximately 2 h period, 3-pyridinecarboxaldehyde (4.80 kg, 44.9 mol) was added to the reaction mixture. The resulting mixture was stirred at 20° C.±5° C. for a minimum of 12 h, as the reaction was monitored by thin layer chromatography (TLC). Upon completion of the reaction, the reaction mixture was filtered through a sintered glass funnel and the filter cake was washed with methanol (74.2 L). The filtrate was concentrated, transferred to a reaction flask, and water (66.0 L) was added. The suspension was stirred for a minimum of 30 min, filtered, and the filter cake was washed with water (90.0 L) until the pH of the rinse was 7-9. The solid was dried under vacuum at 50° C.±5° C. for a minimum of 12 h to give 8.58 kg (89.3%) of 2-((3-pyridinyl)methylene)-1-azabicyclo[2.2.2]octan-3-one.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4].[Br:23]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Br:23])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4]
Reactant: COC(=O)c1ncc2c(Oc3ccccc3)cccc2c1O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc(Br)c2c(Oc3ccccc3)cccc2c1O
Temperature: 25 °C
Yield: 97.7 %

Procedure:
A mixture of 4-hydroxy-8-phenoxy-isoquinoline-3-carboxylic acid methyl ester (103 mg, 0.35 mmol), N-bromosuccinimide (65 mg, 0.37 mmol), benzoyl peroxide (4.2 mg, 0.02 mmol), and carbon tetrachloride (2.5 mL) was refluxed for 4 h before it was cooled to room temperature and filtered. The filtrate was washed with water, saturated aqueous sodium bicarbonate solution, and brine before it was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (128 mg): MS: (+) m/z 374.0, 376.0 (M+1, 79Br/81Br), MS: (−) m/z 372.1, 374.1 (M−1, 79Br/81Br).
Reaction SMILES: [H-].[Na+].C([O:5][C:6](=O)[CH2:7][NH:8][C:9](=[O:34])[CH2:10][C:11]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:14]2[CH:23]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:25]=[C:26]([CH3:27])[C:13]=2[N:12]=1)C.C(OCC)(=O)C.[Cl-].[NH4+]>C1(C)C=CC=CC=1.O1CCCC1>[OH:5][C:6]1[CH2:7][NH:8][C:9](=[O:34])[C:10]=1[C:11]1[N:15]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[C:14]2[CH:23]=[C:24]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[CH:25]=[C:26]([CH3:27])[C:13]=2[N:12]=1
Reactant: CCOC(=O)CNC(=O)Cc1nc2c(C)cc(N3CCOCC3)cc2n1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(N2CCOCC2)cc2c1nc(C1=C(O)CNC1=O)n2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 59.3 %

Procedure:
To a stirred suspension of sodium hydride (60% in oil, 0.014 g, 0.352 mmol)in toluene (5 mL) was added [2-(1-tert-butyloxycarbonyl-4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl)-acetylamino]-acetic acid ethyl ester (0.135 g, 0.293 mmol) in tetrahydrofuran (5 mL) over 5 minutes. The mixture was stirred at 90–100° C. for 2.5 hours, then cooled down to ˜0° C. and ethyl acetate followed by aqueous ammonium chloride (˜3 mL) were added. The aqueous phase was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was quickly purified by silica gel chromatography to give the title material (0.072 g, 59%) as a white solid. LCMS (+ESI, M+H+) m/z 415, (− ESI, M−H−) m/z 413; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.47 (9H, s), 3.06 (4H, br s), 3.74 (4H, br s), 3.94 (2H, br s), 6.83 (1H, s), 6.97 (1H, s), 12.1 (1H, m), 12.56 (1H, s).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH3:11][S:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>C1COCC1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:17]([C:16]1[CH:19]=[CH:20][C:13]([S:12][CH3:11])=[CH:14][CH:15]=1)[OH:18]
Reactant: CSc1ccc(C=O)cc1
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(C(O)c2nccs2)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a −78° C. solution of thiazole (5.0 g, 58.7 mmol) in THF (250 ml) was added n-butyllithium (2.5M in hexanes, 23.5 ml, 58.7 mmol) dropwise and the resulting solution was stirred at −78° C. for 10 min. 4-(Methylthio)benzaldehyde (7.1 ml, 53.4 mmol) was then added at −78° C. The resulting mixture was stirred until completion, and quenched with a saturated aqueous solution of NH4Cl. The mixture was then diluted with EtOAc and HCl 10%, extracted and washed (NaHCO3 (sat.), brine). The organic phase was dried over MgSO4 and concentrated. The residue was then purified by flash chromatography (80% CH2Cl2/20% EtOAc) to yield (1,3-Thiazol-2-yl)[4-(methylthio)phenyl]methanol.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:23]>CS(C)=O>[NH2:23]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 35.0 gm (0.138 mol) of 2-benzoylbenzo[b]-thiophen-3-ol, 24.0 gm (0.311 mol) of ammonium acetate and 25 cc of dimethylsulfoxide was stirrd for one hour at a reaction temperature of 125° C. The cooled reaction mixture was stirred into a mixture of 150 cc of petroleum ether and 300 cc of ice water. The resulting suspension was filtered with suction, and the filter residue was thoroughly washed with water. For purification purposes, the dried crude product was taken up in 40 cc of ethyl acetate, and just enough petroleum ether was added to ensure that no further precipitate formed (about 20 cc). 5 gm of activated carbon were added, followed by boiling and filtering while hot. The pure product was obtained from the crude filtrate by adding 60 cc of petroleum ether and cooling to +10° C. Further product of the same quality was obtained by concentrating the mother liquor to approximately 30 cc total volume. The combined crystalline product was washed with petroleum ether and dried in vacuo, yielding 25.2 gm (72% of theory) of the desired product, m.p. 121.6°-122.5° C., which was found to be identical with that of Example 1 based on its thin-layer chromatogram, mixed melting point and IR spectrum.
Reaction SMILES: C([O:8][N:9]([CH2:12][C:13]1([C:18]([NH:20][NH:21][C:22]2[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:10]=[O:11])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]([CH2:12][C:13]1([C:18]([NH:20][NH:21][C:22]2[N:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:24][N:23]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:10]=[O:11]
Reactant: O=CN(CC1(C(=O)NNc2nccc(C(F)(F)F)n2)CCCC1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=CN(O)CC1(C(=O)NNc2nccc(C(F)(F)F)n2)CCCC1
Reaction time: 4 h
Yield: 37.9 %

Procedure:
To a solution of N-benzyloxy-N-{1-[N′-(4-trifluoromethyl-pyrimidin-2-yl)-hydrazinocarbonyl]-cyclopentylmethyl}-formamide (0.085 g, 0.19 mmol) in methanol (10 mL) was added 10% Pd/C (0.03 g). The reaction mixture was subjected to hydrogenation for 4 h at room temperature. The reaction mixture was then filtered through a pad of Celite@, and washed with methanol (20 mL). Removal of the solvent provided the title compound as a white solid (0.025 g, 38%). MH+348.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10]1([C:13]([OH:15])=O)[CH2:12][CH2:11]1.[Cl-].ClC1N(C)CC[NH+]1C.Cl.[NH2:26][CH2:27][CH2:28][N:29]1[CH:33]=[C:32]([C:34]2[CH:35]=[C:36]([NH:41][C:42]3[N:47]=[C:46]([CH:48]([F:50])[F:49])[CH:45]=[CH:44][N:43]=3)[CH:37]=[C:38]([CH3:40])[CH:39]=2)[CH:31]=[N:30]1>ClCCl>[F:50][CH:48]([F:49])[C:46]1[CH:45]=[CH:44][N:43]=[C:42]([NH:41][C:36]2[CH:35]=[C:34]([C:32]3[CH:31]=[N:30][N:29]([CH2:28][CH2:27][NH:26][C:13]([CH:10]4[CH2:12][CH2:11]4)=[O:15])[CH:33]=3)[CH:39]=[C:38]([CH3:40])[CH:37]=2)[N:47]=1
Reactant: O=C(O)C1CC1
Reactant: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CCN)c2)c1
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CCNC(=O)C3CC3)c2)c1
Reaction time: 0.17 h

Procedure:
Dichloromethane (1 mL) and N,N-diisopropylethylamine (0.087 mL, 0.50 mmol) were added to a vial containing cyclopropanecarboxylic acid (17.2 mg, 0.2 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.025 g, 0.15 mmol). The reaction mixture was stirred for 10 minutes and N-(3-(1-(2-amino ethyl)-1H-pyrazol-4-yl)-5-methylphenyl)-4-(difluoromethyl)pyrimidin-2-amine hydrochloride (38 mg, 0.10 mmol) was added. The reaction mixture was stirred for two hours and then concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile/water with 0.1% TFA modifier) to afford N-(2-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)ethyl)cyclopropanecarboxamide. MS ESI calc'd. for C21H23F2N6O [M+H]+ 413. found 413. 1H NMR (600 MHz, DMSO): δ 9.78 (s, 1H), 8.64 (d, J=4.9 Hz, 1H), 8.19 (s, 1H), 7.96 (s, 1H), 7.77 (s, 1H), 7.76 (s, 1H), 7.29 (s, 1H), 7.01 (d, J=4.9 Hz, 1H), 7.00 (s, 1H), 6.80 (t, J=54.5 Hz, 1H), 4.13 (t, J=6.2 Hz, 2H), 3.44 (q, J=6.0 Hz, 2H), 2.25 (s, 3H), 1.47-1.45 (m, 1H), 0.61-0.59 (m, 4H).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][C:6]=1[CH:7]=O)([O-:4])=[O:3].N1CCCCC1.C(O)(=O)[CH2:26][C:27]([OH:29])=[O:28]>N1C=CC=CC=1>[N+:2]([C:5]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][C:6]=1[CH:7]=[CH:26][C:27]([OH:29])=[O:28])([O-:4])=[O:3]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Yield: 87.6 %

Procedure:
2-Nitro-5-piperazinylbenzaldehyde hydrochloride (47 g) was dissolved in 500 ml of pyridine and 5 g of piperidine and 100 g of malonic acid were added to the solution followed by heating under reflux for 5 hours. After cooling, crystals which formed were collected by filtration to give 42 g of 2-nitro-5-piperazinylcinnamic acid, m.p. 229°-237° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH2:17]([OH:21])[CH2:18][CH2:19][CH3:20].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:7]([O:21][CH2:17][CH2:18][CH2:19][CH3:20])=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: CCCCO
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: CCCCOc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, butanol and DBU in dioxane. ES-MS m/e (%): 314 (M{81Br}+H+, 100), 312 (M{79Br}+H+, 98), 258 ([M{81Br}+H-EtCH═CH2]+, 92), 256 ([M{8Br}+H-EtCH ═CH2]+, 90).
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:18]=[C:17]([C:19]4[N:23]([CH:24]([CH3:26])[CH3:25])[C:22]([CH3:27])=[N:21][CH:20]=4)[C:16]([F:28])=[CH:15][N:14]=3)=[CH:8][CH:7]=2)[CH2:3]1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl.CO>[F:28][C:16]1[C:17]([C:19]2[N:23]([CH:24]([CH3:25])[CH3:26])[C:22]([CH3:27])=[N:21][CH:20]=2)=[N:18][C:13]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([N:4]3[CH2:3][CH:2]([NH:1][C:36](=[O:38])[CH3:37])[CH2:5]3)=[CH:11][CH:10]=2)=[N:14][CH:15]=1
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CC(N)C4)cc3)ncc2F)n1C(C)C
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC(=O)NC1CN(c2ccc(Nc3ncc(F)c(-c4cnc(C)n4C(C)C)n3)cc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81 %

Procedure:
To a stirred solution of N-[4-(3-aminoazetidin-1-yl)phenyl]-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-amine (Example 140; 110 mg, 0.29 mM) and triethylamine (44 μl, 0.317 mM) in dry DCM (4.0 ml), acetic anhydride (30 μl, 0.317 mM) was added. The reaction was stirred at room temperature under nitrogen for 2.5 hours. A few drops of MeOH were added and the solution stirred for 10 minutes. The reaction mixture was then diluted with more DCM and the solution extracted in turn with water (twice) and saturated sodium chloride. The organic layer was then dried with anhydrous sodium sulphate, filtered and evaporated. The crude product was triturated with ether, filtered washed with ether and dried to give the title compound as a yellow solid (99 mg, 81%). NMR 1.4 (d, 6H), 1.8 (s, 3H), 2.5 (s, 3H+DMSO), 3.5 (t, 2H), 4.05 (t, 2H), 4.53 (m, 1H), 5.43 (m, 1H), 6.4 (d, 2H), 7.33 (m, 3H), 8.42 (m, 2H), 9.08 (s, 1H); m/z 424.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]3[CH2:9][CH2:10][C:11](=O)[NH:12][C:13]=3[CH2:14][CH2:15][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8]3[CH2:9][CH2:10][CH2:11][NH:12][C:13]=3[CH2:14][CH2:15][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC2=C(CCc3cccc(Cl)c32)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1cccc2c1C1=C(CC2)NCCC1

Procedure:
20.0 g of 10-chloro-1,4,5,6-tetrahydrobenzo[f]-quinolin-3(2H)-one are added portionwise within 35 minutes at 20° to 25° to a stirred suspension of 6.49 g of lithium aluminum hydride in 240 ml of dry tetrahydrofuran. The reaction mixture is subsequently boiled under reflux for 150 minutes. The mixture is cooled, treated at 0° to 10° with 21.0 ml of 6.5N sodium hydroxide solution, filtered and rinsed several times with 20 ml of tetrahydrofuran each time. Distillation of the solvent in a vacuum gives 10-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline which is processed directly.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:14])[CH2:11][CH:12]=[O:13])[CH:7]=[CH:8][CH:9]=1)[CH3:3].[H][H]>[Pd].C(O)C>[CH3:3][CH:2]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:14])[CH2:11][CH:12]=[O:13])[CH:7]=[CH:8][CH:9]=1)[CH3:1]
Reactant: C=C(C)c1cccc(C(C)CC=O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1cccc(C(C)CC=O)c1
Yield: 78 %

Procedure:
3-(3-Propen-2-ylphenyl)butanal, lb, (100 g) was hydrogenated over palladium on charcoal (5% wet, 1 gram) in 150 ml ethanol for 2.5 hours at 50 psi hydrogen using a Parr-shaker apparatus. The product mixture was decanted, filtered and the ethanol removed on a rotary evaporator to give 97 grams of a mixture which analyzed as 95.8% la, and 2% lb. The mixture was distilled to give 78.1 g pure la, b.p. 84° C./0.3 mm.Hg. Yield 78.0% la. IR and NMR spectra were compatible with the assigned structure. Odor: fresh, floral, melon having qualities found in lily-of-the-valley (muguet) and linden blossom. Odor value: 981,483; Odor threshold value: 0.07 ng/L. EXAMPLE III
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:13][O:12][CH:11]([O:14][CH3:15])[CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: COC(CBr)OC
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(COc1ccc(F)cc1)OC
Reaction time: 120 h
Yield: 59.5 %

Procedure:
Dissolve 4-fluorophenol (5.5 g, 49.1 mmol) in acetonitrile (49 mL) and treat the solution with 2-bromo-1,1-dimethoxyethane (11.6 mL, 98.1 mmol) and K2CO3 (16.95 g, 122.7 mmol). Heat the solution to reflux with stirring for five days. Filter the mixture, and concentrate the filtrate under reduced pressure. Subject the resulting crude material to silica gel chromatography eluting with a gradient of 0% to 50% EtOAc/hexanes. Concentrate the fractions containing the desired product under reduced pressure to furnish the title compound as a colorless oil (5.85 g, 60% yield). Mass spectrum (m/z) 218 (M+NH4)+, 223 (M+Na)+.
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6]([CH3:10])([CH3:9])[C:7]#[CH:8])=O.[C:13]([C:15]1[CH:20]=CC(O)=[CH:17][CH:16]=1)#[N:14]>>[CH3:9][C:6]([O:5][C:3]1[CH:17]=[CH:16][C:15]([C:13]#[N:14])=[CH:20][CH:2]=1)([CH3:10])[C:7]#[CH:8]
Reactant: N#Cc1ccc(O)cc1
Reactant: C#CC(C)(C)OC(=O)C(F)(F)F
Product: C#CC(C)(C)Oc1ccc(C#N)cc1

Procedure:
The 1,1-dimethyl-2-propynyl trifluoroacetate solution, maintained at 0° C., was added to the 4-cyanophenol solution over a 40 minute period while keeping the temperature at ~0° C. The resulting mixture was stirred at ~0° C. (ice bath). After stirring for 5 hours, the mixture was concentrated at reduced pressure. The residue was partitioned between water (50 mL) and toluene (300 mL). The organic fraction was washed with 1N HCl (3×50 mL), 1N NaOH (2×50 mL), 1N NaHCO3, and brine. After drying (magnesium sulfate), the solvent was removed at reduced pressure to give crude title compound as a very pale yellow oil. Distillation of the crude material (bulb to bulb) afforded the title compound as a colorless, low melting solid (8.04 g).
Reaction SMILES: C(NC1C(I)=C(C(I)=C(NC(=O)C)C=1I)C(Cl)=O)(=O)C.C(=O)(O)[O-].[Na+].IC1C=CC(C(N)=O)=C(I)C=1I.[OH:38][CH:39]([CH2:61][OH:62])[CH2:40][NH:41][C:42]([C:44]1[C:49](I)=[C:48]([NH:51][C:52](=[O:54])[CH3:53])[C:47](I)=[C:46]([NH:56][C:57](=[O:59])[CH3:58])[C:45]=1I)=[O:43].[F:63][C:64]([F:69])([F:68])C([O-])=O.[Na+]>CN(C)C=O.CN(C)C(=O)C.[Cu]I>[OH:38][CH:39]([CH2:61][OH:62])[CH2:40][NH:41][C:42]([C:44]1[C:49]([C:64]([F:69])([F:68])[F:63])=[C:48]([NH:51][C:52](=[O:54])[CH3:53])[C:47]([C:64]([F:69])([F:68])[F:63])=[C:46]([NH:56][C:57](=[O:59])[CH3:58])[C:45]=1[C:64]([F:69])([F:68])[F:63])=[O:43]
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)NCC(O)CO)c1I
Reactant: O=C([O-])C(F)(F)F
Agent: [Cu]I
Agent: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)Cl)c1I
Agent: NC(=O)c1ccc(I)c(I)c1I
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(C(F)(F)F)c(NC(C)=O)c(C(F)(F)F)c(C(=O)NCC(O)CO)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3,5-bis(acetylamino)-2,4,6-triiodobenzoyl chloride (32 g, 50 mmol), N-(2,3-dihydroxypropyl)-3-aminomethyl-2,2,5,5-tetramethyl-1-pyrrolidinyloxy, free radical (12.3 g, 50 mmol) and sodium bicarbonate (4.2 g, 50 mmol) in 100 mL of dimethyl formamide is stirred for 18 hours at room temperature. The solvent is evaporated under reduced pressure. The residue is purified by C18 chromatography to give the spin labelled triiodobenzenecarboxamide. The chemical reaction is shown below: ##STR24## A mixture of N-((2,2,5,5-tetramethyl-1-pyrrolidinyloxy)methyl, free radical)-N-(2,3-dihydroxypropyl)-3,5-bis(acetylamino)-2,4,6-triiodobenzenecarboxamide (21 g, 25 mmol), sodium trifluoroacetate (61.2 g, 450 mmol) and copper(I) iodide (42.8 g, 225 mmol) in 500 mL of N,N dimethylacetamide is refluxed under argon for six hours. The solvent is evaporated under reduced pressure. The residue is purified by C18 chromatography to give N-((2,2,5,5-tetramethyl-1-pyrrolidinyloxy)methyl, free radical)-N-(2,3-dihydroxypropyl)-3,5-bis(acetylamino)-2,4,6-tris(trifluoromethyl)benzenecarboxamide. The chemical reaction is shown below: ##STR25##