Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([N:14]=2)=[C:12](Br)[CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.Cl[P:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Mg].ClCCl>O1CCCC1.ClCCl.CCCCCC>[C:19]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:2]2[C:15]3[C:6](=[CH:7][C:8]4[C:13]([N:14]=3)=[C:12]([P:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:11]=[CH:10][CH:9]=4)[CH:5]=[CH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: Brc1cccc2cc3cccc(Br)c3nc12
Agent: [Mg]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCCCCC
Product: c1ccc(P(c2ccccc2)c2cccc3cc4cccc(P(c5ccccc5)c5ccccc5)c4nc23)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 13.1 %

Procedure:
A solution of 337 mg (1 mmol) of 4,5-dibromoacridine (XIX) and 440 mg (2 mmol) of chlorodiphenylphosphane (Ph2PCl) in 40 ml of tetrahydrofuran was added dropwise to a boiling suspension of 72 mg (3 mmol) of magnesium powder in 20 ml of tetrahydrofuran. The mixture was then stirred at room temperature for 20 h. Hydrolysis with water and diluted hydrochlorid acid, extraction with diethyl ether, drying the ether phase over sodium sulfate and distilling off the solvent gave a brown raw product, from which 72 mg (15% of theory) of 4,5-bis(diphenylphosphino)acridine (Ia) was obtained as a yellow powder by several recrystallizations from dichloromethane and dichloromethane/hexane.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:7](OC)(=O)[CH:8](C)[OH:9]>>[C:8]([O:3][CH:2]([CH3:4])[C:1]([OH:6])=[O:5])(=[O:9])[CH3:7]
Reactant: CC(O)C(=O)O
Reactant: COC(=O)C(C)O
Product: CC(=O)OC(C)C(=O)O
Yield: 90 %

Procedure:
In an independent experiment, a molar equivalent of lactic acid was utilized as a starting reagent in place of methyl lactate. The lactic acid reagent utilized was an aqueous solution containing approximately 85% lactic acid, by weight. The reaction conditions were otherwise as indicated above. NMR analysis of the resulting product material indicated a 2-acetoxy propionic acid product yield of greater than about 90% with some dimer or polymer byproduct formation apparent.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[O:15])=[C:9]([C:30]3[CH:35]=[C:34]([NH:36][C:37](=[O:48])[C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=4)[CH:33]=[CH:32][N:31]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>O1CCCC1.O>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:30]3[CH:35]=[C:34]([NH:36][C:37](=[O:48])[C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:45])[F:46])[CH:39]=4)[CH:33]=[CH:32][N:31]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccn2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of methyl 3-(3-((4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzamido)pyridin-2-yl)phenyl)carbamoyl)benzylthio)propanoate (100 mg, 0.15 mmol, 1.00 equiv) and lithium hydroxide hydrate (62.0 mg, 1.48 mmol, 10.00 equiv) in tetrahydrofuran/water (1:1) (10/10 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was combined with the solution of the previous batch and then concentrated under vacuum. The residual solution was adjusted to pH 5˜6 with 1 N acetic acid. The resulting solution was extracted with 2×30 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate. The solvent was removed under vacuum. The crude product (140 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The fractions were collected and lyophilized to yield 100 mg (58%) of product as an off-white solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 11.29 (br, 1H), 8.79 (d, J=6.0 Hz, 1H), 8.42 (s, 1H), 8.31-8.27 (m, 2H), 8.07-7.97 (m, 2H), 7.87-7.74 (m, 3H), 7.53-7.44 (m, 3H), 7.38-7.37 (m, 1H), 3.83 (s, 2H), 3.35 (s, 4H), 2.56 (t, J=6.3 Hz, 2H), 1.74-1.61 (m, 6H). MS (ES, m/z): 663 [M+H]+.
Reaction SMILES: [Cl:1][C:2]([Cl:20])([P:9](OCC)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].P(Cl)(Cl)(Cl)(Cl)[Cl:22]>>[Cl:1][C:2]([Cl:20])([PH:9]([C:11]1([Cl:22])[CH:16]=[CH:15][CH:14]=[CH:13][CH2:12]1)=[O:10])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOP(=O)(c1ccccc1)C(Cl)(Cl)C(=O)OC(C)C
Product: CC(C)OC(=O)C(Cl)(Cl)[PH](=O)C1(Cl)C=CC=CC1
Reaction time: 48 h

Procedure:
To 10.14 g of 1-methylethyl 2,2-dichloro-2-[(ethoxy)phenylphosphinyl]acetate at 60° C. and under a nitrogen atmosphere was added 6.24 g of phosphorus pentachloride in 1 g portions over a 72 hour period. The mixture was stirred an additional 48 hours after addition. Volatile reaction products were distilled at 45°-50° C./0.75 mm Hg leaving 1-methylethyl 2,2-dichloro-2-[(1-chloro)phenylphosphinyl]acetate as a brown oil.
Reaction SMILES: [C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(O[C@@H:45]1[O:57][C@H:56]([CH2:58][O:59][C:60](=[O:62])[CH3:61])[C@@H:51]([O:52][C:53](=[O:55])[CH3:54])[C@H:46]1[O:47][C:48](=[O:50])[CH3:49])(=O)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>ClC(Cl)(Cl)C.C(OCC)(=O)C>[C:48]([O:47][C@@H:46]1[C@H:51]([O:52][C:53](=[O:55])[CH3:54])[C@@H:56]([CH2:58][O:59][C:60](=[O:62])[CH3:61])[O:57][C@H:45]1[N:14]1[CH:13]=[N:12][C:11]2[C:15]1=[N:16][C:17]([C:19]([O:21][CH3:22])=[O:20])=[N:18][C:10]=2[NH:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:50])[CH3:49]
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(Cl)(Cl)Cl
Product: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
A suspension of methyl 6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate (Preparation 7) (1.5 g, 4.02 mmol) in 1,1,1-trichloroethane (40 ml) was treated with N,O-bis(trimethylsilyl)acetamide (4.8 ml, 19.6 mmol). The mixture was heated under reflux for two hours. The solution was allowed to cool to room temperature and the solvent removed under reduced pressure. The residue was taken up in anhydrous toluene (40 ml) and 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose (1.65 g, 5.19 mmol) and trimethylsilyl trifluoromethanesulfonate (0.98 ml, 5.43 mmol) added. The resulting solution was heated under reflux under a nitrogen atmosphere for 3 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (200 ml) and washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was separated, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel using gradient elution with ethyl acetate:pentane (70:30, by volume) then ethyl acetate:pentane (80:20, by volume) then ethyl acetate to afford the title compound as a foam (2.05 g).
Reaction SMILES: C(=O)([O-])O.[Na+].O.C(=O)([O-])O.[Na+].[NH2:12]OS(O)(=O)=O.[CH3:18][O:19][C:20]([C:22]([C:27]([O:29]C)=O)=[C:23]([S:25][CH3:26])[SH:24])=[O:21]>O>[CH3:18][O:19][C:20]([C:22]1[C:27]([OH:29])=[N:12][S:24][C:23]=1[S:25][CH3:26])=[O:21]
Reactant: COC(=O)C(C(=O)OC)=C(S)SC
Reactant: NOS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1c(O)nsc1SC
Temperature: 25 °C
Reaction time: 0.38 h
Yield: 73 %

Procedure:
A separate reaction vessel was charged with water (280 mL, 7 volumes) and sodium hydrogencarbonate (1.5 equiv, 38.2 g). The water/sodium hydrogencarbonate mixture was cooled to 5° C. under nitrogen atmosphere. Hydroxylamine-O-sulfonic acid (1.2 equiv, 41.1 g) was added over 5 minutes, and the mixture was stirred 15-30 minutes. The 2,2-Bis-methoxycarbonyl-1-methylsulfanyl-ethenethiol anion/acetonitrile solution from Example 1 was added over 60-70 minutes. The mixture was warmed to 25° C. over 1 hour, then held for 16 hours at 25° C. Most of the acetonitrile was removed by vacuum distillation (130 Torr, 50° C.). The residue was cooled to room temperature, acidified to pH ˜1 by addition of 37% hydrochloric acid (32 mL). The solids were granulated for 16 hours at 25° C. The slurry was filtered, and the filter cake was washed 3×100 mL with water, once with 200 mL 1:3 ethyl acetate:hexanes (v/v), and once with 100 mL 1:3 ethyl acetate:hexanes (v/v). The wet cake (50.5 g) was dried in a vacuum oven for 16 hours to give 3-Hydroxy-5-methylsulfanyl-isothiazole-4-carboxylic acid methyl ester, providing 45.4 grams (73% yield). 1H NMR: (DMSO-d6) δ 11.92 (s, 1H); 3.74 (s, 3H); 2.53 (s, 3H). MS: (API-ES pos) 206 (M+H)+, base.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1.C1COC2C=CC(NC3N=C(NC4C=CC5OCCOC=5C=4)C(Br)=CN=3)=CC=2O1.[Cl:64]C1C=C(B(O)O)C=CC=1>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:64])[CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: c1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1
Agent: Brc1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc2c(c1)OCCO2
Product: Clc1cccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)c1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine, N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine and 3-chlorophenylboronic acid were reacted to yield N2,N4-bis(3,4-ethylenedioxyphenyl)-5-(3-chlorophenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.77 (s, 1H), 7.45-7.41 (m, 2H), 7.38-7.33 (m, 2H), 7.09 (d, 1H, J=2.4 Hz), 7.01 (d, 1H, J=2.4 Hz), 6.92 (dd, 1H, J=2.4 and 9.0 Hz), 6.86 (dd, 1H, J=2.4 and 8.7 Hz), 6.74 (d, 1H, J=8.7 Hz), 6.67 (d, 1H, J=8.7 Hz), 4.21 (s, 4H), 4.19 (s, 4H); LCMS: ret. time: 27.18 min.; purity: 95%; MS (m/e): 490 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([CH3:24])[N:12]=[C:11]2[C:25](=[O:28])[NH:26][CH2:27][C:10]=12.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.CCN(CC)CC.N1C=CC=CC=1.ClC(Cl)C>CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([N:26]2[CH2:27][C:10]3[C:11](=[N:12][C:13]([CH3:24])=[C:14]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]=3[C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[C:25]2=[O:28])=[CH:32][CH:31]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1nc2c(c(-c3ccc(Cl)cc3Cl)c1CNC(=O)OC(C)(C)C)CNC2=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: Cc1nc2c(c(-c3ccc(Cl)cc3Cl)c1CNC(=O)OC(C)(C)C)CN(c1ccc(Cl)cc1)C2=O
Yield: 61 %

Procedure:
A mixture of Example 11B (29.8 mg, 0.071 mmol), 4-chlorophenylboronic acid (45 mg, 0.288 mmol), Cu(OAc)2 (24 mg, 0.132 mmol), Et3N (45 μL, 0.324 mmol), pyridine (60 μL, 0.743 mmol), and dichloroethane (1 mL) was heated at 75° C. for 1.5 h. Concentration in vacuo followed by flash chromatography (50% to 100% EtOAc/Hexanes) to yield a Example 11C which was further purified by recrystallization fom MeOH to give 23 mg (61%) of a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:17]=1)=[O:6]
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1cccc(F)c1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2cccc(F)c2)cc1
Yield: 42 %

Procedure:
In a manner similar to that described in Example 3, 3-fluorobenzoyl chloride (0.053 g, 0.00033 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol) (Example 1, Step (c)), and the resulting intermediate was hydrolyzed to give 0.0331 g of 4-[4-(3-fluoro-benzoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; mp 239-241° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11](CCl)[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:16]=[CH:17][CH:18]=[N:19][C:5]1=2.Cl.Cl.[NH2:22][CH2:23][CH2:24][C:25]1[N:26]=[CH:27][NH:28][CH:29]=1>>[NH2:22][CH2:23][CH2:24][C:25]1[N:26]=[CH:27][N:28]([C:11]2[CH:12]=[CH:13][C:8]3[S:7][C:6]4[N:16]=[CH:17][CH:18]=[N:19][C:5]=4[N:4]([CH2:3][O:2][CH3:1])[C:9]=3[CH:10]=2)[CH:29]=1
Reactant: NCCc1c[nH]cn1
Reactant: COCN1c2cc(CCl)ccc2Sc2nccnc21
Agent: Cl
Product: COCN1c2cc(-n3cnc(CCN)c3)ccc2Sc2nccnc21
Yield: 116 %

Procedure:
0.5 g of 10-methoxymethyl-8-chloromethyl-10H-pyrazino-[2,3-b][1,4]benzothiazine and 1.0 g of 4-(2-aminoethyl)imidazole dihydorchloride were treated by the same method as the one of Example 1094 to thereby give 0.7 g of crude 8-[4-(2-aminoethyl)imidazol-1-yl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine as a brown solid. This crude product was then treated by the same method as the one of Example 316 to thereby give 0.1 g of N-[2-[1-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4benzothiazin-8-ylmethyl)imidazol-4-yl]ethyl]methanesulfonamide. Further, it was treated by the same method as the one of Example 8 to thereby give 50 mg of the title compound as yellow crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:16])[CH:12]=2)[N:7]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:16][Br:17])[CH:12]=2)[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nc(-c3cccs3)ccc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2nc(-c3cccs3)ccc2c1

Procedure:
11.9 g of 2-(2-thienyl)-6-methyl-quinoline together with 360 ml of carbon tetrachloride, 10.4 g of N-bromosuccinimide and 0.3 g of dibenzoyl peroxide are boiled for 15 hours under reflux. The reaction mixture is cooled and filtered off. Concentration of the filtrate yields 2-(2-thienyl)-6-bromomethyl-quinoline which melts at 95°C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:28][CH2:29][CH3:30])[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=1)[CH3:11]>ClCCl.CCCCCC>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:28][CH2:29][CH3:30])[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=1)[CH3:11]
Reactant: CCOC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)OCC
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)O

Procedure:
The title compound, mp 109-110° C. (dichloromethane-hexane), was prepared from ethyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-ethoxypropanoate by a procedure similar to that describe for Example 2.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@H:16]2[N:12](/[C:13](=[N:21]/[C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:30])[C:23]=3[CH3:31])/[O:14][C@H:15]2[C:17]([F:20])([F:19])[F:18])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.O[C@H]1[C@@H]2N(/C(=N/C3C=CC(C#N)=C(Cl)C=3C)/OC2)CC1>>[OH:8][C@@H:9]1[C@@H:16]2[N:12](/[C:13](=[N:21]/[C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:30])[C:23]=3[CH3:31])/[O:14][C@H:15]2[C:17]([F:18])([F:20])[F:19])[CH2:11][CH2:10]1
Reactant: Cc1c(/N=C2\O[C@@H](C(F)(F)F)[C@H]3[C@@H](O[Si](C)(C)C(C)(C)C)CCN23)ccc(C#N)c1Cl
Agent: Cc1c(/N=C2\OC[C@@H]3[C@H](O)CCN23)ccc(C#N)c1Cl
Product: Cc1c(/N=C2\O[C@@H](C(F)(F)F)[C@@H]3[C@@H](O)CCN23)ccc(C#N)c1Cl

Procedure:
The title compound was prepared from compound 5F following the procedure found in Example 1 for the preparation of compound 1J. LCMS: m/z 360 [M+H]+. The double bond geometry was confirmed via X-ray analysis.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O.C(OCC)(=O)C>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C@H:7]2[CH2:6][C@H:5]([OH:4])[CH2:10][CH2:9][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:23][CH:22]=1
Reactant: CC(=O)O[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(F)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](O)C[C@@H]1c1ccc(F)cc1
Yield: 99 %

Procedure:
A suspention of (±)-(2R,4R)-tert-butyl 4-acetoxy-2-(4-fluorophenyl)piperidine-1-carboxylate (150 mg, 0.40 mmol) and potassium carbonate (1.0 g) in methanol:water 10:1 (11 mL) was stirred for 1 hour then diluted with ethyl acetate (40 mL) and washed with water (25 mL) and brine (25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give (±)-(2R,4R)-tert-butyl 2-(4-fluorophenyl)-4-hydroxypiperidine-1-carboxylate (117 mg, 99% yield). 1H NMR (400 MHz, d6-DMSO): 7.17 (m, 4H), 5.34 (br d, 1H), 4.73 (d, 1H), 4.34 (br d, 1H), 3.41 (m, 1H), 2.67 (m, 1H), 2.42 (br d, 1H), 1.57 (m, 1H), 1.38 (s, 9H).
Reaction SMILES: Br[C:2]1[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]2[CH2:26][CH2:27][NH:28][CH2:29][CH:22]2[C:21]1=[O:30].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.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[Cl:18][C:3]1[C:2]([N:28]2[CH2:27][CH2:26][N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[C:21](=[O:30])[CH:22]3[CH2:29]2)=[CH:7][C:6]([C:8]#[N:9])=[CH:5][C:4]=1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(Br)c1Cl
Reactant: CN1CCN2CCNCC2C1=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CN1CCN2CCN(c3cc(C#N)cc(NC(=O)OC(C)(C)C)c3Cl)CC2C1=O
Temperature: 105 °C
Yield: 60.5 %

Procedure:
A mixture of crude (+/−)-tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate (78 mg, 0.236 mmol), 2-methyloctahydro-1H-pyrazino[1,2-a]pyrazin-1-one (40 mg, 0.236 mmol), Pd2dba3 (21.65 mg, 0.024 mmol), BINAP (44.2 mg, 0.071 mmol) and Cs2CO3 (231 mg, 0.709 mmol) in Dioxane (2.5 mL) was evacuated and filled with nitrogen 3 times and heated at 105° C. for 8 h. LC-MS showed completion of reaction. The reaction mixture was filtered through a plug of Celite and the filtrate was concentrated. Purification via flash chromatography (0-5% MeOH in DCM, 12 g) gave (+/−)-tert-butyl (2-chloro-5-cyano-3-(8-methyl-9-oxohexahydro-1H-pyrazino[1,2-a]pyrazin-2(6H)-yl)phenyl)carbamate (60 mg) as a yellow oil.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:30]=[CH:31][CH:32]=1)[CH2:10][CH:11]1[C:18]2[CH:17]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[N:15](C(OC(C)(C)C)=O)[C:14]=2[CH2:13][CH2:12]1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>C1COCC1.FC(F)(F)C(O)=O>[C:6]([C:7]1[CH:8]=[C:9]([CH:30]=[CH:31][CH:32]=1)[CH2:10][CH:11]1[C:18]2[CH:17]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[NH:15][C:14]=2[CH2:13][CH2:12]1)#[CH:5]
Reactant: COC(=O)c1cc2c(n1C(=O)OC(C)(C)C)CCC2Cc1cccc(C#C[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: C#Cc1cccc(CC2CCc3[nH]c(C(=O)OC)cc32)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The title compound was synthesized in two steps. First, BOC protected methyl 4-(3-bromobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (1-tert-butyl 2-methyl 4-(3-bromobenzyl)-5,6-dihydrocyclopenta[b]pyrrole-1,2(4H)-dicarboxylate) (0.101 g, 0.23 mmol) was coupled with ethynyltrimethylsilane (0.065 mL, 0.46 mmol) according to General Procedure 9.4 to give 1-tert-butyl 2-methyl 4-(3-((trimethylsilyl)ethynyl)benzyl)-5,6-dihydrocyclopenta[b]pyrrole-1,2(4H)-dicarboxylate. The trimethylsilyl group and BOC group were then removed. 1-tert-butyl 2-methyl 4-(3-((trimethylsilyl)ethynyl)benzyl)-5,6-dihydrocyclopenta[b]pyrrole-1,2(4H)-dicarboxylate (0.061 g, 0.135 mmol) was dissolved in anhydrous THF (2 mL), and tetrabutylammoniumfluoride (0.68 mL of 1 M solution in THF, 0.68 mmol) was added, and the reaction was stirred at ambient temperature for 5 min. The reaction was heated to 60° C. and stirred for 3 h, after which 2 drops of trifluoroacetic acid was added. The reaction was stirred at 60° C. for 18 h; then allowed to cool to ambient temperature. Aqueous ammonium chloride was added and the product extracted two times with ethyl acetate. The organic layer was dried over Na2SO4, concentrated and purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-20% EtOAc/heptane to afford both the title compound (methyl 4-(3-ethynylbenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) as well as N-BOC product (1-tert-butyl 2-methyl 4-(3-ethynylbenzyl)-5,6-dihydrocyclopenta[b]pyrrole-1,2(4H)-dicarboxylate). (0.014 g and 0.016 g, respectively). 1H NMR (400 MHz, ACETONE-d6) δ ppm 2.06-2.14 (m, 1H) 2.47-2.58 (m, 1H) 2.58-2.74 (m, 2H) 2.80 (d, J=7.42 Hz, 2H) 3.25-3.33 (m, 1H) 3.60 (s, 1H) 3.71 (s, 3H) 6.27-6.30 (m, 1H) 7.23-7.39 (m, 4H) 10.48 (br. s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[N:18]2[CH2:23][CH2:22][CH:21]([NH:24][CH3:25])CC2)=[CH:4][CH:3]=1.[N:26]#[C:27][NH2:28].[C:29]([OH:32])(=[O:31])[CH3:30]>C(Cl)Cl>[C:29]([OH:32])(=[O:31])[CH3:30].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[N:18]2[CH2:30][CH2:29][CH:21]([N:24]([CH3:25])[C:27]([NH2:28])=[NH:26])[CH2:22][CH2:23]2)=[CH:6][CH:7]=1
Reactant: N#CN
Reactant: CNC1CCN(c2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C(=N)N)C1CCN(c2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 135 °C

Procedure:
A mixture of 10.1 g (0.03 mole) of 1-[1-[(4-fluorophenyl)methyl]-2(1H)-benzimidazolyl]-N-methyl-4-piperidinamine with 1.4 g (0.032 mole) of cyanamide and 1.8 g (0.03 mole) of acetic acid is heated to 135° C. for 1.5 hours. The mixture is cooled and it is then taken up with methylene chloride under reflux, and the precipitate is filtered off and then dried. N-[1-[1-[(4-fluorophenyl)methyl]-2(1H)-benzimidazolyl]-4-piperidinyl]-N-methylguanidine acetate is thus obtained.