Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:7]=1.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>O1CCCC1.[Cu]>[NH:15]1[CH:19]=[CH:18][N:17]=[C:16]1[C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:7]=1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(I)cc1C1OCCO1
Agent: [Cu]
Solvent: C1CCOC1
Product: COc1ccc(-c2ncc[nH]2)cc1C1OCCO1
Temperature: 140 °C
Yield: 36.9 %

Procedure:
In a Pyrex high pressure reaction tube, a solution of the preceding dioxolane (200 mg, 0.66 mmol), 140 mg (2.06 mmol) of imidazole and 90 mg (1.4 mmol) of copper powder in 1 mL of anhydrous tetrahydrofuran (THF) was stirred until homogeneous. The solvent was then evaporated under nitrogen, and the tube was sealed and heated in an oil bath at 140° C. for 16 hours. After cooling, the residue was dissolved in 20 mL of THF, filtered through a pad of diatomaceous earth and concentrated in vacuo to an oil. Chromatography on silica gel (100% ethyl acetate (EtOAc)) gave 60 mg of 2-(5-(2-imidazolyl)-2-methoxyphenyl)-1,3-dioxolane as a yellow oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[N:19]3[C:20]4[C:15]([CH:16]([NH2:21])[CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](Cl)=[O:36].O>ClCCl>[C:1]1([CH2:7][CH2:8][C:9]2[N:19]3[C:20]4[C:15]([CH:16]([NH:21][C:35]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=5)=[O:36])[CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccccn1
Reactant: NC1CCn2c(CCc3ccccc3)nc3cccc1c32
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NC1CCn2c(CCc3ccccc3)nc3cccc1c32)c1ccccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.2 %

Procedure:
A portion (0.4 g) of the 5,6-dihydro-2-(2-phenylethyl)-4H-imidazo[4,5,1-ij]quinolin-6-amine obtained in Step 2 of Example 17 was dissolved in anhydrous dichloromethane (5 mL); following the addition of pyridine (0.26 mL), picolinoyl chloride hydrochloride (0.28 g) was added under cooling with ice. After stirring for 4 hrs at room temperature, water (50 mL) and dichloromethane (50 mL) were added to the reaction solution and then two layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to yield the titled compound as pale brown crystals (0.31 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]([OH:18])=O)=[CH:10]1.[NH2:19][C:20]1[CH:21]=[C:22]([CH:29]=[CH:30][C:31]=1[CH3:32])[C:23]([NH:25][CH:26]1[CH2:28][CH2:27]1)=[O:24].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O.CCN(CC)CC>[CH:26]1([NH:25][C:23]([C:22]2[CH:29]=[CH:30][C:31]([CH3:32])=[C:20]([NH:19][C:16]([C:11]3[CH:12]=[CH:13][C:14](=[O:15])[N:9]([C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[CH:10]=3)=[O:18])[CH:21]=2)=[O:24])[CH2:28][CH2:27]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Reactant: O=C(O)c1ccc(=O)n(-c2c(Cl)cccc2Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(=O)n(-c2c(Cl)cccc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.7 %

Procedure:
To a solution of 1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (56 mg) in DMF (0.76 mL) were added 3-amino-N-cyclopropyl-4-methylbenzamide (45 mg), WSC—HCl (57 mg), HOBt (35 mg) and Et3N (27 mg), and the mixture was stirred under a nitrogen atmosphere at room temperature for 16 hr. The reaction mixture was diluted with EtOAc (2 mL), washed with water (4 mL×2) and brine successively, dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by preparative thin layer chromatography eluting with 10% MeOH in CH2Cl2 to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide (60 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:27])[C:13](=[O:18])[N:12]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:23])([CH3:25])[CH3:24])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)C(=O)OCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: Cn1c(=O)c2c(ncn2Cc2ccccc2)n(COC(=O)C(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
2,2-Dimethylpropionic Acid [7-benzyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl]methyl ester (2.66 g) was dissolved in N,N-dimethylformamide (30 ml), potassium carbonate (1.6 g) and iodomethane (1 ml) were added to the solution, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and washed with water and 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then, the solvent was removed by distillation. The residue was triturated with toluene to give 2.16 g of the title compound.
Reaction SMILES: C(N(CC)CC)C.BrCC[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.Cl.[C:20]1([CH3:28])[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1>C(O)C>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([N:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:28])=[CH:21][CH:22]=2)[NH2:27])=[CH:16][CH:15]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(N(N)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
Triethylamine (5.2 mL 37.8 mmol) and (1-(2-Bromoethyl)-4-methoxybenzene (1.9 mL, 12.60 mmol) were added to a solution of p-tolylhydrazine hydrochloride (2 gm, 12.60 mmol) in ethanol (30 mL) and the resulting solution was stirred at RT for an 1 h after which it was heated at 90° C. for 2-3 h. The reaction mixture was concentrated to dryness and basified with aq. saturated NaHCO3, and extracted in ethyl acetate. The combined organic layers was dried over Na2SO4 and concentrated to obtain (1-(4-methoxyphenyl)-1-p-tolylhydrazine (2.8 g). (1-(4-methoxyphenyl)-1-p-tolylhydrazine (2.8 g, 10.9 mmol) and 8-methyl-8-azabicyclo[3.2.1]octan-3-one (1.5 gm, 10.9 mmol) were taken in ethanolic HCl (30 mL), and stirred at RT for 15 min and the solvent was removed in vacuo. The residue was taken in ethanol (30 mL) and heated at 90° C. for 3. After completion of the reaction (the progress of the reaction was monitored by LCMS), the reaction mixture was concentrated to dryness and basified with aq. saturated NaHCO3. The product was extracted in ethyl acetate and the organic layers were separated, dried over Na2SO4 and concentrated. The resulting crude product was purified over neutral alumina (10% Me-OH in dichloromethane) to obtain the product as free base (500 mg). The NMR data for the compound is as follows: 1H NMR (DMSO)—7.40-7.35 (d, 1H), 7.25 (s, 1H), 6.90-6.85 (d, 1H), 6.85-6.80 (d, 2H), 6.80-6.75 (d, 2H), 4.25-4.10 (t, 2H), 3.85-3.75 (m, 1H), 3.65 (s, 3H), 3.00-2.80 (t, 2H), 2.65-2.55 (d, 2H), 2.30 (s, 3H), 2.20-2.00 (m, 1H), 1.95 (s, 3H), 1.45-1.40 (m, 2H), 1.40-1.35 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([OH:15])=[CH:9][CH:10]=3)[CH:5]([CH3:16])[C:4]=2[CH:3]=1.[C:17]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)(=[O:20])[CH:18]=[CH2:19].[CH2:38](Cl)[CH2:39]Cl.ClCCl>CN(C1C=CN=CC=1)C.O>[C:17]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:39]1[CH:38]=[CH:36][C:32]([C:33]([O:1][C:2]2[CH:14]=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][C:8]([O:15][C:33](=[O:34])[C:32]5[CH:36]=[CH:37][C:29]([O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:17](=[O:20])[CH:18]=[CH2:19])=[CH:30][CH:31]=5)=[CH:9][CH:10]=4)[CH:5]([CH3:16])[C:4]=3[CH:3]=2)=[O:34])=[CH:31][CH:30]=1)(=[O:20])[CH:18]=[CH2:19]
Reactant: CC1c2cc(O)ccc2-c2ccc(O)cc21
Reactant: ClCCCl
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc3c(c2)C(C)c2cc(OC(=O)c4ccc(OCCCCCCOC(=O)C=C)cc4)ccc2-3)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 10.6 %

Procedure:
A mixture of 2,7-dihydroxy-9-methylfluorene (0.5 g), 4-(6-acryloyloxyhexyloxy)benzoic acid (1.52 g), EDC (0.99 g), DMAP (5.76 mg) and dichloromethane (30 mL) was stirred at a room temperature for 12 hours. Water was added to the reaction mixture, and the separated organic layer was washed with water and dried on anhydrous magnesium sulfate. The solvent was distilled off from this organic layer under reduced pressure, and the resulting residue was purified by means of column chromatography (silica gel, eluting solvent: toluene/ethyl acetate [95/5]) and recrystallization (ethanol/ethyl acetate) to obtain 2,7-bis(4-(6-acryloyloxyhexyl)oxybenzoyloxy)-9-methylfluorene (0.19 g) of a white solid matter.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[CH:30]([NH:33][CH:34]([CH3:36])[CH3:35])([CH3:32])[CH3:31]>O>[CH:30]([N:33]([CH2:6][CH2:7][C@@H:8]([C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:34]([CH3:36])[CH3:35])([CH3:32])[CH3:31].[CH:30]([N:33]([CH2:6][CH2:7][CH:8]([C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:34]([CH3:36])[CH3:35])([CH3:32])[CH3:31]
Reactant: CC(C)NC(C)C
Reactant: CS(=O)(=O)OCCC(c1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Solvent: O
Product: CC(C)N(CCC(c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C(C)C
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C(C)C

Procedure:
100 g 3-(2-(benzyloxy)-5-bromophenyl)-3-phenylpropyl methanesulfonate of formula (D) and 400 ml diisopropyl amine and 100 ml water under closed reaction condition in SSR autoclave for 48 to 50 hours. The reaction mass was cooled to 0° C. to 5° C. followed by filtration and then washing with 25 ml water. After distillation of solvent completely under vacuum and work up with MDC and water in acidic pH and basic afforded title compound N,N-Diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropylamine of formula (E) in residue form.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7](I)=[CH:6]2)[CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26](B4OC(C)(C)C(C)(C)C4)=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([CH2:4][N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[N:23]4)=[CH:28][CH:27]=3)=[CH:6]2)[CH2:3][CH2:2]1
Reactant: Nc1ncnc2c1c(I)cn2CC1CC1
Reactant: CC1(C)CB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2CC1CC1

Procedure:
Following the general procedure for the Suzuki coupling, 7-cyclopropylmethyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (94.0 mg, 0.299 mmol) was reacted with 2-phenyl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline (104 mg, 0.314 mmol), Na2CO3 (79.0 mg, 0.745 mmol) and Pd(PPh3)4 (21 mg, 0.018 mmol) in DMF (7.5 mL)/water (1.5 mL). The crude material was purified by an SCX column (2 g/6 mL barrel) followed by column chromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with CH2Cl2 (1-14)→1% MeOH in CH2Cl2 (15-34)→2% MeOH in CH2Cl2 (35-56)], yielding the title compound as an off-white yellow solid. 1H NMR (CDCl3, 400 MHz): δ=0.44-0.50 (m, 2H), 0.63-0.71 (m, 2H), 1.29-1.39 (m, 1H), 4.15 (d, J=7.2 Hz, 2H), 5.20 (brs, 2H), 7.29 (s, 1H), 7.46-7.52 (m, 11H), 7.52-7.58 (m, 2H), 7.71 (dd, J=1.8, 8.2 Hz, 11H), 7.91 (d, J=8.8 Hz, 11H), 7.93 (d, J=8.4 Hz, 1H), 8.17-8.22 (m, 2H), 8.27 (d, J=8.8 Hz, 1H), 8.29-8.32 (m, 1H), 8.36 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=4.05 (2C, −), 11.31 (+), 48.99 (−), 100.98 (Cquart), 115.67 (Cquart), 118.96 (+), 123.30 (+), 125.94 (Cquart), 127.46 (+), 127.55 (2C, +), 128.23 (+), 128.47 (+), 128.87 (2C, +), 129.50 (+), 136.50 (Cquart), 136.55 (+), 139.45 (Cquart), 148.52 (Cquart), 150.97 (Cquart), 152.04 (+), 156.99 (Cquart), 158.12 (Cquart). MS (ES+): m/z 392.1 (100) [MH+], 338.2 (22) [MH+—C4H6]. HPLC: tR=2.9 min (OpenLynx, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][C:29]([OH:31])=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:32].C[N:34]1CCO[CH2:36][CH2:35]1.CN1CCCC1=O.Cl.CN(C)CCCN=C=NCC.C(N)C>CCOC(C)=O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][C:29]([NH:34][CH2:35][CH3:36])=[O:31])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:32]
Reactant: CN1CCOCC1
Reactant: Cc1cc(F)ccc1-c1nc(NCC(=O)O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCNC(=O)CNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reaction time: 1 h
Yield: 68.1 %

Procedure:
The product of Example 191 (50 mg, 0.11 mmol), n-hydroxybenzotriazole (21 mg, 0.34 mmol), 1-methylmorpholine (19 uL, 0.172 mmol), N-methylpyrrolidinone (2.5 mmol) were dissolved together, then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (66 mg, 0.34 mmol) was added, stirred 1 h, and then ethylamine (2 M in THF) (1.0 mL, 2.0 mmol) was added and the reaction was stirred at 23° for 16 h, diluted with EtOAc (50 mL), and washed with 10% aq citric acid (2×20 mL), H2O (20 mL), and satd aq NaCl (20 mL), dried (MgSO4) concentrated and purified by chromatotron chromatography (CH2Cl2/CH3OH) to afford 35 mg of the title compound 2-[[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7,8-dihydro-7-oxopyrido[2,3-d]pyrimidin-2-yl]amino]-N-ethylacetamide as a white powder. mp=250-253 (dec). LC MS (m/e)=468.2 (MH+). Rt=1.87 min.
Reaction SMILES: [P:1]([O-:38])([O:34][CH2:35][CH2:36]Br)([O:3][CH2:4][CH:5]([O:28][C:29]1[CH:33]=[CH:32][O:31][N:30]=1)[CH2:6][O:7][C:8](=[O:27])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:2].[CH3:39][N:40]1[CH:44]=[CH:43][N:42]=[CH:41]1>C1(C)C=CC=CC=1>[P:1]([O-:38])([O:34][CH2:35][CH2:36][N+:42]1[CH:43]=[CH:44][N:40]([CH3:39])[CH:41]=1)([O:3][CH2:4][CH:5]([O:28][C:29]1[CH:33]=[CH:32][O:31][N:30]=1)[CH2:6][O:7][C:8](=[O:27])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCNC(=O)OCC(COP(=O)([O-])OCCBr)Oc1ccon1
Reactant: Cn1ccnc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCNC(=O)OCC(COP(=O)([O-])OCC[n+]1ccn(C)c1)Oc1ccon1
Reaction time: 15 h

Procedure:
A mixture of 0.900 g of (2RS)-3-(N-heptadecylcarbamoyloxy)-2-(3-isoxazolyloxy)propyl 2-bromoethyl phosphate [prepared as described in Example 11(a)], 1.14 ml of N-methylimidazole and 1.0 ml of toluene was heated on an oil bath kept at 80° C. for 15 hours, whilst stirring. The toluene was then distilled off, and the resulting residue was dissolved in 10 ml of a 95:5 by volume mixture of tetrahydrofuran and water. The resulting solution was passed through a column of 14 ml of Amberlite MB-3 resin. The eluate wa repeatedly passed two times through the same column and the column was finally washed with a 95:5 by volume mixture of tetrahydrofuran and water. The eluates and the washings were combined and concentrated by evaporation under reduced pressure. The residue was purified by medium pressure liquid chromatography using a Lobar B column. 0.656 g of the title compound was obtained as a white powder melting at 45°-46° C. from the fractions eluted with a 160:35:5 by volume mixture of methylene chloride, methanol and water.
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Br:8][C:9]1[CH:10]=[C:11]([NH2:15])[CH:12]=[N:13][CH:14]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[Br:8][C:9]1[CH:10]=[C:11]([NH:15][S:4]([CH:1]2[CH2:3][CH2:2]2)(=[O:6])=[O:5])[CH:12]=[N:13][CH:14]=1
Reactant: Nc1cncc(Br)c1
Reactant: O=S(=O)(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=S(=O)(Nc1cncc(Br)c1)C1CC1
Reaction time: 15 h

Procedure:
Cyclopropanesulfonyl chloride was added dropwise to a solution of 5-Bromo-pyridin-3-ylamine (346 mg, 2 mmol), 4-dimethylaminopyridine (25 mg, 0.205 mmol) and triethylamine (0.558 mL, 4 mmol) in dichloromethane (4 mL) at room temperature under nitrogen. The reaction was stirred at this temperature for 15 h. The reaction mixture was diluted with ethyl acetate (50 mL) and the resulting solution was washed with saturated NaHCO3 solution (25 mL). The aqueous phase was extracted with ethyl acetate (50 mL). The combined organic phase was dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by flash column (0-10% CH3OH in CH2Cl2 v/v) and 248 mg of the desired product as a white solid was obtained. ESI-MS m/z: 278.9 [M+1]+, Retention time 1.02 min; 1HNMR (MeOD, 400.342 MHz) δ 1.00-1.10 (m, 4H), 2.63-2.69 (m, 1H), 3.31 (s, 1H), 7.94 (t, J=2 Hz, 1H), 8.39 (s, 1H), 8.40 (d, J=2 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH3:22].O>CN(C)C=O.C(OCC)(=O)C>[CH2:21]([O:13][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]([F:11])([F:12])[F:10])=[CH:7][C:2]=1[Br:1])[CH3:22]
Reactant: Oc1ccc(OC(F)(F)F)cc1Br
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1ccc(OC(F)(F)F)cc1Br
Temperature: 25 °C

Procedure:
2-Bromo-4-trifluoromethoxyphenol (Description 11, 1 g) was dissolved in N,N dimethylformamide (12 ml) and potassium carbonate (1.07 g) was added. Iodoethane (0.78 ml) was added and the mixture was stirred at room temperature. Water (150 ml) and ethyl acetate were added and the layers were separated. The organic layer was washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (100:0 increasing to 95:5) to give the title compound as a colourless oil (1.02 g). 1H NMR (250 MHz, CDCl3) δ1.47 (3 H, t, J 7.0 Hz), 4.09 (2 H, q, J 7.0 Hz), 6.85 (1 H, d, J 9.0 Hz), 7.11 (1 H, m), and 7.43 (1 H, m).
Reaction SMILES: S(OC)(OC)(=O)=O.[F:8][C:9]1[CH:21]=[CH:20][C:12]([CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=O)=[CH:11][CH:10]=1.C[O-].[Na+].[Na].[N+:26]([CH3:29])([O-:28])=[O:27]>O.CO>[F:8][C:9]1[CH:21]=[CH:20][C:12]([CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[CH:29][N+:26]([O-:28])=[O:27])=[CH:11][CH:10]=1
Reactant: O=C1CCCN1Cc1ccc(F)cc1
Reactant: C[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: CO
Product: O=[N+]([O-])C=C1CCCN1Cc1ccc(F)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
26.1 g (0.207 mol) of dimethyl sulphate are added to 40 g (0.207 mol) of 1-p-fluorobenzyl-pyrrolidin-2-one and the mixture is heated to 60° for 4 hours. It is then cooled and a solution of sodium methylate prepared from 4.75 g (0.207 gram atom) of sodium and 100 ml of methanol is introduced slowly, at 0°. When the addition is complete, the mixture is stirred for 30 minutes at 50° C. and again cooled to 0°, and 18.9 g (0.31 mol) of nitromethane are added dropwise whilst continuing the stirring. The reaction mixture is left at ambient temperature for 12 hours and is then heated to 50° for 2 hours. It is cooled, and poured into 500 ml of water, which are then extracted with chloroform. The organic layer is now separated off, washed with water and dried over magnesium sulphate, and the solvent is driven off. The residual product is washed with ether and recrystallised from ethanol. 27 g (55.2% yield) of 1-p-fluorobenzyl-2-nitromethylene-pyrrolidine are thus collected in the form of light yellow crystals melting at 108.5°-109°.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1([C:14]([OH:16])=[O:15])[CH:11]2[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:13][CH:5]1[CH2:6]3)[CH2:10]2.[C:17]1([N:27]2[C:31]([C:32]3[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[CH:34][C:33]=3[O:40][CH3:41])=[CH:30][C:29]([C:42](Cl)=[O:43])=[N:28]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.Cl>O.O1CCCC1>[C:17]1([N:27]2[C:31]([C:32]3[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[CH:34][C:33]=3[O:40][CH3:41])=[CH:30][C:29]([C:42]([NH:3][C:4]3([C:14]([OH:16])=[O:15])[CH:11]4[CH2:10][CH:9]5[CH2:8][CH:7]([CH2:6][CH:5]3[CH2:13]5)[CH2:12]4)=[O:43])=[N:28]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(OC)c1-c1cc(C(=O)Cl)nn1-c1cccc2ccccc12
Reactant: NC1(C(=O)O)C2CC3CC(C2)CC1C3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(OC)c1-c1cc(C(=O)NC2(C(=O)O)C3CC4CC(C3)CC2C4)nn1-c1cccc2ccccc12
Reaction time: 0.17 h

Procedure:
0.107 g of sodium hydroxide in 1.36 ml of water and 0.51 ml of tetrahydrofuran are cooled to 0° C. 0.52 g of 2-amino-2-adamantanecarboxylic acid is added in a single portion, and 0.53 g of 1-(1-naphthyl)-5-(2,6-dimethoxyphenyl)-3-pyrazolecarbonyl chloride, dissolved in 3 ml of tetrahydrofuran, is then added dropwise. The mixture is left for 10 minutes, and the same amount of the above acid chloride, in 3 ml of tetrahydrofuran, is added again; simultaneously, 1.32 ml of 2N sodium hydroxide are added. The reaction mixture is left for 4 days at room temperature; successively, ice-cold water is added and concentrated hydrochloric acid is added to pH 1, and the precipitate is filtered off. The crystals are washed with diisopropyl ether.