Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]3[CH2:16][CH2:15][C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5(CCCCC)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)=[CH:20][C:19]=4[F:35])(O)[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:36]1(C)[CH:41]=[CH:40]C(S(O)(=O)=O)=[CH:38][CH:37]=1.C1(C)C=CC=CC=1>O>[F:35][C:19]1[CH:20]=[C:21]([CH:24]2[CH2:25][CH2:26][CH:27]([CH2:38][CH2:37][CH2:36][CH2:41][CH3:40])[CH2:28][CH2:29]2)[CH:22]=[CH:23][C:18]=1[C:14]1[CH2:13][CH2:12][CH:11]([CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH2:16][CH:15]=1
Reactant: CCCCCC1(c2ccc(C3(O)CCC(C4CCC5(CC4)OCCO5)CC3)c(F)c2)CCCCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(c2ccc(C3=CCC(C4CCC5(CC4)OCCO5)CC3)c(F)c2)CC1
Temperature: 30 °C
Yield: 537.4 %

Procedure:
The compound (3) (108.6 g), p-toluenesulfonic acid (4.02 g) and toluene (500 ml) were mixed, and the mixture was heated under reflux for 1.5 hours while the water being distilled was removed. The reaction mixture was cooled to 30° C., and then water (1,000 ml) and toluene (1,800 ml) were added and mixed with it. The mixture was then allowed to stand until it had separated into two phases, the organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent of the solution was distilled off under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=7:3 by volume) as an eluent and silica gel as a stationary phase powder, and further purified by means of recrystallization from heptane and dried, giving 58.8 g of 8-{4-[2-fluoro-4-(4-pentyl-cyclohexyl)-phenyl]-cyclohex-3-enyl}-1,4-dioxa-spiro[4,5] decane (4). The yield based on the compound (1) was 53.4%.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:31]=[CH:30][CH:29]=[CH:28][C:7]=2[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C:11]3([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[C:10]2=[O:27])[N:3]=[CH:4][CH:5]=1.C(O)(C(F)(F)F)=O>ClCCl>[N:1]1[N:2]([C:6]2[CH:31]=[CH:30][CH:29]=[CH:28][C:7]=2[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C:11]3([CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[C:10]2=[O:27])[N:3]=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCN(Cc3ccccc3-n3nccn3)C2=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1N(Cc2ccccc2-n2nccn2)CCCC12CCNCC2
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 209.6 %

Procedure:
To a solution of tert-butyl 2-(2-(2H-1,2,3-triazol-2-yl)benzyl)-1-oxo-2,9-diazaspiro[5.5]-undecane-9-carboxylate (1.76 g, 4.09 mmol) in dichloromethane (15 mL) was added TFA (3.15 mL, 40.9 mmol). The solution was stirred for 25 min at rt. After completion of the reaction the mixture was evaporated to dryness. The residue was dried under high vacuum to yield the title compound as a solid (2.79 g, quant.). [1H NMR (400 MHz, DMSO-d6) ♀ ppm 8.42 (br s, 2H), 8.11 (s, 2H), 7.64-7.60 (m, 1H), 7.51-7.47 (m, 2H), 7.24 (d, 1H), 4.55 (s, 2H), 3.24-3.18 (m, 2H), 3.13-3.11 (m, 2H), 3.09-2.97 (m, 2H), 2.13-2.04 (m, 2H), 1.82-1.70 (m, 4H), 1.65-1.55 (m, 2H); LCMS RtA=0.60, [M+H]+=326.3].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([Cl:9])[CH:3]=1.C([Mg]Cl)(C)C.[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:17]=1[C:18](Cl)=[O:19].CCOC(C)=O.O.Cl>C1COCC1.[Cl-].[Cl-].[Zn+2].CC([O-])=O.CC([O-])=O.[Cu+2].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]([C:17]2[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:16]=2[Cl:15])=[O:19])=[C:4]([Cl:9])[CH:3]=1
Reactant: Clc1cc(Br)ccc1I
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Br)cc1Cl)c1cc([N+](=O)[O-])ccc1Cl
Temperature: -35 °C
Reaction time: 1.5 h

Procedure:
The reaction was run under an argon atmosphere using dry glassware. 4-Bromo-2-chloro-iodobenzene (5.00 g, 15.8 mmol) was dissolved in dry THF (25 mL) and cooled to −35° C. Isopropylmagnesium chloride (2 M in THF, 8.27 mL, 16.5 mmol) was added under stirring during 90 minutes. A solution of ZnCl2 (2.17 g, 15.9 mmol) in dry THF (35 mL) was slowly added to the reaction mixture at −35° C. The reaction mixture was allowed to come to RT after 1 h and a solution of 2-chloro-5-nitro-benzoyl chloride (3.64 g, 16.5 mmol) in THF (45 mL) was added followed by Cu(OAc)2.H2O (63 mg, 0.32 mmol). The resulting reaction mixture was stirred at RT for 18 h. The reaction mixture was poured into a mixture of EtOAc/water/HCl (1N). The organic phase was washed with water, brine and then dried (MgSO4), filtered and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography using DCM/petroleum ether (40-60) 1:6; 1:4 and 1:2 as the eluent to afford the title compound as yellow solid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH:23]=O)([CH3:18])([CH3:17])[CH3:16].[F:28][C:29]1[C:30]([CH3:36])=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][NH:32][C:31]1[CH:33]=[CH:34][CH:35]=[C:29]([F:28])[C:30]=1[CH3:36])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1c(N)cccc1F
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1c(F)cccc1NCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
5.8 g of sodium triacetoxyborohydride (27.0 mmol) was added to a solution of 3.5 g of (1,1-dimethyl-2-oxoethyl)carbamic acid t-butyl ester obtained in Reference Example 3 (18.7 mmol), 2.25 g of 3-fluoro-2-methylaniline (18.0 mmol) and 1.0 ml of acetic acid (18.0 mmol) in methylene chloride (190 ml) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=5/1) to obtain 3.97 g of the title compound (yield: 74%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.Cl.[CH3:10][CH:11]1[NH:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:19]=[C:12]12.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:8][C:6]1[CH:7]=[C:2]([N:16]2[CH2:15][CH2:14][N:13]3[C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][N:19]=[C:12]3[CH:11]2[CH3:10])[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: CC1NCCn2c(C(F)(F)F)cnc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CC1c2ncc(C(F)(F)F)n2CCN1c1cncc(Br)c1
Temperature: 90 °C
Yield: 47.5 %

Procedure:
To a nitrogen degassed mixture of 3,5-dibromopyridine (294 mg, 1.242 mmol), 8-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine hydrochloride (CA, 100 mg, 0.414 mmol) and sodium t-butoxide (119 mg, 1.242 mmol), in Toluene (2 ml) was added BINAP (51.5 mg, 0.083 mmol) and tris(dibenzylideneacetone)dipalladium(0) (37.9 mg, 0.041 mmol). The reaction was sealed and heated at 90° C. for ½ hrs. LCMS (215 nM) showed the reaction complete. The reaction was cooled, quenched into water (10 mL) and aqueous. KHSO4 (2 mL) and ethyl acetate (25 mL) added. Aqueous NaHCO3 was added to adjust pH to 7.5 and the ethyl acetate layer removed. Aqueous layer washed with ethyl acetate (25 mL) and organic extracted combined, washed with brine (10 mL), dried over sodium sulfate and concentrated to an oil. Oil chromatographed on silica using 25-70% ethyl acetate/hexanes to give 71 mg product, I-6, as a foam.
Reaction SMILES: [N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.Br[C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1C(=O)CCC1>ClCCl.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:16]([O:15][C:13]([N:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(N2CCC(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)cc1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A 100 mL reaction flask was charged with tert-butyl 4,4′-bipiperidine-1-carboxylate (1.14 g; 4.25 mmol), methyl 4-bromobenzoate (913 mg; 4.25 mmol), cesium carbonate (4.15 g; 12.74 mmol), Pd(OAc)2 (48 mg; 0.212 mmol) and 2-(diphenylphosphino)-2′-(N—N-dimethylamino)biphenyl (162 mg; 0.425 mmol). NMP (outgassed by bubbling with nitrogen for 10 min; 10 mL) was added and the mixture stirred at 90° C. for 18 hr. The mixture was diluted with dichloromethane (100 mL) and filtered through Celite. The filtrate was washed with water (4×25 mL). The organic was dried over magnesium sulfate, filtered and evaporated to a solid. The solid was digested at reflux (MTBE). After cooling, the white solid was recovered by filtration. The filtrate was evaporated and chromatographed (Horizon; 0% to 100% EtOAc/hex; linear gradient). The fractions containing the desired compound were recovered and combined with the solid to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)=[O:9])=[O:5].[CH:24]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1)=[CH2:25].C(#N)C>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([CH:24]=[CH2:25])=[CH:27][CH:28]=2)[CH2:12]1)=[O:9])=[O:5]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: C=Cc1ccc(CN2CC[C@@H](NC(=O)CNC(=O)c3cc(C(F)(F)F)ccc3N)C2)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A mixture of (R)-3-[{N-(2-amino-5-(trifluoromethyl)benzoyl)glycyl}amino]pyrrolidine (0.05 mmol), 4-vinylbenzyl chloride (9.9 mg, 0.065 mmol), piperidinomethylpolystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.30 mL) was stirred at 50° C. for 12 h. The reaction mixture was cooled, loaded onto Varian™ SCX column and washed with CH3OH (15 mL). Product was eluted using 2 N NH3 in CH3OH (5 mL) and concentrated to afford (R)-3-[{N-(2-amino-5-(trifluoromethyl)benzoyl)glycyl}amino]-1-(4-vinylbenzyl)pyrrolidine (Compound No. 1701) (19.6 mg, 88%): The purity was determined by RPLC/MS (92%); ESI/MS m/e 547.2 (M++H, C23H25ClF3N4O2).
Reaction SMILES: C[O:2][C:3](=[O:49])[CH2:4][N:5]([CH2:44][C:45]([O:47]C)=[O:46])[C:6](=[O:43])[C:7]1[CH:12]=[CH:11][C:10]([O: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][CH2:26][CH3:27])=[C:9]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:8]=1.[OH-].[Na+]>CO.O1CCOCC1>[C:45]([CH2:44][N:5]([C:6](=[O:43])[C:7]1[CH:12]=[CH:11][C:10]([O: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][CH2:26][CH3:27])=[C:9]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:8]=1)[CH2:4][C:3]([OH:49])=[O:2])([OH:47])=[O:46]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)N(CC(=O)OC)CC(=O)OC)cc1OCCCCCCCCCCCCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(CC(=O)O)CC(=O)O)cc1OCCCCCCCCCCCCCC
Yield: 59.3 %

Procedure:
A solution of 0.90 g (1.3 mmol) of N-(2-methoxy-2-oxoethyl)-N-[3,4-bis(tetradecyloxy)benzoyl]glycine methyl ester and 1.0 ml (6 mmol) of 6N NaOH in 80 ml of methanol and 35 ml of dioxane was stirred at reflux for 6 hours. The solvents were removed at reduced pressure, the residue was acidified and the product was removed by filtration. Recrystallization from ethyl acetate-hexane gave 0.51 g (59% yield, mp 84°-87° ) of N-(carboxymethyl)-N-[3,4-bis(tetradecyloxy)benzoyl]glycine.
Reaction SMILES: [H-].[Na+].C1(C([C:11]2[C:16]([CH2:17][O:18][CH2:19][C:20]3[C:25]([C:26]4C(=CC=[C:31]([OH:33])[CH:32]=4)O)=CC=CC=3)=[CH:15][CH:14]=[CH:13][CH:12]=2)=CC(=CC=1)O)O.Br[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]([CH3:43])[CH2:41][CH3:42]>CN(C)C=O>[CH3:43][CH:40]([CH2:41][CH3:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][O:33][C:31]1[CH:32]=[CH:26][CH:25]=[CH:20][C:19]=1[O:18][CH2:17][C:16]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Oc1ccc(O)c(-c2ccccc2COCc2ccccc2-c2cc(O)ccc2O)c1
Reactant: CCC(C)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)CCCCCOc1ccccc1OCc1ccccc1
Reaction time: 0.33 h

Procedure:
A 100-ml 4-neck flask was charged with 3.74 g of NaH (containing 50% of oil) and 50 ml of N,N-dimethylformamide, and a solution of 15.46 g of hydroquinone monobenzyl ether in 30 ml of N,N-dimethylformamide was added under a nitrogen current over a period of 20 minutes in an ice water bath. After 20 minutes, 16 g of optically active 1-bromo-6-methyloctane was added over a period of 45 minutes, and reaction was carried out at room temperature for 6 hours. The reaction mixture was extracted with ether. The ether layer was washed with water, 5% NaOH, water and a saturated aqueous solution of sodium chloride in sequence and dried, and the organic solvent was distilled under reduced pressure to obtain a crude product. The crude product was purified to obtain 24.37 g of an ether compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[C:9]1[Br:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24]>>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:22][C:23](=[O:24])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[C:9]1[Br:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccccc1
Product: Cn1c(=O)n(CC(=O)c2ccccc2)c(=O)c2c1nc(Br)n2Cc1ccccc1

Procedure:
7-Benzyl-8-bromo-3-methyl-3,7-dihydropurine-2,6-dione (77A) and 2-bromoacetophenone were reacted and purified as described in the General procedure G, Step B, to afford 77B.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([N:11]2[CH2:16][CH2:15][NH:14][C@H:13]([CH3:17])[CH2:12]2)=[N:6][CH:5]=1.Cl[C:20]1[NH:24][C:23]2[CH:25]=[C:26]([C:38]([F:41])([F:40])[F:39])[CH:27]=[C:28]([C:29]3[CH:34]=[C:33]([F:35])[C:32]([F:36])=[C:31]([F:37])[CH:30]=3)[C:22]=2[N:21]=1>>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([N:11]2[CH2:16][CH2:15][N:14]([C:20]3[NH:21][C:22]4[C:28]([C:29]5[CH:30]=[C:31]([F:37])[C:32]([F:36])=[C:33]([F:35])[CH:34]=5)=[CH:27][C:26]([C:38]([F:41])([F:39])[F:40])=[CH:25][C:23]=4[N:24]=3)[C@H:13]([CH3:17])[CH2:12]2)=[N:6][CH:5]=1
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(Cl)nc23)cc(F)c1F
Reactant: COC(=O)c1cnc(N2CCN[C@H](C)C2)c(Cl)c1
Product: COC(=O)c1cnc(N2CCN(c3nc4cc(C(F)(F)F)cc(-c5cc(F)c(F)c(F)c5)c4[nH]3)[C@H](C)C2)c(Cl)c1

Procedure:
5-Chloro-6-[(3R)-3-methyl-piperazin-1-yl]-nicotinic acid methyl ester from step (b) above (271 mg, 1.0 mmol) and 2-chloro-6-trifluoromethyl-4-(3,4,5-trifluoro-phenyl)-1H-benzoimidazole (350 mg, 1.0 mmol, Example 51b) reacted under the conditions of Example 3c to give the title compound as a white solid. MS ESI, pos. ion) m/e: 584 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=3)[CH2:17][CH2:18]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccc(I)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccc(I)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.5 %

Procedure:
To a solution of methyl 4-((4-(((trans-2-(4-iodophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate (50 mg, 0.099 mmol) in methanol (2 mL) was added sodium hydroxide (6M, 0.5 mL, 0.500 mmol), and the mixture was stirred at room temperature for 18 h. The mixture was purified using reverse-phase HPLC. The fractions containing the product as combined, treated with 1N HCl and concentrated. The residue was dried under vacuum to give 25 mg of product (HCl salt) as yellow solid. MS: (M+H)+=491.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.33 (m, 1H), 1.51-1.70 (m, 3H), 1.88-2.09 (m, 3H), 2.96 (br. s., 4H), 3.12 (br. s., 1H), 4.34 (br. s., 2H), 6.98-7.10 (m, 2H), 7.62-7.81 (m, 4H), 8.01 (d, J=8.34 Hz, 2H).
Reaction SMILES: [O-2].[Nd+3:2].[O-2].[O-2].[Nd+3].[C:6]([OH:11])(=[O:10])[C:7]([CH3:9])=[CH2:8]>O>[C:6]([O-:11])(=[O:10])[C:7]([CH3:9])=[CH2:8].[Nd+3:2].[C:6]([O-:11])(=[O:10])[C:7]([CH3:9])=[CH2:8].[C:6]([O-:11])(=[O:10])[C:7]([CH3:9])=[CH2:8]
Reactant: C=C(C)C(=O)O
Agent: [Nd+3]
Agent: [O-2]
Solvent: O
Product: C=C(C)C(=O)[O-]
Temperature: 60 °C
Yield: 78 %

Procedure:
Ten (10) g of neodymium oxide, 17 g of methacrylic acid and 100 g of water were mixed. The resultant mixture in the form of suspension was stirred as refluxed at 60° C. for three hours. The reaction mixture was filtered to separate off the unaltered solids. The filtrate was concentrated under a vacuum by distillation of water to produce crystals. By washing the crystals with acetone and drying under a vacuum, there was obtained neodymium methacrylate. The yield was 78%. Example Synthesis 2
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[C:10]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[C:17]2[C:16](=[O:27])[N:15]([CH2:28][CH2:29][CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[C:14](=[O:39])[N:13]([CH3:40])[C:12]=2[N:11]=1>C1COCC1.O>[Si:32]([O:31][CH2:30][CH2:29][CH2:28][N:15]1[C:16](=[O:27])[C:17]2[N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C:10]([O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:11][C:12]=2[N:13]([CH3:40])[C:14]1=[O:39])([C:35]([CH3:36])([CH3:37])[CH3:38])([CH3:33])[CH3:34]
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(OC1CCCC1)n2Cc1ccc(Cl)cc1
Reaction time: 1 h
Yield: 99.3 %

Procedure:
Step 1 Cyclopentanol (0.21 mL, 2.31 mmol) was dissolved in THF (5 mL) and sodium hydride (60% in oil, 0.092 g, 2.31 mmol) was added. The reaction was stirred for 1 h. 8-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.25 g, 0.46 mmol, intermediate 77) was added and the reaction was stirred at room temperature for 15 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to give 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-8-(cyclopentyloxy)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.25 g, 100% yield) as a golden oil. LCMS retention time=5.843 min and 71% purity, LCMS MH+ 547.
Reaction SMILES: [C:1]([O:14]C)(=[O:13])[CH2:2][C:3]1[C:4](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]C)=O.[C:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([C:16]2[C:24]3[C:29]([C:12]4[CH:11]=[CH:10][CH:9]=[C:4]5[C:5](=[O:7])[O:14][C:1](=[O:13])[C:2]=2[C:3]=45)=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)Cc1ccccc1C(=O)OC
Product: O=C1OC(=O)c2c(-c3ccccc3)c3ccccc3c3cccc1c23

Procedure:
As described in example 14, the following compounds were prepared from dimethyl homophthalate and benzophenone:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].FC(F)(F)CCCC(O[C:18]([CH3:21])([CH3:20])[CH3:19])=O>>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([O:7][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:6]
Reactant: CC(C)(C)OC(=O)CCCC(F)(F)F
Reactant: O=C(O)CCC(F)(F)F
Product: CC(C)(C)OC(=O)CCC(F)(F)F

Procedure:
Preparation 4A was prepared from 4,4,4-trifluorobutanoic acid (4.99 g, 35.1 mmol) using the general procedure shown for Preparation 1A. Preparation 4A (5.58 g, 80%) was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.47-2.52 (2H, m), 2.37-2.45 (2H, m), 1.46 (9H, s).
Reaction SMILES: [CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].COCCOC(N=NC(OCCOC)=O)=O>C1(C)C=CC=CC=1.O>[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:9][C@@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30].[CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCCCCC[C@H](C)O
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC[C@@H](C)OC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 3.5 h

Procedure:
After (S)-2-octanol (300 mg, 2.30 mmol), triphenylphosphine (725 mg, 2.76 mmol), 4-nitrobenzoic acid (463 mg, 2.76 mmol), and toluene (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (648 mg, 2.76 mmol) dissolved in toluene (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for 3.5 hours. Water (10 mL) was added, and separation was carried out. Then, the aqueous layer was extracted using toluene (10 mL,×1). The resulting organic layer was collectively washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 5% ethyl acetate-hexane solution) to give (R)-2-(4-nitrobenzoyloxy)octane as a pale yellow liquid substance (615 mg, yield: 96%/(S)-2-octanol).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.CN.[N+:18]([C:21]1[CH:30]=[CH:29][C:24]([CH2:25][N:26]=[C:27]=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19].[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][NH:26][C:27]([N:2]([CH:3]2[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]2)[CH3:1])=[O:28])=[CH:29][CH:30]=1)([O-:20])=[O:19]
Reactant: O=C=NCc1ccc([N+](=O)[O-])cc1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)NCc1ccc([N+](=O)[O-])cc1)C1CCNCC1

Procedure:
The title compound was prepared by the reaction of 4-(N-methylamino)-1-tert-butoxycarbonylpiperidine (prepared by the method described in Example 1, Step A, using methylamine in place of ethylamine) with (4-nitrobenzyl)isocyanate (prepared from phosgene and (4-nitrobenzyl)amine), followed by treatment of the product with 50% TFA in CH2Cl2 to remove the tert-butoxycarbonyl group, affording the title compound. ESI-MS: 293.1 (M+H).