Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:6]1[CH2:11][CH2:10][N:9]2[N:12]=[C:13]([NH2:15])[CH:14]=[C:8]2[CH2:7]1)[CH3:5].Br[C:17]1[C:18](=[O:25])[N:19]([CH3:24])[CH:20]=[C:21]([Br:23])[CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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].O1CCOCC1>[Br:23][C:21]1[CH:22]=[C:17]([NH:15][C:13]2[CH:14]=[C:8]3[CH2:7][N:6]([CH:4]([CH3:5])[CH2:3][O:2][CH3:1])[CH2:11][CH2:10][N:9]3[N:12]=2)[C:18](=[O:25])[N:19]([CH3:24])[CH:20]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: COCC(C)N1CCn2nc(N)cc2C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COCC(C)N1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (40 mL), 300b (400 mg, 1.9 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (H-001) (508 mg, 1.9 mmol), and cesium carbonate (1.24 g, 3.8 mmol). After bubbling nitrogen through the suspension for 20 minutes, xantphos (109 mg, 0.19 mmol) and Pd2(dba)3 (87 mg, 0.095 mmol) were added. The system was subjected to three cycles of vacuum/argon flush and heated at reflux for 5 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (2×30 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80/1 to 30/1) to afford 300c (436 mg, 58%) as yellow solid. MS-ESI: [M+H]+ 396.0
Reaction SMILES: [C:1]([O:4][CH2:5][C@:6]1([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:14][CH:9](OC(=O)C)[C@H:8]([O:15][C:16](=[O:18])[CH3:17])[C@@H:7]1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2].[C:36]([NH:44][C:45]1[N:53]=[CH:52][N:51]=[C:50]2[C:46]=1[NH:47][CH:48]=[N:49]2)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>ClCCl>[C:16]([O:15][C@@H:8]1[C@H:7]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:14][C@H:9]1[N:49]1[CH:48]=[N:47][C:46]2[C:50]1=[N:51][CH:52]=[N:53][C:45]=2[NH:44][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:18])[CH3:17]
Reactant: O=C(Nc1ncnc2nc[nH]c12)c1ccccc1
Reactant: CC(=O)OC[C@]1(COCc2ccccc2)OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
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: ClCCl
Product: CC(=O)OC[C@]1(COCc2ccccc2)O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Temperature: 25 °C

Procedure:
To a stirred suspension of the anomeric mixture 33 (5.0 g, 10.3 mmol) and 6-N-benzoyladenine (3.76 g, 15.7 mmol) in anhydrous dichloromethane (200 cm3) was added N,O-bis(trimethylsilyl)acetamide (15.54 cm3, 61.8 mmol). The reaction mixture was stirred at reflux for 1 h and then cooled to room temperature. Trimethylsilyl triflate (7.0 cm3, 38.7 mmol) was added dropwise and the mixture was refluxed for 20 h. The reaction mixture was allowed to cool to room temperature and the volume of the mixture was reduced to ¼ under reduced pressure. Dichloromethane (250 cm3) was added, and the solution was washed with a saturated aqueous solution of sodium hydrogencarbonate (3×50 cm3) and water (50 cm3). The organic phase was dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (99.5:0.5, v/v) as eluent to give nucleoside 58 as white solid material (3.65 g, 52%). δH (CDCl3) 9.25 (1H, br s, NH), 8.71 (1H, s, 8-H), 8.24 (1H, s, 2-H), 8.0 (2H, d, J 7.5, Bz), 7.60-7.23 (13H, m, Bn, Bz), 6.35 (1H, d, J 4.6, 1′-H), 5.99 (1H, dd, J 4.9, 5.3, 2′-H), 4.78 (1H, d, J 5.6, 3′-H), 4.64-4.42 (5H, m, Bn, 1″-Ha), 4.25 (1H, d, J 12.1, 1″-Hb), 3.72 (1H, d, J 10.1, 5′-Ha), 3.56 (1H, d, J 10.1, 5′-Hb), 2.07 (3H, s, COCH3), 2.02 (3H, s, COCH3). δC (CDCl3) 170.42, 169.72 (COCH3), 164.60 (NHCO), 152.51 (C-6), 151.45 (C-2), 149.46 (C-4), 141.88 (C-8), 137.04, 137.00, 133.50, 132.60, 128.86, 128.66, 128.53, 128.41, 128.38, 128.18, 128.06, 127.91, 127.88, 127.79, 127.63, 123.26 (Bz, Bn, C-5), 86.38 (C-1′), 86.25 (C-4′), 77.74, 74.74, 74.44, 73.48 (C-2′, C-3′, 2×Bn), 70.11 (C-1″), 63.42 (C-5′), 20.70, 20.54 (COCH3). FAB-MS m/z 666 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15]C3CCCCO3)[C:9]=2[O:8][CH:7]=1.Br[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CN(C=O)C.O>[C:26]1([CH2:25][CH2:24][CH2:23][O:3][CH2:4][CH2:5][C:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[C:14]([OH:15])[C:9]=3[O:8][CH:7]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCCCc1ccccc1
Reactant: OCCc1coc2c(OC3CCCCO3)cccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1cccc2c(CCOCCCc3ccccc3)coc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
Sodium hydride (60%, 27 mg) was suspended in DMF (1 ml) and the obtained suspension was cooled to 0° C. To this solution, a solution of 3-(2-hydroxyethyl)-7-tetrahydropyranyloxybenzofuran (118 mg) in DMF (0.5 ml) was added dropwise and the obtained mixture was stirred at 0° C. for 10 minutes. To this solution, 1-bromo-3-phenyl-propane (0.27 ml) was added and the solution was stirred at 0° C. for 1 hour and then at room temperature for 45 hours. A catalytic amount of concentrated hydrochloric acid was added to the reaction solution and the solution was stirred for 2 hours. The reaction solution was poured into water layer (30 ml) and the resultant was extracted twice with ethyl acetate (15 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=3/1) using silica gel to obtain the desired compound (106 mg, yield: 80%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1F)[CH2:3][OH:4].O1CCOCC1.CC([O-])(C)C.[K+].Cl>C(O)C>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH2:5][C@H:2]([NH2:1])[CH2:3]1
Reactant: N[C@H](CO)CSc1ccccc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: C1COCCO1
Product: N[C@@H]1COc2ccccc2SC1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
In a round-bottom flask maintained under an inert atmosphere, 3.55 g (17.6 mmoles) of (2R)-2-amino-3-[(2-fluorophenyl)sulfanyl]propan-1-ol (4a-1) and 71 mL of dioxane are introduced. The solution is cooled to 0° C. then 9.90 g (88.2 mmoles) of potassium tert-butylate is added in portions, followed by stirring at ambient temperature for 12 hours. The mixture is then concentrated under reduced pressure and the residue taken up with water then extracted with ethyl acetate. The combined organic phases are washed with water, then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The brown oil thus obtained is taken up with a solution of 2.2 N HCl in ethanol (10.9 mL). The mixture is concentrated under reduced pressure and the chlorhydrate of the title compound is precipitated with the addition of isopropyl ether. The solid is filtered, washed with isopropyl ether, then dried under vacuum. The chlorhydrate of the title compound is obtained in the form of a solid cream (2.73 g, 12.5 mmoles).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C(=O)(O)[O-].[Na+].C(Cl)Cl.CO>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH3:27])[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: Cc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccccc3C)cc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 100 °C
Yield: 67.6 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indazole-4-carboxamide (120 mg, 0.29 mmol) and [(2-methylphenyl)boronic acid (58.6 mg, 0.43 mmol) in dioxane/water (3 mL: 1 mL). PdCl2(dppf)-CH2Cl2 (11.74 mg, 0.014 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (72.5 mg, 0.86 mmol) was added and the insoluble mixture was heated in a microwave at 100° C. for 15 min. DCM/MeOH (1:1) was added, it was pre-absorbed on silica gel and purified by SiO2 chromatography (eluent: gradient 100% DCM to 80:20:2 DCM/MeOH/NH4OH). Fractions were evaporated. EtOAc was added along with some hexanes, it was sonicated and the solids that precipitated were filtered and dried to afford the title compound (84 mg, 66%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (s, 1H) 8.55 (t, J=4.80 Hz, 1H) 8.41 (s, 1H) 7.80 (s, 1H) 7.55 (d, J=1.01 Hz, 1H) 7.27-7.35 (m, 4H) 5.87 (s, 1H) 5.09 (quin, J=6.57 Hz, 1H) 4.36 (d, J=5.05 Hz, 2H) 2.26 (s, 3H) 2.20 (s, 3H) 2.11 (s, 3H) 1.49 (s, 3H) 1.47 (s, 3H). MS(ES) [M+H]+ 429.1.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([O:9]CC2C=CC=CC=2)=[O:8])[N:4]([C:17](=[O:40])[C@@H:18]([NH:20][C@H:21]([C:30]([O:32]CC2C=CC=CC=2)=[O:31])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:19])[C:3]1=[O:41]>[Pd]>[CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([OH:9])=[O:8])[N:4]([C:17](=[O:40])[C@@H:18]([NH:20][C@H:21]([C:30]([OH:32])=[O:31])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:19])[C:3]1=[O:41]
Reactant: C[C@H](N[C@@H](CCc1ccccc1)C(=O)OCc1ccccc1)C(=O)N1C(=O)N(C)C[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Product: C[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1C(=O)N(C)C[C@H]1C(=O)O
Yield: 79.9 %

Procedure:
4.7 g of benzyl (4S)-1-methyl-3-{(2S)-2-[N-((1S)-1-benzyloxycarbonyl-3-phenylpropyl)amino]propionyl]-2-oxo-imidazolidine-4-carboxylate and 300 mg of palladium black are treated in the same manner as described in Example 1-(2), whereby 2.54 g of (4S)-1-methyl-3-{(2S)-2-[N-((1S)-1-carboxy-3-phenylpropyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylic acid are obtained as colorless crystals. Yield: 79.9%
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[C@@H:10]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:58]([NH2:65])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:24])[C@@H:10]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:12][C:13](=[O:15])[NH:65][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)NCc1ccccc1)C(=O)OCc1ccccc1

Procedure:
To a solution of 1.00 g (S)-2-tert-butoxycarbonylamino-pentanedioic acid 1-benzyl ester in 15 ml DMF were added 1.24 g HATU, 1.1 ml DIPEA and 0.32 ml benzylamine at 0° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[OH:9][CH2:10][CH:11]1[CH2:15][N:14]([CH3:16])[C:13](=[O:17])[CH2:12]1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:9][CH2:10][CH:11]2[CH2:15][N:14]([CH3:16])[C:13](=[O:17])[CH2:12]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CN1CC(CO)CC1=O
Product: CN1CC(COc2ccc(Br)cn2)CC1=O

Procedure:
Prepared from 2,5-dibromopyridine and 4-hydroxymethyl-1-methylpyrrolidine-2-one by the method of Example 10 (b).
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.ClN1C(=O)CCC1=O.[CH2:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]#[CH:20].C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]2[CH:20]=[C:19]([CH2:18][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[O:9][N:8]=2)[CH:3]=1
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: ON=Cc1cccnc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cc(-c2cccnc2)no1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 59.2 %

Procedure:
To a solution of 33 (161 mg, 1.3 mmol) in anhydrous DMF (5 mL) at 0° C. was added N-chlorosuccinimide (202 mg, 1.3 mmol) portionwise over 20 min. The resultant solution was heated to 50° C. and stirred for 50 min. The solution was cooled to room temperature and transferred to a flask containing CH2Cl2 (3 mL). To the solution was added a solution of tert-butyl prop-2-ynylcarbamate (204 mg, 1.3 mmol) in CH2Cl2 (3 mL), the solution was cooled to 0° C. and triethylamine (0.18 mL, 1.3 mmol) was added dropwise, the ice bath was removed and the solution was stirred at ambient temperature for 3 h. To the solution was added saturated aqueous sodium bicarbonate (30 mL), the organic fraction was collected and the aqueous fraction was extracted with CH2Cl2 (2×15 mL), back washed with water (30 mL), and brine (30 mL), dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (EtOAc/Hex, 50/50, Rf=0.16) to afford the title compound 34 (212 mg, 59% yield) as a an off white solid: mp=67-69° C.; 1H NMR (CDCl3) δ 8.93 (br s, 1H), 8.62 (m, 1H), 8.05 (m, 1H), 7.34 (m, 1H), 6.50 (s, 1H); 5.63 (br s, 1H); 4.43 (d, J=6 Hz, 1H), 1.40 (s, 9H); LRMS (ESI) calcd for C14H18N3O3 [M+H]+ 276. found 276.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]([NH:15][C:16]2[S:20][C:19]([NH:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)=[N:18][C:17]=2[C:32]([NH2:34])=[O:33])=[O:14])=[CH:11][CH:10]=1)=[O:7])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[OH:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]2[S:20][C:19]([NH:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)=[N:18][C:17]=2[C:32]([NH2:34])=[O:33])=[O:14])=[CH:35][CH:36]=1)=[O:7]
Reactant: CC(=O)OCC(=O)Nc1ccc(C(=O)Nc2sc(Nc3ccc4ccccc4c3)nc2C(N)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccc(NC(=O)CO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.7 %

Procedure:
To a mixture of 5-[4-(2-acetoxyacetamido)benzamido]-2-(naphthalen-2-ylamino)thiazole-4-carboxamide (0.10 g, 0.20 mmol) in MeOH (10 mL) was added K2CO3 (0.14 g, 0.99 mmol) and 1 drop of water at rt. The mixture was stirred for 16 hrs at rt. The insoluble material was filtered off, and the filtrate was concentrated in vacuo. The resulting solids were collected and washed with Et2O to give 0.008 g (5% yield) of the titled compound.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[C:7]([C:19]([F:22])([F:21])[F:20])[CH:6]=1)C.[OH-].[Na+].Cl>C(O)C>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:23])=[O:3])=[CH:6][C:7]=2[C:19]([F:22])([F:20])[F:21])[CH2:13][CH2:14]1
Reactant: CCOC(=O)c1ccc(CN2CCN(C)CC2)c(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCN(Cc2ccc(C(=O)O)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.4 %

Procedure:
To a solution of 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzoic acid ethyl ester 37 (21 mg, 0.064 mmol) in ethanol (5 mL) was added 2N NaOH (0.318 mL, 0.636 mmol). The resulting mixture was stirred at rt for 2 h. The reaction mixture was acidified with 2N HCl solution and concentrated in vacuo to give the crude 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzoic acid 38 (20 mg, 104%) which was used without further purification.
Reaction SMILES: [CH3:1][Si:2]([CH3:32])([CH3:31])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:30]=[CH:29][C:21]([CH:22]=[CH:23][C:24]([O:26]CC)=[O:25])=[CH:20][CH:19]=1.[OH-].[Na+].O.C(O)C>C(O)(=O)C>[CH3:32][Si:2]([CH3:1])([CH3:31])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:19]=[CH:20][C:21]([CH:22]=[CH:23][C:24]([OH:26])=[O:25])=[CH:29][CH:30]=1
Reactant: CCOC(=O)C=Cc1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C=CC(=O)O)cc1

Procedure:
A mixture of 5.0 g. ethyl 4-aminocinnamate, 9.14 g. of 14-(trimethylsilyl)tetradecyl bromide and 3.6 g. of powdered anhydrous potassium carbonate in hexamethylphosphoramide is heated for 20 hours at 60° C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated to provide ethyl 4-[14-(trimethylsilyl)tetradecylamino]cinnamate. The ester is hydrolyzed with.sodium hydroxide in a 1:9 water:ethanol solution at steam bath temperature for 10 hours. The hot solution is then acidified with acetic acid, cooled and filtered and the solid is washed with water. Recrystallization from chloroform yields the title product as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([CH2:14][CH3:15])[CH2:12][CH:11]([NH:16][C:17]2[N:22]=[CH:21][C:20]([OH:23])=[CH:19][N:18]=2)[CH2:10][CH:9]1[CH2:24][CH3:25])=[O:7])([CH3:4])([CH3:3])C.C(=O)([O-])[O-].[K+].[K+].[CH2:32](N)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C=O)C>[CH:1]([O:5][C:6]([N:8]1[CH:13]([CH2:14][CH3:15])[CH2:12][CH:11]([NH:16][C:17]2[N:18]=[CH:19][C:20]([O:23][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:21][N:22]=2)[CH2:10][CH:9]1[CH2:24][CH3:25])=[O:7])([CH3:3])[CH3:4]
Reactant: NCc1ccccc1
Reactant: CCC1CC(Nc2ncc(O)cn2)CC(CC)N1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC1CC(Nc2ncc(OCc3ccccc3)cn2)CC(CC)N1C(=O)OC(C)C
Reaction time: 2 h
Yield: 171.7 %

Procedure:
To a mixture of 2,6-diethyl-4-(5-hydroxy-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.72 mmol, 580 mg) and potassium carbonate (3.23 mmol, 1.12 g) in DMF (12 mL) is added benzylamine (3.53 mmol, 0.42 mL) at room temperature and stirred for 2 hours. Water is added to the mixture, and the precipitate is collected and washed with hexane to give 4-(5-benzyloxy-pyrimidin-2-ylamino)-2,6-diethylpiperidine-1-carboxylic acid isopropyl ester (1.26 g, 74%) as a colorless solid. To a solution of 4-(5-benzyloxy-pyrimidin-2-ylamino)-2,6-diethylpiperidine-1-carboxylic acid isopropyl ester (2.86 mmol, 1.26 g) in DMF (28 mL) is added sodium hydride (60% oil suspension, 5.72 mmol, 230 mg) at 0° C. and stirred at room temperature for 20 min. To the mixture is added 1-bromomethyl-3,5-bis(trifluoromethyl)benzene (4.29 mmol, 0.79 mL) at 0° C. and stirred at room temperature for 17 hours. To the mixture is added sodium hydride (60% oil suspension, 2.86 mmol, 115 mg) and 1-bromomethyl-3,5-bis(trifluoromethyl)benzene (2.73 mmol, 0.5 mL) at 0° C. and stirred at room temperature for 5 hours. To the mixture is added water, and extracted with EtOAc. The combined organic layer is dried over Na2SO4, filtrated, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give cis-4-[(5-benzyloxy-pyrimidin-2-yl)-(3,5-bis(trifluoromethyl)benzyl)-amino]-2,6-diethylpiperidine-1-carboxylic acid 4-methoxycarbonyl-cyclohexyl ester (880 mg, 46%); ESI-MS m/z: 667 [M+1]+, Retention time 2.69 min (condition A).
Reaction SMILES: I[CH2:2][C:3]([OH:5])=[O:4].[CH3:6][O:7][CH2:8][C:9]1[S:13][C:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:11][N:10]=1.[H-].[Na+]>O1CCCC1>[C:17]([O:16][C:15]([N:14]=[C:12]1[N:11]([CH2:2][C:3]([OH:5])=[O:4])[N:10]=[C:9]([CH2:8][O:7][CH3:6])[S:13]1)=[O:21])([CH3:20])([CH3:19])[CH3:18]
Reactant: COCc1nnc(NC(=O)OC(C)(C)C)s1
Reactant: O=C(O)CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1nn(CC(=O)O)c(=NC(=O)OC(C)(C)C)s1
Temperature: 60 °C
Yield: 89.8 %

Procedure:
Iodoacetic acid (409.3 g, 2.2 mol, 1.5 eq) is added in one portion to a solution of tert-butyl [5-(methoxymethyl)-1,3,4-thiadiazol-2-yl]carbamate a31 (360 g, 1.468 mol, 1 eq) in tetrahydrofurane (3 l) at room temperature. Sodium hydride (52.83 g, 2.2 mol, 1.5 eq) is then added portionwise, in 30 minutes, at room temperature. The reaction mixture is heated at 60° C. for the night, and the solvent is evaporated under reduced pressure. Water is added to the residue, the solution is acidified to pH=2 with aqueous 6N HCl, then extracted with CH2Cl2. The organic layer is washed with 10% aqueous Na2S2O3 (to remove the coloration of iodine) and evaporated to dryness to furnish 455.7 g of {2-[(tert-butoxycarbonyl)imino]-5-(methoxymethyl)-1,3,4-thiadiazol-3(2H)-yl}acetic acid a33 which is used directly in the next step without any further purification.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:28][C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[C:13]([S:19][C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)=[C:14]([CH:16]([CH3:18])[CH3:17])[N:15]=1)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>Cl>[Cl:26][C:24]1[CH:25]=[C:20]([S:19][C:13]2[N:12]([CH2:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[C:11]([CH2:10][CH2:9][OH:8])=[N:15][C:14]=2[CH:16]([CH3:18])[CH3:17])[CH:21]=[C:22]([Cl:27])[CH:23]=1
Reactant: CC(C)c1nc(CCOCc2ccccc2)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)c1nc(CCO)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 100 °C
Yield: 67.3 %

Procedure:
In 12 ml of cocentrated hydrochloric acid was dissolved 2.3 g (4.5 mmol) of the benzyl compound (122b), and the mixture was heated at 100° C. for 4 hours. The mixture was neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (7% methanol/ethyl acetate) to give 1.28 g of 2-[5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridin-4-ylmethyl)-1H-imidazol-2-yl]ethanol (123b) as crystals (yield 67%). mp 121-122° C.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32]>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[O:31][CH3:32])([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: COc1ccccc1Br
Product: COc1ccccc1C1(O)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 43 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 2-bromoanisole, the hydrochloride salt of the title compound was formed in 43% yield as a white solid, mp 290-293 C. elemental