Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)[C:3](F)(F)[C:4](F)(F)[C:5](F)(F)S([O-])(=O)=O.[K+].[N+:19]([C:22]1[CH:23]=[C:24]([CH:28]([S:30]([O-:33])(=[O:32])=[O:31])[CH3:29])[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]>CC(C)=O>[N+:19]([C:22]1[CH:23]=[C:24]([CH:28]([S:30]([O-:33])(=[O:31])=[O:32])[CH3:29])[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20].[CH2:2]([N+:19]([CH2:22][CH2:23][CH2:24][CH3:28])([CH2:25][CH2:24][CH2:28][CH3:29])[CH2:23][CH2:22][CH2:27][CH3:26])[CH2:3][CH2:4][CH3:5]
Reactant: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CC(c1cccc([N+](=O)[O-])c1)S(=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCC[N+](CCCC)(CCCC)CCCC

Procedure:
5.2 g of potassium nonafluorobutanesulphonate dissolved in 12 cm3 of acetone are added to a solution of 10.5 g of a mixture of the A and B forms (about 15/85 in moles) of N-benzylquininium 1-(3-nitrophenyl)ethanesulphonate in 16 cm3 of acetone. The insoluble product is filtered off and then dissolved in 9 cm3 of water. 8.4 cm3 of an aqueous 1N hydrochloric acid solution and 1.15 g of (R)-(-)-phenylglycinol are added. The solution obtained is concentrated to dryness under reduced pressure (2.7 kPa) at 50° C. The residue obtained is extracted with 3 times 15 cm3 of acetonitrile under reflux. The organic phases are combined and concentrated to about 7 cm3 ; after cooling, the crystals are filtered off and dissolved in 7.5 cm3 of an aqueous 1N sodium hydroxide solution. The solution obtained is washed with 8 times 25 cm3 of diethyl ether, after which 60 cm3 of an aqueous 0.5M solution of potassium dihydrogenphosphate and 2.3 g of tetra-n-butylammonium hydrogensulphate are added. The mixture is extracted with 3 times 30 cm3 of methylene chloride. The combined organic phases are dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. 2.8 g of the laevorotatory isomer of tetra-n-butylammonium 1-(3-nitrophenyl)ethanesulphonate are thus obtained in the form of an oil which is used as such in the subsequent syntheses.
Reaction SMILES: [C:1]([OH:22])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C([O-])(O)=O.[Na+:27]>>[C:1]([O-:22])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[Na+:27]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)[O-]

Procedure:
Arachidonic acid (99% pure, a product of Sigma Co., Ltd.) was dissolved in 0.1 M NaHCO3, and a 3.3 mM solution of sodium arachidonate was prepared. The solution was diluted with physiological saline to a concentration of 1 mM and used in the experiments. The 3.3 mM solution was stored in a refrigerator as a stock solution, and the 1 mM solution was newly prepared from the stock solution every time it was used.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][C:20](OCC)=[O:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][C:20]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCC(=O)OCC
Reactant: C1COCCN1
Product: CCOCc1nc2cnc3ccccc3c2n1CCC(=O)N1CCOCC1
Temperature: 110 °C
Yield: 92.3 %

Procedure:
A solution of ethyl 3-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate (5.0 g, 15 mmol) and morpholine (10 mL, 100 mmol) was heated overnight in a high-pressure vessel at 90° C. An analysis by HPLC indicated the reaction was incomplete. The reaction was then heated overnight in a high-pressure vessel at 110° C., allowed to cool to ambient temperature, and concentrated under reduced pressure to provide 5.1 g of 2-(ethoxymethyl)-1-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[CH:9]=[C:8]([C:16](O)=[O:17])[C:7]1=[O:19].C(Cl)(=O)C([Cl:27])=O.CN(C)C=O>ClCCl>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[CH:9]=[C:8]([C:16]([Cl:27])=[O:17])[C:7]1=[O:19]
Reactant: COc1ccccc1Cn1c(=O)c(C(=O)O)cc2cccnc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccccc1Cn1c(=O)c(C(=O)Cl)cc2cccnc21
Temperature: 40 °C
Reaction time: 1 h

Procedure:
3.83 g (12.3 mmol) of 1-(2-methoxybenzyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid was dissolved in dichloromethane (100 mL), and 7.5 mL (89 mmol) of oxalyl chloride was added thereto. One droplet of N,N-dimethylformamide was added to the above mixture, and the resulting mixture was stirred for one hour at 40° C. The reaction solution was concentrated under reduced pressure, and thus 1-(2-methoxybenzyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid chloride was obtained. The acid chloride thus obtained was dissolved in dichloromethane (100 mL), and this solution was added to a dichloromethane (100 mL) solution of 1.52 g (13.6 mmol) of 1,3-cyclohexanedione and 2.11 mL (14.8 mmol) of triethylamine under ice cooling. The mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into an aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with dichloromethane. The organic phase was dried and concentrated. The residue was washed with diisopropyl ether, and thus 4.82 g of the title compound was obtained as a light yellow solid (yield: 97%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:16]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:15][CH:14]=[CH:13][C:5]=1[CH2:6][N:7]([CH3:12])[C:8](=[O:11])[CH:9]=[CH2:10])[CH3:2].C(N(C(C)C)CC)(C)C.Br[C:32]1[CH:45]=[N:44][C:35]2[NH:36][C:37](=[O:43])[C:38]([CH3:42])([CH3:41])[NH:39][CH2:40][C:34]=2[CH:33]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:41][C:38]1([CH3:42])[C:37](=[O:43])[NH:36][C:35]2[N:44]=[CH:45][C:32](/[CH:10]=[CH:9]/[C:8]([N:7]([CH3:12])[CH2:6][C:5]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][C:18]([F:19])([F:20])[F:21])[C:4]=3[O:3][CH2:1][CH3:2])=[O:11])=[CH:33][C:34]=2[CH2:40][NH:39]1
Reactant: C=CC(=O)N(C)Cc1cccc(OC(F)(F)F)c1OCC
Reactant: CC1(C)NCc2cc(Br)cnc2NC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNC(C)(C)C(=O)N3)cccc1OC(F)(F)F
Yield: 45.7 %

Procedure:
A solution of N-(2-ethoxy-3-trifluoromethoxybenzyl)-N-methylacrylamide (0.447 g, 1.47 mmol) in propionitrile (5 mL) and DMF (1 mL) was deoxygenated with Ar for 20 min and then treated with diisopropylethylamine (0.40 mL, 2.3 mmol) and 7-bromo-3,3-dimethyl-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (0.300 g, 1.11 mmol). The solution was deoxygenated with Ar for 20 minutes. Pd(OAc)2 (0.024 g, 0.111 mmol) and P(o-tol)3 (0.067 g, 0.222 mmol) were added and the solution deoxygenated with Ar for 20 min. The mixture was heated to reflux for 18 h then, allowed to cool. The mixture was diluted with EtOAc (30 mL) and was washed with H2O (3×50 mL) and brine (2×50 mL), dried (Na2SO4) and concentrated to a yellow-orange solid. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 100 to 98:2) gave the title compound (0.25 g, 31%) as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 9.80-9.78 (m, 1H), 8.40-8.37 (m, 1H), 8.01-7.93 (m, 1H), 7.56-7.49 (m, 1H), 7.36-7.09 (m, 4H), 4.87-4.68 (m, 2H), 4.06-3.83 (m, 4H), 3.31-2.88 (m, 4H), 1.36-1.29 (m, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[Cl:15][C:16]1[C:17]([C:26]([F:29])([F:28])[F:27])=[N:18][N:19]([CH2:22][C:23](O)=[O:24])[C:20]=1[CH3:21]>>[Cl:15][C:16]1[C:17]([C:26]([F:28])([F:27])[F:29])=[N:18][N:19]([CH2:22][C:23]([N:12]2[CH2:13][CH2:14][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:10][CH2:11]2)=[O:24])[C:20]=1[CH3:21]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: COc1cccc(N2CCNCC2)c1
Product: COc1cccc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)c1

Procedure:
Title compound was prepared following protocol P, wherein 1-(3-methoxyphenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a white solid: 1H NMR (DMSO-d6, 400 MHz) 7.15 (t, 1H), 6.65 (d, 1H), 6.60 (s, 1H), 6.47 (d, 1H), 5.38 (s, 2H), 3.72 (s, 3H), 3.65 (m, 4H), 3.28 (m, 2H), 3.19 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expect=417.1, found=417.1.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.O[CH2:12][C:13]1[C:14]2[N:15]([CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:21]=2)[CH:16]=[CH:17][CH:18]=1.C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>Br.O>[C:22]1([C:20]2[N:21]=[C:14]3[C:13]([CH2:12][S:1][C:2]4[NH:6][C:5]5[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=5[N:3]=4)=[CH:18][CH:17]=[CH:16][N:15]3[CH:19]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: OCc1cccn2cc(-c3ccccc3)nc12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: c1ccc(-c2cn3cccc(CSc4nc5ccccc5[nH]4)c3n2)cc1
Temperature: 25 °C

Procedure:
A mixture of 1.24 g (10 mmole) of 3-hydroxymethyl-2-pyridinamine and 2.0 g (10 mmole) of α-bromoacetophenone in 25 ml of ethanol was stirred at room temperature. After 18 hours the resultant solid was collected, washed with ethano, and dissolved in water. The solution was made basic with aqueous potassium carbonate and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with diethyl ether, collected by filtration, washed with diethyl ether, and air dried to yield 1.4 g of 8-hydroxymethyl-2-phenylimidazo[1,2-a]pyridine, as confirmed by the nmr and infrared spectra and by elemental analysis. [Calcd. for C14H12N2O2 : C, 74.98; H, 5.39; N, 12.49. Found: C, 74.68; H, 5.39; N, 12.40.] A mixture of 871 mg (5.8 mmole) of 2-mercaptobenzimidazole and 1.3 g (5.8 mmole) of 8-hydroxymethyl-2-phenylimidazo[1,2-a]pyridine was dissolved in 10 ml of 47% aqueous hydrobromic acid and 10 ml of acetic acid and heated to reflux. After being cooled to room temperature, the mixture was poured into water, made alkaline with potassium carbonate, and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Trituration of the residue with diethyl ether yielded 1.8 g of the analytically pure title compound. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]([C:13]2[CH:17]=[CH:16][O:15][CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([CH3:18])=[CH:8][CH:9]=2)[N:4]=1)#[N:2].C1C(=O)N([Br:26])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:26][CH2:18][C:7]1[CH:6]=[C:5]2[C:10]([C:11]([C:13]3[CH:17]=[CH:16][O:15][CH:14]=3)=[CH:12][C:3]([C:1]#[N:2])=[N:4]2)=[CH:9][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(-c3ccoc3)cc(C#N)nc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(-c2ccoc2)c2ccc(CBr)cc2n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-cyano-4-(3-furyl)-7-methylquinoline (4.2 g) in refluxing CCl4 (400 mL) was added NBS (3.3 g) and AIBN (150 mg) portionwise. After 90 min., the mixture was cooled to r.t. and filtered through a pad of silica gel washing with CH2Cl2. The filtrate was concentrated and swished with Et2O for 15 h. The solid precipitate was collected and NMR analysis indicated that it contained 85% of the title compound. This material was used as such in the subsequent reactions.
Reaction SMILES: [CH2:1]([CH:3]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:4][O:5][C:6](=[O:21])[C:7]([CH2:9][C:10]([O:12]CC(CC)CCCC)=O)=[CH2:8])[CH3:2].[CH2:26]([CH:28]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:29][NH2:30])[CH3:27]>>[CH2:1]([CH:3]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:4][O:5][C:6]([CH:7]1[CH2:9][C:10](=[O:12])[N:30]([CH2:29][CH:28]([CH2:26][CH3:27])[CH2:31][CH2:32][CH2:33][CH3:34])[CH2:8]1)=[O:21])[CH3:2]
Reactant: CCCCC(CC)CN
Reactant: C=C(CC(=O)OCC(CC)CCCC)C(=O)OCC(CC)CCCC
Product: CCCCC(CC)COC(=O)C1CC(=O)N(CC(CC)CCCC)C1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Bis(2-ethylhexyl)itaconate (400 g; 1.13 Mol) was charged to a 1 L reaction vessel and the material stirred mechanically under nitrogen while heating to 45° C. 2-Ethylhexylamine (1.02 equiv.: 1.15 Mol; 148.7 g) was charged to a pressure-equalizing addition funnel and the amine added dropwise to the stirred diester over the course of one hour. During the addition, a moderate exotherm was observed and the mixture was allowed to heat to 70° C. When the addition was complete, the mixture was heated to 75° C. and held for one hour before cooling to room temperature overnight. The following day, the vessel was equipped with a distillation sidearm/condenser and heated to 120 to 125° C. under reduced pressure (−30″ Hg) (−762 mm) in order to remove 2-ethylhexanol and excess amine. When stripping was complete, the apparatus was backfilled with nitrogen and cooled to room temperature. The amount of 2-ethylhexanol collected was 141.7 g (1.09 Mol; 96.5% of theoretical recovery). The stripped product was warmed to 50° C. and filtered through a 1″ (2.5 cm) plug of silica gel, giving the final product as a light yellow liquid. H-NMR analysis of the product was consistent with the expected product. Sample materials were collected from this preparation and designated 1-(2-ethylhexyl)-5-oxo-3-pyrrolidinecarboxylic acid 2-ethylhexyl ester for comparison testing described in the Examples below.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:16][C:9]2=[N:10][CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]2[CH:7]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[CH3:15][O:14][C:13]1[CH:12]=[CH:11][N:10]=[C:9]2[NH:16][C:6]([CH2:4][OH:3])=[CH:7][C:8]=12
Reactant: CCOC(=O)c1cc2c(OC)ccnc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccnc2[nH]c(CO)cc12

Procedure:
To a suspension of 2-ethoxycarbonyl-4-methoxypyrrolo-[2,3-b]pyridine 3 (1.90 g, 8.62 mmol) in anhydrous THF (25 mL) was added LiAlH4 (0.218 g, 17.2 mmol) in small portions under N2 atmosphere. The mixture was stirred at reflux temperature for 50 min. After cooling, it was poured into cool H2O (20 mL) and extracted with EtOAc (4×15 mL). The combined organic layers were washed with brine (20 mL) and dried (Na2SO4). After filtration, the filtrate was concentrated to dryness and the residue was chromatographed on a silica gel column using 5% methanol in CH2Cl2 to give 4 as white solid. Mp 210-212° C.; Yield: 1.10 g, 71%; ESI MS: m/z 178.9 (M+1).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[N+:2]=[N-:3].CCN(CC)CC.C(OCl)(C)(C)C.[Li][CH:30]([C:35]([O:37][CH3:38])=[O:36])[C:31]([O:33][CH3:34])=[O:32]>C1COCC1.CCOCC.O.[Cl-].[Cl-].[Zn+2]>[CH3:34][O:33][C:31](=[O:32])[CH:30]([C:7]1[NH:8][C:9]2[C:14]([C:6]=1[CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[C:35]([O:37][CH3:38])=[O:36]
Reactant: [N-]=[N+]=NCCc1c[nH]c2cc(F)ccc12
Reactant: [Li]C(C(=O)OC)C(=O)OC
Agent: CC(C)(C)OCl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C(C(=O)OC)c1[nH]c2cc(F)ccc2c1CCN=[N+]=[N-]
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2-azidoethyl)-6-fluoro-1H-indole (4.77 g, 23.3 mmol) and NEt3 (3.63 mL, 25.8 mmol) in dry THF (0.13 L) at −78° C. under argon was added tBuOCl (3.04 mL, 26.9 mmol). The reaction mixture was stirred for 30 min at −78° C. A solution of 1 M ZnCl2 in Et2O (5.0 mL) was added. After 15 min a solution of dimethyl lithiomalonate (28.1 mmol in THF/hexanes) was added. The mixture was stirred at −78° C. for 1 h and at rt overnight, diluted with cold water, then extracted with Et2O. The Et2O extracts were dried, filtered, and concentrated to give the title compound: TLC Rf=0.46 (CH2Cl2); MS (ESI−) m/z 333.1; 1H NMR (CDCl3, 300 MHz) δ 8.97 (1H), 7.45 (1H), 7.05 (1H), 6.89 (1H), 5.02 (1H), 3.80 (6H), 3.50 (2H), 2.97 (2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:19][C:20]1([OH:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:24][CH2:25][C:20]([CH3:19])([OH:26])[CH2:21][CH2:22]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CC1(O)CCNCC1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Solvent: CO
Product: CC1(O)CCN(c2nc(Cl)nc3c2CCC3c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (400 mg, 1.413 mmol) in MeOH (14.100 mL) was added 4-methylpiperidin-4-ol (163 mg, 1.413 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was then concentrated in vacuo. Purification by flash chromatography (Silica, EtOAc/Hexanes) gave 1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-methylpiperidin-4-ol (374 mg, 1.034 mmol, 73.2% yield). LC-MS (M+H)+=362.0. 1H NMR (500 MHz, MeOD) δ ppm 7.12-7.21 (2H, m), 7.04 (2H, t, J=8.85 Hz), 4.11-4.30 (3H, m), 3.48-3.63 (2H, m), 3.14-3.23 (1H, m), 3.00-3.12 (1H, m), 2.54-2.66 (1H, m), 1.94-2.09 (1H, m), 1.68 (4H, t, J=4.12 Hz), 1.28 (3H, s).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:38]2[C:50](=[O:51])[C:49]3[S:48][C:47]4[CH2:46][CH2:45][CH2:44][CH2:43][C:42]=4[C:41]=3[CH:40]=[N:39]2)=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:34][O:33][CH2:32]4)[CH2:27][C@@H:26]3[CH3:35])=[CH:21][N:20]=2)[C:15](=[O:36])[N:14]([CH3:37])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:38]2[C:50](=[O:51])[C:49]3[S:48][C:47]4[CH2:46][CH2:45][CH2:44][CH2:43][C:42]=4[C:41]=3[CH:40]=[N:39]2)=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]4[CH2:32][O:33][CH2:34]4)[CH2:27][C@@H:26]3[CH3:35])=[CH:21][N:20]=2)[C:15](=[O:36])[N:14]([CH3:37])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cnc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)ccnc1-n1ncc2c3c(sc2c1=O)CCCC3
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CN(C2COC2)CCN1c1cnc(Nc2cc(-c3ccnc(-n4ncc5c6c(sc5c4=O)CCCC6)c3CO)cn(C)c2=O)cn1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 46.3 %

Procedure:
A mixture of 230j (80 mg, 0.11 mmol) and lithium hydroxide (27 mg, 1.1 mmol) in i-propanol/THF (1:1, 10 mL) and water (2 mL) was stirred at 35° C. for 0.5 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by reverse-phase prep-HPLC to afford 230 (34 mg, 45%). MS-ESI: [M+H]+ 668.2. 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.56 (d, J=6.0 Hz, 1H), 8.46 (s, 1H), 8.40 (d, J=2.5 Hz, 1H), 8.34 (d, J=1.5 Hz, 1H), 7.85 (s, 1H), 7.53 (d, J=6.0 Hz, 1H), 7.49 (d, J=2.5 Hz, 1H), 4.84 (bs, 1H), 4.58-4.54 (m, 2H), 4.50-4.47 (m, 1H), 4.43-4.36 (m, overlap, 4H), 3.78-3.75 (m, 1H), 3.59 (s, 3H), 3.39-3.35 (m, 1H), 3.02-3.0 (m, 1H), 2.98-2.95 (m, 2H), 2.90-2.82 (m, 2H), 2.78-2.76 (m, 1H), 2.60-2.56 (m, 1H), 2.10-2.09 (m, 1H), 1.95-1.88 (m, overlap, 5H), 1.10 (d, J=8.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[CH3:8][C:5]1[CH:4]=[C:3]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:2]([N:1]=[C:15]=[S:16])=[CH:7][CH:6]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1ccc(N)c(-c2ccccc2)c1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(N=C=S)c(-c2ccccc2)c1

Procedure:
Reaction of 2-amino-5-methylbiphenyl (7 g) with thiophosgene (5.7 g) in a mixture of dioxan (20 ml) and water (50 ml) at 0°-5° C. for 30 minutes and at ambient temperature for 1 hour gave 5-methyl-2-biphenylyl isothiocyanate as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])(CC)C.Br[CH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH:13]1[CH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)CC1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)CC1Cc1ccc2ccccc2c1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To a solution of 4-benzyl-piperazine-1-carboxylic acid tert-butyl ester (2 g) in diethylether (35 mL) was added tetramethylethylenediamine (1.4 mL). The resulting mixture was cooled to −70° C. and sec-butyllithium (7 mL of a 1.3 M solution) was added dropwise, after complete addition the solution was slowly warmed to −10° C., at which temperature the mixture was stirred for one hour. Subsequently, the mixture was recooled to −70° C.; then a solution of 2-(bromomethyl)naphthalene (2 g) in diethylether was added dropwise and stirring continued at −70° C. was continued for one hour. The resulting mixture was stirred and allowed to come to room temperature overnight, then partitioned between saturated ammonium chloride (aq) and ethyl acetate. The organic layer was dried over magnesium sulphate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, CH2Cl2/MeOH 99/1) to afford 4-benzyl-2-(naphthalen-2-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester as an oil. 0.8 g (27 %) Rf 0.47 (CH2Cl2/MeOH 99/1), MH+ 417.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35](=[O:38])[O:36][CH3:37])[CH:23]=1)[C:18]([OH:20])=O.S(Cl)(Cl)=O.[NH:44]([CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>>[CH2:49]([O:48][C:46](=[O:47])[CH2:45][N:44]([CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])[C:18](=[O:20])[C:17]1[CH:21]=[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35](=[O:38])[O:36][CH3:37])[CH:23]=[C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:39])[CH:16]=1)[CH3:50]
Reactant: COC(=O)CCCCCCCCCCOc1cc(OCCCCCCCCCCC(=O)OC)cc(C(=O)O)c1
Reactant: CCOC(=O)CNCC(=O)OCC
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CN(CC(=O)OCC)C(=O)c1cc(OCCCCCCCCCCC(=O)OC)cc(OCCCCCCCCCCC(=O)OC)c1

Procedure:
Conversion of 3,5-bis[(11-methoxy-11-oxoundecyl)oxy]benzoic acid to the acid chloride with thionyl chloride followed by treatment with diethyl iminodiacetate as in Example 21 gave N-(2-ethoxy-2-oxoethyl)-N-[3,5-bis[(11-methoxy-11-oxoundecyl)oxy]-benzoyl]glycine ethyl ester as an oil after chromatography on 125 g of silica gel using 20% ethyl acetate-hexane.