Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:21][CH:22]=2)O1>>[Br:8][C:4]1[N:3]=[C:2]([C:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])[CH2:19][CH:18]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC1(C)OB(C2=CCN(C(=O)OCc3ccccc3)CC2)OC1(C)C
Product: O=C(OCc1ccccc1)N1CC=C(c2cccc(Br)n2)CC1

Procedure:
The title compound was prepared by using the procedure listed in Example 177 Step 3 with 2,6-dibromopyridine (0.77 g, 3.21 mmol) and benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.05 g, 3.06 mmol) as the starting materials.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[C:25]3[C:20](=[CH:21][C:22]([O:30][CH3:31])=[C:23]([O:26][CH:27]([CH3:29])[CH3:28])[CH:24]=3)[CH2:19][C:18](=[O:32])[NH:17]2)=[CH:12][CH:11]=1.Br[C:34]1[CH:39]=[CH:38][C:37]([C:40]([C:43]23[CH2:50][CH2:49][CH:46]([CH2:47][CH2:48]2)[O:45][CH2:44]3)([OH:42])[CH3:41])=[CH:36][CH:35]=1.N[C@@H]1CCCC[C@H]1N>O1CCOCC1.[Cu]I>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C@H:16]2[C:25]3[C:20](=[CH:21][C:22]([O:30][CH3:31])=[C:23]([O:26][CH:27]([CH3:28])[CH3:29])[CH:24]=3)[CH2:19][C:18](=[O:32])[N:17]2[C:34]2[CH:35]=[CH:36][C:37]([C:40]([OH:42])([C:43]34[CH2:48][CH2:47][CH:46]([CH2:49][CH2:50]3)[O:45][CH2:44]4)[CH3:41])=[CH:38][CH:39]=2)=[CH:14][CH:15]=1
Reactant: CC(O)(c1ccc(Br)cc1)C12CCC(CC1)OC2
Reactant: COc1cc2c(cc1OC(C)C)[C@H](c1ccc(Cl)cc1)NC(=O)C2
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC(C)C)[C@H](c1ccc(Cl)cc1)N(c1ccc(C(C)(O)C34CCC(CC3)OC4)cc1)C(=O)C2

Procedure:
A dry microwave vial was charged with K3PO4 (255 mg, 1.203 mmol), (S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-1,2-dihydroisoquinolin-3(4H)-one (208 mg, 0.601 mmol), 1-(4-bromo-phenyl)-1-(2-oxa-bicyclo[2.2.2]oct-4-yl)ethanol (225 mg, 0.722 mmol) and dioxane (1.9 ml). The reaction mixture was degassed with argon, then trans-1,2-diaminocyclohexane (69 mg, 0.072 ml, 0.601 mmol) and copper(I)iodide (115 mg, 0.601 mmol) were added. The vial was sealed and heated for 17 hrs to 97° C. in an oil bath. The reaction mixture was diluted with dioxane, filtered through a pad of hyflo, the residue was washed with dioxane and the filtrate concentrated to dryness. The crude product was purified by silica gel column chromatography (eluting with a gradient of DCM:DCM/EtOH (9/1) 95:05 to 50:50) yielding the title example (223 mg, 0.387 mmol, 64%) as a beige resin.
Reaction SMILES: C[Al](C)C.[C:5]1([NH2:12])[C:6]([NH2:11])=[CH:7][CH:8]=[CH:9][CH:10]=1.C.C(OC([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([C:35](OCC)=O)[CH:29]=2)[CH2:23][CH2:22]1)=O)(C)(C)C>C1(C)C=CC=CC=1.CO.O>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([N:24]2[CH2:25][CH2:26][CH2:27][NH:21][CH2:22][CH2:23]2)=[CH:29][C:30]=1[C:35]1[NH:12][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:11]=1
Reactant: CCOC(=O)c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1Cl
Reactant: Nc1ccccc1N
Agent: C
Agent: C[Al](C)C
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccc(N2CCCNCC2)cc1-c1nc2ccccc2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a solution of trimethylaluminium (2.0 M solution in toluene) (90 mL, 180 mmol) in toluene (300 mL) cooled to 0° C. under nitrogen was added benzene-1,2-diamine (6.5 g, 60 mmol) portionwise. The solution was stirred for 30 minutes at 0° C. then at 15-20° C. until evolution of methane ceased. 4-(4-chloro-3-ethoxycarbonyl-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (15.2 g, 40 mmol) was added in one portion to the resulting solution. The reaction was heated to reflux for 24 h then cooled to 0° C. Water (70 mL) was added carefully followed by MeOH (700 mL) The solid precipitated was filtered and the filtrate was concentrated under reduced pressure. The precipitate was washed with hot DCM:MeOH 1:1 (400 mL) followed by AcOEt (200 mL) The solution was concentrated under reduced pressure. Two extracts were combined and purified by flash chromatography (eluent: AcOEt:MeOH:NH3 gradient from 100% AcOEt to AcOEt:MeOH:NH3 73:25:2) to afford 9.3 g of a mixture of 2-(2-Chloro-5-[1,4]diazepan-1-yl-phenyl)-1H-benzoimidazole and N-(2-amino-phenyl)-2-chlorodiazepan-1-yl-benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:3]=1[CH2:4][C:5]1[C:10]2[N:11]=[CH:12][N:13](COCC[Si](C)(C)C)[C:9]=2[C:8]([C:22]#[N:23])=[C:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32](=[O:38])[N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:27][C:26]=2[O:39][CH3:40])[N:6]=1.O.C(=O)(O)[O-:48].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:3]=1[CH2:4][C:5]1[C:10]2[N:11]=[CH:12][NH:13][C:9]=2[C:8]([C:22]([NH2:23])=[O:48])=[C:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32](=[O:38])[N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:27][C:26]=2[O:39][CH3:40])[N:6]=1
Reactant: O=C([O-])O
Reactant: COc1cc(CC(=O)N2CCCC2)ccc1Nc1nc(Cc2c(Cl)cccc2Cl)c2ncn(COCC[Si](C)(C)C)c2c1C#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1cc(CC(=O)N2CCCC2)ccc1Nc1nc(Cc2c(Cl)cccc2Cl)c2nc[nH]c2c1C(N)=O
Temperature: 85 °C

Procedure:
The product of Example 30E (80 mg, 0.12 mmol) was dissolved in concentrated sulfuric acid (3 mL) and water (0.5 mL) was added and the solution was heated at 85° C. for 0.5 hours. After cooling to ambient temperature, the mixture was neutralized with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by preparative HPLC using a gradient of 10/90 to 75/25 acetonitrile/water (containing 0.1% trifluoroacetic acid) to give the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 14.11 (s, 1 H), 11.83 (s, 1 H), 9.59 (s, 1 H), 8.59 (s, 1 H), 7.71-7.68 (m, 2 H), 7.60-7.58 (m, 2 H), 7.44 (t, J=7.8 Hz, 1 H), 6.77 (s, 1 H), 6.31 (d, J=8.1 Hz, 1 H), 4.79 (s, 2 H), 3.81 (s, 3 H), 3.51 (s, 2 H), 3.46 (t, J=6.6 Hz, 2 H), 3.33 (t, J=6.3 Hz, 2 H), 1.93-1.78 (m, 4 H). MS: 553 (M+H+).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([F:19])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)C.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[F:19][C:6]1([CH2:5][CH2:4][OH:3])[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]1
Reactant: CCOC(=O)CC1(F)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(CCO)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-fluoropiperidine-1-carboxylate (3.8 g) in DCM (20 ml) at −78° C. under nitrogen was added by syringe diisobutylaluminum hydride (2.2M in Toluene, 24 ml). The mixture was stirred at −78° C. for 2 hours, then warmed up to room temperature. The mixture was then poured to ice (100 g), acidified to pH 3, and extracted with ethyl acetate (200 ml+100 ml×3). Combined ethyl acetate layer was then dried over sodium sulphate, solvent removed to give tert-butyl 4-fluoro-4-(2-hydroxyethyl)piperidine-1-carboxylate which is contaminated with HF eliminated allylic alcohol in ˜3:1 ratio in favour of desired product (3 g). As purification proved to be difficult, this was used for next step as a mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10](O)([CH3:12])[CH3:11].[CH2:14]([O:16][C:17](=[O:25])[C:18]([O:20][Si](C)(C)C)=[CH2:19])[CH3:15].[Sn](Cl)(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:14]([O:16][C:17](=[O:25])[C:18](=[O:19])[CH2:20][C:10]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([CH3:9])[C:3]=1[O:2][CH3:1])([CH3:12])[CH3:11])[CH3:15]
Reactant: C=C(O[Si](C)(C)C)C(=O)OCC
Reactant: COc1c(C)cccc1C(C)(C)O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C(=O)CC(C)(C)c1cccc(C)c1OC
Reaction time: 3 h
Yield: 41.6 %

Procedure:
71.37 g (395.96 mmol) of 2-(2-methoxy-3-methylphenyl)-propan-2-ol and 149 g (791.92 mmol) of 2-trimethylsilanyloxyacrylic acid ethyl ester are introduced into 1.1 l of dichloromethane. At −78° C., 44.8 ml (379.91 mmol) of tin tetrachloride is added in drops, and the batch is then stirred for three hours at this low temperature. 1.4 l of semiconcentrated potassium carbonate solution is carefully added in drops, and the reaction mixture is thus brought to room temperature. The batch is filtered, and the filtrate is extracted three times with ethyl acetate. The combined organic extracts are washed with brine, dried on sodium sulfate, and the solvent is spun off. The residue is chromatographed several times on silica gel (mobile solvent ethyl acetate/hexane). 45.81 g (41.6%) of the desired compound is isolated.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=2)[C:7]([CH3:17])=[CH:6]1)(=[O:4])=[O:3]>C(O)C.[Pt]=O>[CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH2:14])[CH:12]=2)[C:7]([CH3:17])=[CH:6]1)(=[O:4])=[O:3]
Reactant: Cc1cn(S(C)(=O)=O)c2cc([N+](=O)[O-])ccc12
Agent: O=[Pt]
Solvent: CCO
Product: Cc1cn(S(C)(=O)=O)c2cc(N)ccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 1-methanesulfonyl-3-methyl-6-nitro-1H-indole (1.17 g, 4.60 mmol) and platinum oxide (52 mg, 0.23 mmol) in 20 ml of absolute ethanol was stirred at room temperature under an atmosphere of hydrogen gas for 12 hr. The mixture was filtered through a fine Whatman glass fiber filter to remove the catalyst. A quantitative amount of 1-methanesulfonyl-3-methyl-6-amino-1H-indole was obtained after removing the ethanol at reduced pressure.
Reaction SMILES: [Br:1]Br.[CH2:3]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[CH:13]=[CH:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:3]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]([Br:1])=[CH:12][N:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cn1c(Cc2ccccc2)nccc1=O
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1c(Cc2ccccc2)ncc(Br)c1=O
Reaction time: 0.5 h

Procedure:
Br2 (2.62 mL, 52 mmol) was added to 2-benzyl-3-methyl-3H-pyrimidin-4-one (Step 2, 9.3 g, 47 mmol) in CHCl3 (100 mL) and sat NaHCO3 (100 mL). After 30 min, the organic layer was separated, dried (Na2SO4) and filtered through a plug of silica. The filtrate was concentrated under reduced pressure, and azeotroped with CHCl3 (2×). The crude compound was dried under high vacuum for 16 h to provide the title compound. MS (ESI pos. ion) m/z: 279.0, 281.1. Calc'd for C12H11BrN2O: 278.01.
Reaction SMILES: [C:1](=[N:14][NH2:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1>>[C:2]1([C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:14][NH:15][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: Fc1ccc(Br)cc1
Product: Fc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1

Procedure:
General procedure A was used to convert benzophenone hydrazone (1.962 g, 10.0 mmol; Aldrich) and 1-bromo-4-fluorobenzene (1.75 g, 10.0 mmol; source) to the title compound. MS (DCI/NH3) m/z 291 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.CC(C)=O.[SH2]=N.[C:21]1([NH:27][C:28](C2C=CC=CC=2C(O)=O)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[C:21]1([NH:27][C:28]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccccn1
Reactant: O=C(O)c1ccccc1C(=O)Nc1ccccc1
Agent: N=[SH2]
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)Nc1ccccn1
Yield: 54.5 %

Procedure:
A solution of 0.5 g aminopyridin and 0.7 ml triethylamine with 5 ml acetone was added dropwise to a suspension of 1.5 g phenylcarbamoyl-benzoic acid sulfimide with 15 ml aceton, under stirring. The reaction mixture was stirred for 45 minutes at room temperature, then diluted with 100 ml water. The acetone was distilled off, the residue was cooled, and the precipitated solid product was filtered, washed with water and dried. 0.6 g 1-phenyl-3-(2-pyridyl)-urea was obtained with a melting point of 185°-186° C.
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([CH3:18])[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)(C)(C)C>[OH-].[Na+]>[CH3:18][C:16]1[CH:17]=[C:8]([CH2:7][C:6]([OH:19])=[O:5])[CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2
Reactant: Cc1cc(CC(=O)OC(C)(C)C)cc2cccnc12
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(CC(=O)O)cc2cccnc12

Procedure:
3.5 g of (8-methyl-quinolin-6-yl)-acetic acid tert-butyl ester in 18 ml of NaOH (4N, aq.) was heated to reflux for 3 h. The mixture was washed with ethyl acetate and the water layer was acidified with 1N hydrochloric acid to pH 4-5 and extracted with dichloromethanfe. The solvent was evaporated and the resulting solid was washed with water and dried in vacuo to return the title compound as an off white solid (1.3 g, 48%). 1H NMR (DMSO-d6, 300 MHz) δ 12.42 (s, 1H), 8.90 (m, 1H), 8.30 (m, 1H), 7.66 (s, 1H), 7.54 (m, 2H), 3.74 (s, 2H), 2.70 (s, 3H).
Reaction SMILES: COC1C=CC2CC3C(=O)C(C)(C=2C=1)CCCC3.[CH3:19][C:20]1([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][C:21]1=[O:30].[H-].[Na+]>CN(C)C=O>[CH3:19][C:20]12[C:21](=[O:30])[CH:22]([CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=31)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2
Reactant: CC1(CCCCCBr)C(=O)CCc2ccccc21
Agent: COc1ccc2c(c1)C1(C)CCCCC(C2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC12CCCCCC(Cc3ccccc31)C2=O
Yield: 40.4 %

Procedure:
Using a procedure analogous to that described in Example X for the preparation of 6,7,8,9,10,11-hexahyro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one there is prepared from 1-methyl-1-(5-bromopentyl)-2-tetralone (19.8 g., 0.0675 mole) and sodium hydride (3.57 g., 0.081 mole, of a 54.5% dispersion in mineral oil) in dimethylformamide (250 ml.); 6.2 g. (40.4%) of the title product, b.p. 126° to 135° C. (0.3 mm.).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[N:22]1([CH2:26][C:27]2[CH:28]=[C:29]([CH:49]=[CH:50][CH:51]=2)[CH2:30][N:31]2[C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:40]([CH3:43])=[N:41][N:42]=4)[C:34]=3[CH:33]=[C:32]2[C:44]2[CH:48]=[CH:47][NH:46][N:45]=2)[CH2:25][CH2:24][CH2:23]1.[C:52](#[N:55])[CH:53]=[CH2:54].N12CCCN=C1CCCCC2>CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[N:22]1([CH2:26][C:27]2[CH:28]=[C:29]([CH:49]=[CH:50][CH:51]=2)[CH2:30][N:31]2[C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:40]([CH3:43])=[N:41][N:42]=4)[C:34]=3[CH:33]=[C:32]2[C:44]2[CH:48]=[CH:47][N:46]([CH2:54][CH2:53][C:52]#[N:55])[N:45]=2)[CH2:23][CH2:24][CH2:25]1
Reactant: C=CC#N
Reactant: Cc1nnc2ccc3c(cc(-c4cc[nH]n4)n3Cc3cccc(CN4CCC4)c3)n12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc2ccc3c(cc(-c4ccn(CCC#N)n4)n3Cc3cccc(CN4CCC4)c3)n12

Procedure:
6-[3-(Azetidin-1-ylmethyl)benzyl]-1-methyl-7-(1H-pyrazol-3-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (7.0 mg, 0.018 mmol, from Example 182) in MeCN (0.23 mL) was treated with 2-propenenitrile (2.3 μL, 0.035 mmol, Aldrich) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.6 μL, 0.018 mmol, Aldrich) for 8 minutes. The product was purified via preparative HPLC-MS (Waters SunFire C18, eluting with a gradient of MeCN/H2O containing 0.1% TFA). Yield: (9.8 mg, 82%).
Reaction SMILES: COC(C1N=C2N([CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)C3C=CC=CC=3N2C(=O)C=1OC(=O)C)=O.C(OC(N1CCN(CC[N:53]2[C:57]3=[N:58][C:59]([C:64](=[O:75])[NH:65][CH2:66][C:67]4[CH:72]=[CH:71][C:70]([Cl:73])=[C:69]([Cl:74])[CH:68]=4)=[C:60]([OH:63])[C:61](=[O:62])[N:56]3[C:55]3[CH:76]=[CH:77][CH:78]=[CH:79][C:54]2=3)CC1)=O)(C)(C)C>>[C:30]([O:29][C:27]([N:24]1[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][N:58]2[C:59]([C:64](=[O:75])[NH:65][CH2:66][C:67]3[CH:72]=[CH:71][C:70]([Cl:73])=[C:69]([Cl:74])[CH:68]=3)=[C:60]([OH:63])[C:61](=[O:62])[N:56]3[C:55]4[CH:76]=[CH:77][CH:78]=[CH:79][C:54]=4[N:53]=[C:57]23)[CH2:22][CH2:23]1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: COC(=O)c1nc2n(CCN3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc3n2c(=O)c1OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCN(CCn2c3ccccc3n3c(=O)c(O)c(C(=O)NCc4ccc(Cl)c(Cl)c4)nc23)CC1
Product: CC(C)(C)OC(=O)N1CCN(CCn2c(C(=O)NCc3ccc(Cl)c(Cl)c3)c(O)c(=O)n3c4ccccc4nc23)CC1

Procedure:
The product from Example 15.2 was converted to 4-{2-[2-(3,4-Dichloro-benzylcarbamoyl)-3-hydroxy-4-oxo-4H-benzo[4,5]imidazo[1,2-a]pyrimidin-10-yl]-ethyl}-piperazine-1-carboxylic acid tert-butyl ester following a procedure adapted from Example 6.
Reaction SMILES: [C:1]([O:8][C:9]([C:12]([CH2:15][CH2:16]I)([F:14])[F:13])([F:11])[F:10])([C:4]([F:7])([F:6])[F:5])([F:3])[F:2].CN1CCCC1=[O:24]>O>[C:1]([O:8][C:9]([C:12]([CH2:15][CH2:16][OH:24])([F:14])[F:13])([F:11])[F:10])([C:4]([F:7])([F:6])[F:5])([F:3])[F:2]
Reactant: CN1CCCC1=O
Reactant: FC(F)(F)C(F)(F)OC(F)(F)C(F)(F)CCI
Solvent: O
Product: OCCC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F
Yield: 52 %

Procedure:
The flask was charged with 130 g of C2F5OCF2CF2CH2CH2I, 643 mL of the methylpyrrolidinone and 48 mL of deionized (DI) water. The reaction mixture was heated to 132 C for 20 hours. DI water was added and the lower layer was separated. The lower layer was dissolved in ether, washed with saturated sodium sulfite, and dried over anhydrous sodium sulfate. After rotary vaporization, 48 g of C2F5OCF2CF2CH2CH2OH was obtained by distillation in 52% yield. The boiling point was 70˜72° C. at 60 mm Hg pressure (7980 Pa).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]#[N:14].[OH-].[Na+].Cl[CH2:18][CH2:19][N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22].C(Cl)Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]([CH2:18][CH2:19][N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[C:13]#[N:14]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: N#CCc1ccc2ccccc2c1Br
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)N(CCC(C#N)c1ccc2ccccc2c1Br)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
69 Parts of α-(1-bromo-2-naphthyl)acetonitrile is stirred in 150 parts by volume of 50% sodium hydroxide and then 0.7 parts of benzyltriethylammonium chloride is added to the mixture. To this mixture is added slowly a solution of 41.82 parts of 2-chloro-N,N-diisopropylethylamine in 150 parts by volume of methylene chloride and the resulting mixture is stirred at room temperature for about 2 hours. Then, additional quantities of methylene chloride and water are added to the reaction mixture. The organic layer is then separated, dried over anhydrous sodium sulfate and concentrated to give α-(1-bromo-2-naphthyl)-α-[2-(diisopropylamino)ethyl]acetonitrile, as a solid. This compound is represented by the following structural formula ##STR34##
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:69])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[O:53][CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH:46]([O:67][CH3:68])[CH2:45]2)[CH:7]([CH3:70])[CH:6]([O:71][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:79])[CH3:2].C1C=CN=CC=1.F>C1COCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:69])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)[O:53][CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH:46]([O:67][CH3:68])[CH2:45]2)[CH:7]([CH3:70])[CH:6]([OH:71])[CH2:5][C:4]1=[O:79])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(OCc4ccccc4)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(OCc4ccccc4)c4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
To a solution of the product from Step A (22 mg) in THF (100 μl) was added hydrogen fluoride/pyridine and the reaction stirred at room temperature for 6 hours. The reaction was then quenched by the addition of saturated aqueous sodium bicarbonate and extracted into ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated. The crude material was purified by column chromatography on silica gel eluting with 50% hexane:50% ethyl acetate to give the title compound (15 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:13]2[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:12]=2[N:11]([C:19]([NH:21][C@@H:22]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([OH:25])=[O:24])=[O:20])[N:10]=1.[CH2:30]=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:13]2[CH2:14][N:15]([CH2:18][CH3:30])[CH2:16][CH2:17][C:12]=2[N:11]([C:19]([NH:21][C@@H:22]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([OH:25])=[O:24])=[O:20])[N:10]=1
Reactant: C=O
Reactant: CN1CCc2c(c(-c3cc(F)ccc3F)nn2C(=O)N[C@H](C(=O)O)C(C)(C)C)C1
Product: CCN1CCc2c(c(-c3cc(F)ccc3F)nn2C(=O)N[C@H](C(=O)O)C(C)(C)C)C1

Procedure:
Compound 82 was prepared according to the procedure described for the synthesis of compound 81 by replacing formaldehyde with acetadehyde. LCMS (+ESI) m/z=421.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:37]=[C:36]([C:38]2[CH:39]([CH3:45])[NH:40][C:41](=[O:44])[NH:42][N:43]=2)[CH:35]=[CH:34][C:20]=1[O:21][CH2:22][C:23]([NH:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:24]>O1CCCC1>[Cl:18][C:19]1[CH:37]=[C:36]([C:38]2[CH:39]([CH3:45])[NH:40][C:41](=[O:44])[NH:42][N:43]=2)[CH:35]=[CH:34][C:20]=1[O:21][CH2:22][C:23]([NH:25][CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][N:31]([C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:32][CH2:33]1)=[O:24]
Reactant: CC1NC(=O)NN=C1c1ccc(OCC(=O)NCCN2CCNCC2)c(Cl)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1NC(=O)NN=C1c1ccc(OCC(=O)NCCN2CCN(C(=O)c3ccc(Cl)cc3)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
0.43 g of p-chlorobenzoyl chloride and 0.25 g of triethylamine were added to a suspension of 0.5 g of α-[2-chloro-4-(2,3,4,5-tetrahydro-5-methyl-3-oxo-1,2,4-triazin-6-yl)phenoxy-N-[2-(1-piperazinyl)ethyl]acetamide (prepared as described in Example 10) in 10 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 1 hour. The tetrahydrofuran used as the solvent was removed by evaporation under reduced pressure, and the residue was extracted with methylene chloride. The extract was washed with water and dried over anhydrous magnesium sulfate, after which the residue was purified by column chromatography through silica gel, eluted with a 98:2 by volume mixture of methylene chloride and ethanol, to give 0.2 g of a colorless oil. This oil was crystallized from ethanol and then recrystallized, also from ethanol, to give 0.16 g of the title compound as colorless fine crystals melting at 186°-188° C.