Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Cl:32])[C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[C:23]([OH:30])[C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[O:21][C:20](=[O:31])[CH:19]=1>>[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Cl:32])[C:16]=1[NH:17][C:18]1[C:27]2[C:22](=[C:23]([O:30][CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[O:21][C:20](=[O:31])[CH:19]=1
Reactant: BrCCc1ccccc1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCc1ccccc1

Procedure:
The title compound was prepared from (2-bromoethyl)benzene and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.35-7.23 (m, 4H), 7.19 (d, 2H), 4.64 (s, 1H), 4.22 (t, 2H), 3.89 (s, 3H), 3.03 (t, 2H); MS (ESI): 456.9.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C:15]2=[O:21])[C:3]=1[CH3:22].[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[C:34]([NH2:35])=[CH:33][C:32]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[N:26]1([C:29]2[C:34]([NH:35][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([N:14]4[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C:15]4=[O:21])[C:3]=3[CH3:22])=[CH:33][C:32]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)=[CH:31][N:30]=2)[CH2:25][CH2:24][O:23][CH2:28][CH2:27]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(N2CCN(C)CC2=O)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(N2CCN(C)CC2=O)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to Procedure H using 1-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-4-methylpiperazin-2-one (25.0 mg, 0.077 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give 1-(4-((2,5-di-4-morpholinyl-3-pyridinyl)amino)-5,7-difluoro-3-methyl-2-quinolinyl)-4-methyl-2-piperazinone. 1H NMR (400 MHz, chloroform-d) δ ppm 8.12 (1H, br. s.), 7.68 (1H, d), 7.45 (1H, d, J=9.4 Hz), 7.04 (1H, ddd, J=13.6, 8.6, 2.4 Hz), 6.51 (1H, br. s.), 4.64 (1H, d, J=12.9 Hz), 3.84-4.00 (6H, m), 3.73-3.84 (4H, m), 3.36-3.54 (3H, m), 3.20-3.36 (2H, m), 3.15 (4H, br. s.), 2.93-3.09 (2H, m), 2.78 (3H, br. s.), 1.98 (3H, s). Mass Spectrum (ESI) m/e=554.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Br:23]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:23])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COCCOc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COCCOc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
6-Amino-9-benzyl-2-(2-methoxyethoxy)purine (93 mg, 0.31 mmol) and bromine (1 ml) were dissolved in methylene chloride (100 ml). The solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (75 mg, yield 64%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[H-].[Na+].Cl[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1.[I-].[Na+]>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(CCl)cc1
Reactant: Oc1ccc2ccccc2c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2ccc3ccccc3c2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 82.2 %

Procedure:
To a solution of 2-naphthol (26 g) in DMF (300 ml) is added sodium hydride (7.2 g of 60% dispersion). When gas evolution ceases, methyl 4-(chloromethyl)benzoate (32.9 g) and sodium iodide (10 g) are added, and the reaction mixture is stirred at 140° for 3 hr, and at 90° for an additional 18 hr. The mixture is cooled, poured into 2000 ml ice water, and the product extracted with 1:1 ether-hexane. The extracts are dried, filtered, and concentrated, providing methyl 4-(2-naphthyloxymethyl)benzoate as a tan solid (42.8 g, 91%). The ester is reduced with lithium aluminum hydride in THF in the usual fashion, and the resulting benzyl alcohol is converted by Swern oxidation (oxalyl chloride /DMSO) to 4-(2-naphthyloxymethyl)benzaldehyde. By the method of example 1, this is converted to the title compound, obtained as a pale yellow solid, mp. 213°-215° after recrystallization from hexane-ethyl acetate.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:16])([F:15])[C:5]1[CH:6]=[N:7][C:8]2[CH2:9][CH2:10][NH:11][CH2:12][C:13]=2[CH:14]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]1[CH2:29][CH2:28][C@:27]([CH:33]([CH3:35])[CH3:34])([C:30](O)=[O:31])[CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH:33]([C@:27]1([C:30]([N:11]2[CH2:10][CH2:9][C:8]3[N:7]=[CH:6][C:5]([C:4]([F:15])([F:3])[F:16])=[CH:14][C:13]=3[CH2:12]2)=[O:31])[CH2:28][CH2:29][C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:26]1)([CH3:35])[CH3:34]
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1cnc2c(c1)CNCC2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.7 %

Procedure:
To a solution of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine dihydrochloride (159 mg, 0.574 mmol) of Step A-1, (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (0.21 g, 0.79 mmol) of Step A-4 in Example 1 in dichloromethane (10 mL) were added 4-dimethylaminopyridine (38 mg, 0.32 mmol) and diisopropylethylamine (180 mg, 1.4 mmol) followed by bromotris(pyrrolydino)phophonium hexafluorophosphate (270 mg, 0.57 mmol). After being stirred overnight at room temperature, the solution was diluted with dichloromethane, washed with saturated NaHCO3, water and brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by flash chromatography on silica eluting with 30% ethyl acetate in hexanes to give 300 mg of desired product. MS calculated for C23H32F3N3O3: (M+H)+456; found 356.2 (M−Boc+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([F:8])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(F)ccc1Cl
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(F)c([N+](=O)[O-])cc1Cl
Temperature: 28 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a stirred solution of 2-chloro-5-fluorotoluene (0.500 g, 3.46 mmol, Lancaster, used as received) in conc. H2SO4 (5.0 mL) at 0° C., KNO3 (0.350 g, 3.46 mmol) was added in one lot. The resulting pale yellow solution was allowed to warm to 28° C. and stirred overnight at 28° C. It was then poured into ice (50 g) and extracted with ether (2×50 mL). The ether was dried over anhydrous Na2SO4, removed under vacuum, and the resulting oil was dried further under vacuum to afford 0.616 g (94%) of the title compound as an oil, which was used as such for the next reaction; 1H NMR (CDCl3): δ2.459 (s, 3H), 7.193 (d, 1H, J1 =11.1 Hz), 8.083 (d, 1H, J1 =6.6 Hz).
Reaction SMILES: Cl[CH2:2][C:3]([CH3:38])([CH3:37])[C:4]([N:6]([C@H:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1)[CH2:7]/[CH:8]=[CH:9]/[C:10]1[CH:11]=[C:12]2[CH2:27][C@@:17]3([C:25]4[C:20](=[N:21][CH:22]=[CH:23][CH:24]=4)[NH:19][C:18]3=[O:26])[CH2:16][C:13]2=[N:14][CH:15]=1)=[O:5].[Na+].[I-:40]>CC(C)=O>[C@H:28]1([N:6]([CH2:7]/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]3[CH2:27][C@@:17]4([C:25]5[C:20](=[N:21][CH:22]=[CH:23][CH:24]=5)[NH:19][C:18]4=[O:26])[CH2:16][C:13]3=[N:14][CH:15]=2)[C:4](=[O:5])[C:3]([CH3:37])([CH3:38])[CH2:2][I:40])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1
Reactant: [I-]
Reactant: CC(C)(CCl)C(=O)N(C/C=C/c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21)[C@@H]1CCc2ccccc21
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(CI)C(=O)N(C/C=C/c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21)[C@@H]1CCc2ccccc21
Temperature: 120 °C

Procedure:
To a solution of 3-chloro-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-2,2-dimethyl-N-{(2E)-3-[(6S)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-3-yl]prop-2-en-1-yl}propanamide (120. mg, 0.228 mmol) in acetone (2.3 mL) was added NaI (683 mg, 4.55 mmol). This mixture was heated to 120° C. in a microwave reactor for 30 minutes. After cooling, the bulk of the acetone was removed in vacuo and the residue was partitioned between DCM and water. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to provide a residue. The residue was then applied to a silica gel column for purification, eluting with a gradient of 1-8% MeOH (containing 10% conc. NH4OH) in DCM to provide the title compound. MS: m/z=619 (M+1).
Reaction SMILES: [NH3:1].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:3]=1.[Cl-].[NH4+]>C(OCC)(=O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([NH2:1])(=[O:10])=[O:9])[CH:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A 25% aqueous ammonia solution (2 mL) was added to pyridine-3-sulfonyl chloride (300 mg, 1.7 mmol) and the mixture was stirred at room temperature for 2 hours. Then, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure and thereby Compound FA (154 mg, yield: 58%) was obtained.
Reaction SMILES: N[C:2]1[C:6]([C:7](=[O:9])[CH3:8])=[CH:5][N:4]([CH:10]([CH3:12])[CH3:11])[N:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O.N([O-])=O.[Na+].[I-:29].[K+]>C(#N)C.O>[I:29][C:2]1[C:6]([C:7](=[O:9])[CH3:8])=[CH:5][N:4]([CH:10]([CH3:12])[CH3:11])[N:3]=1
Reactant: CC(=O)c1cn(C(C)C)nc1N
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1cn(C(C)C)nc1I
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of Intermediate 1-(3-amino-1-isopropyl-1H-pyrazol-4-yl)ethanone (3.97 g, 24 mmol) and p-TsOH.H2O (9.07 g, 48 mmole, 2 eq) in 150 ml of acetonitrile at 0° C. was added dropwise a solution of sodium nitrite (2.97 g, 43 mmole, 1.8 eq) and potassium iodide (8.0 g, 48 mmol, 2.0 eq) in 20 ml water. The mixture was stirred at this temperature for 10 minutes and then allowed to warm to rt and stirred for 3 h. The mixture was concentrated and then diluted with water and neutralized with aqueous sodium carbonate solution to pH 9 to 10. The mixture was extracted with ethyl acetate (3×). The combined organic layers were washed with sodium thiosulfate solution, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (1:1 hexanes/ethyl acetate eluant) to provide the title compound as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 4.53 (m, 1H), 2.37 (s, 3H), 1.41 (d, J=7 Hz, 6H); MS m/z 279.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH2:21][CH2:20][CH2:19]4)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]([C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:21][CH2:20][CH2:19]4)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(-c2nc(-c3ccc4c(c3)CCCN4)cs2)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(-c2nc(-c3ccc4c(c3)CCCN4C(=O)c3ccccc3)cs2)cc1OC
Reaction time: 5 h
Yield: 54 %

Procedure:
In 10 ml of pyridine was dissolved 1 g of 2-(3,4-dimethoxyphenyl)-4-(1,2,3,4-tetrahydroquinolin-6-yl) thiazole. Thereto was added 0.44 g of benzoyl chloride at 0° C., and the mixture was stirred for 5 hours. The solution was concentrated and mixed with ethanol and water in this order. The resulting crystals were collected by filtration and recrystallized from ethanol to obtain 0.7 g of 2-(3,4-dimethoxyphenyl)-4-(1-benzoyl-1,2,3,4-tetrahydroquinolin-6-yl)thiazole as a light yellow powder.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH2:15]OS(C)(=O)=O)=[CH:11][C:10]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][NH:30][CH3:31]>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH2:15][N:30]([CH3:31])[CH3:29])=[CH:11][C:10]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:28])[CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccccc3)n2)ccc1F
Reactant: CNC
Product: Cc1cc(-c2cc(CN(C)C)c(=O)n(Cc3ccccc3)n2)ccc1F
Yield: 92.7 %

Procedure:
Following the procedure of Example 7, 2-benzyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as a yellow oil (yield: 92.7%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[CH:6]=1)[OH:4].O=[C:14]([CH3:28])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:27][O:26][C:24]([CH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH:14]([NH:1][CH2:2][CH:3]([C:5]2[CH:6]=[C:7]([Cl:12])[CH:8]=[C:9]([Cl:11])[CH:10]=2)[OH:4])[CH3:28])=[CH:22][CH:21]=1)=[O:25]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: NCC(O)c1cc(Cl)cc(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cc(Cl)cc(Cl)c2)cc1
Yield: 60 %

Procedure:
Following a procedure similar to that described in Example 3, but using 3.0 g of 2-amino-1-(3,5-dichlorophenyl)ethanol (prepared as described in Preparation 39), 3.87 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 80 ml of benzene, 60 ml of absolute methanol and 2.9 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using ethyl acetate as the eluent, 3.6 g of the title compound were obtained, having an Rf=0.51 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([CH3:30])=[CH:24][C:25]=2[C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[ClH:34]>O1CCOCC1.C(OCC)C>[ClH:34].[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([CH3:30])=[CH:24][C:25]=2[C:26]([F:27])([F:28])[F:29])=[CH:18][CH:19]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)[C@@H](N)Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1
Reaction time: 4 h
Yield: 92 %

Procedure:
To a solution of N-[(1,1-dimethylethoxyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester (132 mg, 0.33 mmol) in dioxane (3 mL) was added 4 N HCl solution in dioxane (4.5 mL) at room temperature. The solution was stirred for 4 h as a white solid was formed. The mixture was diluted with diethyl ether (50 mL) and solid was collected by filtration washing with diethyl ether. After drying under high vacuum, 315 mg (92% yield) of 4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester hydrochloride salt was obtained as an amorphous white solid. ES-HRMS m/e calcd for C18H19F3N2O3 (M+Na) 391.1241, found 391.1241.
Reaction SMILES: C#CCC.BrCCCCCCOC1CCCCO1.[C:19]([O:22][CH2:23][CH2:24]/[CH:25]=[CH:26]/[CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])(=[O:21])[CH3:20].O1CCCCC1OCCC#CCCC/C=C\C/C=C\CC.C(OCC/C=C/CCC/C=C\C/C=C\CC)(=O)C.C[Si](C)(C)OCCCCCCC/C=C\C/C=C\CC.O1CCCCC1OCCC/C=C\CCCCC>C(Cl)(Cl)(Cl)Cl>[C:19]([O:22][CH2:23][CH2:24]/[CH:25]=[CH:26]/[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH3:36])(=[O:21])[CH3:20]
Reactant: CCCCC/C=C\CCC/C=C/CCOC(C)=O
Agent: BrCCCCCCOC1CCCCO1
Agent: C#CCC
Agent: CC/C=C\C/C=C\CCC/C=C/CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC/C=C\CCCCCC/C=C/CCOC(C)=O
Yield: 15 %

Procedure:
Starting from 1-butyne and 1-bromo-6-(tetrahydropyran-2-yloxy)-hexane (22), the (3E,11Z)-3,11-tetradecadien-1-yl acetate (30) was prepared by a synthetic route similar to that used for the preparation of (3E,8Z)-3,8-tetradecadien-1-yl acetate (21), as depicted in the following scheme. ##STR18## The yield was 15% [17 mg; 96% isomeric purity (GC)] based on the starting material, 1-bromo-6-(tetrahydropyran-2-yloxy)hexane (22). 1H NMR (500 MHz) δ: 5.51 (dtt, J=15.1, 6.8, 6.8, 1.2, 1.5 Hz, 1H, =CH -3), 5.35 (m, 3H, CH=CH -4, 11, 12), 4.06 (t, J=6.8, 6.8 Hz, 2H, CH2 -1), 2.31 (dddt, J=1.2, 1.2, 6.8, 6.8, 6.8 Hz, 2H, CH2 -2), 2.05 (s, 3H, COCH3), 2.02 (m, 6H, CH2 -5, 10, 13), 1.36-1.24 (m, 6H, CH2 -6, 7, 8, 9), 0.95 (t, J=7.3, 7.6 Hz, 3H, CH3). 13 C NMR (100.6 MHz) δ: 171.1 (C=O), 133.6 (=CH-3), 131.6 (=CH-12), 129.3 (=CH-11), 125.0 (=CH-4), 64.1 (CH2 -1), 32.6 (CH2 -2), 31.9 (CH2 -6), 29.7 (CH2 -8), 29.3 (CH2 -7), 29.1 (CH2 -9), 29.0 (CH2 -10), 27.1 (CH2 -5), 21.0 (COCH3), 20.5 (CH2 -13), 14.4 (CH3 -14). MS [EI, m/z(%)] 192 (M+ -60, 6), 163 (6), 149 (9), 135 (12), 121 (16), 107 (16), 96 (28), 95 (37), 93 (25), 82 (50), 81 (60), 80 (35), 79 (36), 69 (33) 68 (64), 67 (97), 55 (45), 43 (100), 41 (67). IR (CCl4, cm-1) 3006 (=CH cis str), 1743 (C=O), 1238, 1036 (C--O), 969 (=CH trans wag). IR (gas phase, cm-1) 3012 (cis =C--H str), 2934 (CH2), 1761 (C=O), 1231, 1038 (--O--), 968 (=CH trans wag).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:47][O:48][C:49]1[N:54]=[C:53]([CH2:55]O)[CH:52]=[CH:51][CH:50]=1>ClCCl>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH2:55][C:53]1[CH:52]=[CH:51][CH:50]=[C:49]([O:48][CH3:47])[N:54]=1
Reactant: COc1cccc(CO)n1
Reactant: Oc1ccc2c(nnn2CC2CC2)c1Br
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cccc(COc2ccc3c(nnn3CC3CC3)c2Br)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4-Bromo-1-(cyclopropylmethyl)-1H-benzotriazol-5-ol (25 mg, 0.093 mmol) and triphenylphosphine (32 mg, 0.12 mmol, 1.3 equiv) were dissolved in dichloromethane (0.5 mL). To the stirring mixture was added diethyl diazene-1,2-dicarboxylate (25 mg, 0.12 mmol, 1.3 equiv), followed by (6-methoxypyridin-2-yl)methanol (16 mg, 0.11 mmol, 1.2 equiv) and the mixture stirred at ambient temperature for 14 hours. The mixture was concentrated in vacuo and the residue was purified by preparative reverse phase HPLC (5: 95 to 95:5; acetonitrile:water containing 0.1% trifluoroacetic acid), providing the title compound as a clear oil: 1H-NMR (400 MHz, d6-DMSO) δ 7.94 (1H, d, J=9.1 Hz), 7.76 (1H, t, J=7.7 Hz), 7.60 (1H, d, J=8.9 Hz), 7.21 (1H, d, J=7.9 Hz), 6.77 (1H, d, J=7.9 Hz), 5.32, (2H, s), 4.59 (2H, d, J=7.31 Hz), 3.84 (3H, s), 1.40-1.32 (1H, m), 0.56-0.53 (2H, m), 0.48-0.44 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 389.0617 [(M+H)+; calculated for C17H17BrN4O2: 389.0607].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](Cl)[N:3]=1.[NH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([NH:17][CH3:18])=[O:16].C(N(CC)C(C)C)(C)C>C(OCC)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([NH:17][CH3:18])=[O:16])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][N:7]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1[N+](=O)[O-]
Yield: 49 %

Procedure:
In a similar fashion as outlined in Example 191a, 2,6-dichloro-5-nitropyrimidine was reacted with 2-amino-N-methylbenzamide and N,N-diisopropylethylamine in ethyl ether (no microwave −20° C., 3 hours) to afford 2-(2-chloro-5-nitro-pyrimidin-4-ylamino)-N-methyl-benzamide as a yellow solid in 49% yield. Mp: 201-3° C. (dec); MS: 308.09 (M+H); 1H NMR (d6-dmso): δ 12.43 (s, 1H), δ 9.20 (s, 1H), δ 8.75 (br s, 1H), δ 8.19 (d, J=9 Hz, 1H), δ 7.71 (d, J=8 Hz, 1H), δ 7.58 (t, J=8 Hz, 1H), δ 7.33 (t, J=8 Hz, 1H), δ 2.78 (d, J=5 Hz, 3H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH:13]=[CH:12]2)([OH:3])=O.ClC(OCC(C)C)=O.[CH:28]1([CH2:34][NH:35][CH2:36][CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH:28]1([CH2:34][N:35]([CH2:36][CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[CH:12]3)=[O:3])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: C1CCC(CNCCN2CCCC2)CC1
Reactant: O=C(O)CCCCOc1ccc2[nH]c(=O)ccc2c1
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C(CCCCOc1ccc2[nH]c(=O)ccc2c1)N(CCN1CCCC1)CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.00 Grams of 6-(4-carboxybutoxy)carbostyril is suspended in 60 ml of chloroform. Thereto is added 1.40 g of DBu. The mixture is stirred for 30 minutes at room temperature. 1.05 g of isobutyl chloroformate is added with ice cooling. Then, there is dropwise added at room temperature 1.61 g of N-(cyclohexylmethyl)-N-[2-(1-pyrrolidinyl)ethyl]amine. The mixture is stirred for 3 hours at room temperature. Then, a 0.5N aqueous sodium hydroxide solution is added, and the mixture is stirred for 10 minutes. Extraction with chloroform is effected. The extract is washed with water and dried with anhydrous magnesium sulfate. The solvent is removed by evaporation. The resulting residue is purified by a silica gel column chromatography (chloroform:methanol=20:1) and recrystallized from diethyl ether to obtain 1.00 g of 6-[4-{N-cyclohexylmethyl-N-[2-(1-pyrrolidinyl)ethyl]aminocarbonyl}butoxy]carbostyril.
Reaction SMILES: [C:1]1([B:7]([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(COC)OC>[C:3]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:4]=[CH:5][CH:6]=[C:1]([B:7]([OH:9])[OH:8])[CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: OB(O)c1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: OB(O)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Yield: 87 %

Procedure:
Phenyl boronic acid (1) (106.2 g, 871.4 mmol), 3-bromophenylboronic acid (2) (35.0 g, 174.2 mmol), palladium acetate (9.8 g, 4.357 mmol), triphenylphosphine (4.64 g, 17.4 mmol), and 2M K2CO3 aqueous solution (470 ml) were added to 950 mL of dimethoxyethane and refluxed for 17 hours. The mixture was cooled to room temperature and the aqueous layer was separated from the organic layer. The aqueous layer was then extracted twice with 200 mL of ethyl acetate. The organic layers were combined and washed with brine and dried over magnesium sulfate. The solids were removed by vacuum filtration and the organic solvent evaporated to the crude product. The crude product was purified by Kugelehor distillation to give of 3 (30 g, 86.7%).