Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C=CC2C=CC=CC=2)C=CC=CC=1.[C:15]1([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25](C(C3C=CC=CC=3)=C)[CH:24]=2)=[CH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C(C2C=CC(C(C3C=CC=CC=3)=C)=CC=2)=C)C=CC=CC=1>>[C:15]1([C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=C(c1ccccc1)c1cccc(C(=C)c2ccccc2)c1
Agent: C(=Cc1ccccc1)c1ccccc1
Agent: C=C(c1ccccc1)c1ccc(C(=C)c2ccccc2)cc1
Product: C=C(c1ccccc1)c1ccccc1

Procedure:
For instance, in accordance with an embodiment of the present inveniton, a living macrocarbocation, e.g., living cationic polyisobutylene, is reacted with a double diphenylethylene, e.g., 1,3-bis(1-phenylethenyl)benzene (sometimes referred to as meta-double diphenylethylene) or 1,4-bis(1-phenylethenyl)benzene (sometimes referred to as para-double diphenylethylene), to produce a 1,1-diphenylethylene end-functionalized carbocationic polymer. The carbocation is then alkylated with a suitable alkylating agent, e.g., with an organometallic compound such as dimethylzinc, whereupon the resulting macromonomer is readily metallated with a suitable organometallic compound such as an alkyllithium compound, thereby providing a living anionic macroinitiator in near quantitative yield. A sterically hindered lithium compound, e.g., a 1,1-diphenylalkyllithium species, is used in certain embodiments to remove impurities that may be present alongside the 1,1-diphenylethylene end-functionalized polymer, thereby preventing premature termination of the living macroanion.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH3:24][NH:25][C:26]1[CH2:30][S:29][C:28](=[O:31])[N:27]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:30]2/[C:26]([NH:25][CH3:24])=[N:27][C:28](=[O:31])[S:29]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.00 g) in 2-propanol (15 mL) were added 4-(methylamino)-1,3-thiazol-2(5H)-one (0.77 g) and piperidinium acetate (0.44 g). The reaction mixture was stirred at 60° C. overnight and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (0.71 g).
Reaction SMILES: C(Cl)(=O)C(C)(C)C.[CH3:8][C:9]([CH3:24])([O:11][C:12]([NH:14][C@@H:15]1[CH2:20][CH2:19][C@H:18]([C:21](O)=[O:22])[CH2:17][CH2:16]1)=[O:13])[CH3:10].[NH3:25]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:9]([O:11][C:12](=[O:13])[NH:14][C@H:15]1[CH2:20][CH2:19][C@@H:18]([C:21](=[O:22])[NH2:25])[CH2:17][CH2:16]1)([CH3:24])([CH3:10])[CH3:8]
Reactant: N
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(N)=O)CC1
Reaction time: 1 h
Yield: 91.8 %

Procedure:
Pivaloyl chloride (0.36 ml, 2.96 mmol) was added to a solution of cis-4-[[(1,1-dimethylethoxy)carbonyl]amino]-cyclohexanecarboxylic acid (600 mg, 2.47 mmol) in CHCl3 (10 ml), triethylamine (0.7 ml) at 0° C. and stirred for 1 h. Then aqueous ammonia was added to the reaction mixture and stirred for 1 h. After completion of reaction, the reaction mixture was diluted with CHCl3 (2×25 ml). The organic layer was washed with saturated sodium bicarbonate solution, brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under vacuum, the crude compound was washed with hexane (2×6 ml) and dried to afford 500 mg (91.8%) of cis-tert-butyl-4-carbamoylcyclohexylcarbamate as white color solid.
Reaction SMILES: N=[N+]=[N-].[N-:4]=[N+]=[N-].[Na+].O.[C@H:9]1(C(O)=O)[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([OH:17])=[O:16])[CH2:10]1>C(Cl)(Cl)Cl.S(=O)(=O)(O)O>[NH2:4][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([OH:17])=[O:16])[CH2:10]1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)[C@@H]1CCC[C@H](C(=O)O)C1
Agent: O=S(=O)(O)O
Agent: [N-]=[N+]=N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: N[C@@H]1CCC[C@H](C(=O)O)C1
Temperature: 0 °C
Yield: 93.9 %

Procedure:
A 7% (w/v) stock solution of hydrazoic acid in CHCl3 (196 ml, 0.32 mol, the stock solution was prepared by adding 400 g of NaN3 into 400 ml of water to CHCl3 (2 l)). Sulfuric acid (167 ml) was added under stirring at 0° C. slowly. The upper CHCl3 layer was decanted, dried over anhydrous sodium sulfate, filtrated and kept in the refrigerator. Titration analysis was done before usage. The solution was added dropwise over a period of 8 h to a solution of cis-cyclohexane-1,3-dicarboxylic acid (50.0 g, 0.29 mol) in a mixture of sulfuric acid (150 ml) and CHCl3 (500 ml) at 35° C. After the completion of addition, the reaction mixture was stirred at 40° C. for 10 h and further stirred at 50° C. for 3 h. The reaction mixture was cooled to room temperature and the acid layer was separated. The acid layer was basified with barium hydroxide to pH˜9 and the suspension was filtered. The filtrate was neutralized with diluted sulfuric acid and the suspension was filtered again. The filtrate was concentrated under vacuo to get the crude compound which was washed with MeOH (30 ml) to get 39.0 g (93.8%) of cis-3-aminocyclohexanecarboxylic acid as solid. [TLC system: 15% MeOH in CHCl3, Rf 0.1].
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:25]=3[NH:24][C:23](=[O:26])[CH:22]=[N:21]4)[CH:10]=2)=[CH:5][CH:4]=1.[C:29]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.O>[CH3:29][N:24]1[C:25]2[C:20](=[CH:19][CH:18]=[CH:17][C:16]=2[O:15][C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:27])([F:1])[F:28])=[CH:4][CH:5]=3)[N:14]=[CH:13][N:12]=2)[N:21]=[CH:22][C:23]1=[O:26]
Reactant: O=C([O-])[O-]
Reactant: O=c1cnc2cccc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c2[nH]1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(=O)cnc2cccc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 8-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-1H-quinoxalin-2-one, (Example 32(e)), (0.10 g, 0.26 mmol) and K2CO3 (0.043 g, 0.31 mmol, Aldrich) in DMF (1 mL) was added iodomethane (0.019 mL, 0.31 mmol, Aldrich). The mixture was stirred at room temperature for 20 h, diluted with water and extracted with 25% i-PrOH/CHCl3 (3×). After being concentrated in vacuum, the residue was purified by flash chromatography (0→2% 2M NH3 in MeOH/CH2Cl2) to afford the title compound as an off-white amorphous solid. Mp: 158° C. MS (ESI, pos. ion) m/z: 399 (M+1).
Reaction SMILES: C(Cl)(=O)C.C(O[C:10]([N:12](C)[CH:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH2:34][C:35]2[CH:36]=[C:37]([C:43]3[CH:48]=[CH:47][N:46]=[C:45]([C:49]([O:51][CH3:52])=[O:50])[CH:44]=3)[CH:38]=[CH:39][C:40]=2[O:41][CH3:42])[C:20]([C:22]2[S:26][C:25]3[C:27]([F:32])=[CH:28][CH:29]=[C:30]([F:31])[C:24]=3[C:23]=2[Cl:33])=[O:21])[CH2:15][CH2:14]1)=O)(C)(C)C>CO>[Cl:33][C:23]1[C:24]2[C:30]([F:31])=[CH:29][CH:28]=[C:27]([F:32])[C:25]=2[S:26][C:22]=1[C:20]([N:19]([CH2:34][C:35]1[CH:36]=[C:37]([C:43]2[CH:48]=[CH:47][N:46]=[C:45]([C:49]([O:51][CH3:52])=[O:50])[CH:44]=2)[CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH:16]1[CH2:17][CH2:18][CH:13]([NH:12][CH3:10])[CH2:14][CH2:15]1)=[O:21]
Reactant: COC(=O)c1cc(-c2ccc(OC)c(CN(C(=O)c3sc4c(F)ccc(F)c4c3Cl)C3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2)ccn1
Solvent: CC(=O)Cl
Solvent: CO
Product: CNC1CCC(N(Cc2cc(-c3ccnc(C(=O)OC)c3)ccc2OC)C(=O)c2sc3c(F)ccc(F)c3c2Cl)CC1
Reaction time: 2 h

Procedure:
Acetyl chloride (5 mL) is added to anhydrous MeOH (10 mL) at 0° C. tert-Butyl carbamate 148 (247 mg, 0.35 mmol) is then treated with this solution and stirred 2 h. On removal of the solvents in vacuo, the reaction mixture is dissolved in DCM (25 mL) and extracted into 2 M HCl (4×10 mL). The combined HCl phases are washed with DCM (2×20 mL) then taken to pH 9 by careful addition of solid NaHCO3. The resultant aqueous suspension is then extracted into DCM (3×20 mL), the combined DCM phases dried (Na2SO4) and reduced in vacuo to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:19]([O:21]CC)=[O:20])[C:5]([CH3:18])=[C:6]2[C:11]=1[S:10](=[O:13])(=[O:12])[CH2:9][CH2:8][C:7]12[O:17][CH2:16][CH2:15][O:14]1.[OH-].[Na+]>C(O)C.O.[Zn]>[C:19]([C:4]1[C:5]([CH3:18])=[C:6]2[C:11](=[CH:2][CH:3]=1)[S:10](=[O:13])(=[O:12])[CH2:9][CH2:8][C:7]12[O:17][CH2:16][CH2:15][O:14]1)([OH:21])=[O:20]
Reactant: CCOC(=O)c1cc(Cl)c2c(c1C)C1(CCS2(=O)=O)OCCO1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)ccc2c1C1(CCS2(=O)=O)OCCO1
Temperature: 60 °C
Yield: 70.5 %

Procedure:
28 Grams (77 mmol) of 8-chloro-6-ethoxycarbonyl-4,4-ethylenedioxy-5-methylthiochroman-1,1-dioxide was dissolved in 100 ml of ethanol, and 13.6 g (208 mmol) of a zinc powder was added. Further, a solution of 27 g (400 mmol) of sodium hydroxide in 50 ml of water and 50 ml of ethanol was added, and then the mixture was stirred under heat at 60° C. for 6 hours. After the completion of the reaction, an insoluble solid was removed by filtration, and an aqueous layer was washed with methylene chloride. The aqueous layer was acidified with a 5 wt % hydrochloric acid aqueous solution and extracted with ethyl acetate, and an organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 16.2 g (yield 69%) of the titled compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[C:7](=[O:9])[CH:8]=1.C1[CH2:35][O:34][CH2:33]C1.[H-].[Na+].ClCOC>O>[CH3:33][O:34][CH2:35][O:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[C:7](=[O:9])[CH:8]=1
Reactant: C1CCOC1
Reactant: O=c1cc(CO)occ1OCCCCCSc1ccnc2cc(C(F)(F)F)ccc12
Agent: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCOCc1cc(=O)c(OCCCCCSc2ccnc3cc(C(F)(F)F)ccc23)co1
Reaction time: 0.08 h
Yield: 67 %

Procedure:
2-Hydroxymethyl-5-[5-(7-trifluoromethyl-quinolin-4-ylsulfanyl)-pentyloxy]-4H-pyran-4-one EHT 5909 (0.10 g, 0.227 mmol) was charged in a 25 mL three necked round bottom flask equipped with a magnetic stirrer and under a nitrogen atmosphere. THF (6 mL) and NaH (60% dispersion in oil, 10 mg, 0.25 mmol) were added at room temperature. After the reaction mixture was stirred for 5 min, methyl choromethyl ether (18.1 μl, 0.24 mmol, 1.05 eq.) was added via syringe and the reaction mixture was stirred for 2 h 30 at room temperature. The reaction mixture was poured in H2O (60 mL) and extracted with EtOAc (3×20 mL). The organic layer was dried over MgSO4, filtered and evaporated in vacuo. The crude product was purified by chromatography on silica using as eluent MeOH:CH2Cl2=2:98. After evaporation and drying to the vacuum pump a white pale yellow solid EHT 2168 was obtained (74 mg, 67% yield).
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[O:7]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][C:15]([C:17]([NH:19][CH2:20][C:21]3[CH:30]=[CH:29][C:24]([C:25](OC)=[O:26])=[CH:23][CH:22]=3)=[O:18])=[C:14]([C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=3)[CH:13]=2)=[CH:8]1.O>CO.C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1.C(O)(=O)C>[O:7]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][C:15]([C:17]([NH:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH:2][OH:3])=[O:26])=[CH:29][CH:30]=3)=[O:18])=[C:14]([C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=3)[CH:13]=2)=[CH:8]1
Reactant: COC(=O)c1ccc(CNC(=O)c2[nH]c(-c3ccoc3)cc2-c2ccc(O)cc2)cc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NO)c1ccc(CNC(=O)c2[nH]c(-c3ccoc3)cc2-c2ccc(O)cc2)cc1
Reaction time: 26 h
Yield: 93.9 %

Procedure:
To a solution of hydroxylamine hydrochloride (0.48 g, 7.5 mmol) and phenolphtalein (1 mg) in methanol (1.25 ml) under inert atmosphere, an aliquot of sodium methoxide in methanol (taken from a solution of 2.70 g, 50 mmol of sodium methoxide in 10 ml of methanol) was added dropwise until a permanent pink color was observed. Methyl 4-[({[5-(3-furyl)-3-(4-hydroxyphenyl)-1H-pyrrol-2-yl]carbonyl}amino)methyl]benzoate (0.52 g, 1.25 mmol) and sodium methoxide in methanol (12.5 mmol, 2.46 ml of the previously prepared solution) were subsequently added. The reaction mixture was stirred for 26 h, the formation of a dense precipitate being observed. Water (3 ml) was added, and this solution was acidified with glacial acetic acid and extracted with CH2Cl2 (3×10 ml). The combined organic fractions were dried over Na2SO4 and evaporated under reduced pressure, to obtain 0.49 g of 5-(3-furyl)-N-{4-[(hydroxyamino)carbonyl]benzyl}-3-(4-hydroxyphenyl)-1H-pyrrole-2-carboxamide: Yield 94%; m.p. 159-160° C.; IR 3406, 3243, 1626, 1526, 1268 cm−1; 1H-NMR (500 MHz, δ ppm, DMSO-d6) 11.50 (s, 1H), 11.13 (s, 1H), 9.36 (s, 1H), 8.94 (s, 1H), 8.13 (s, 1H), 7.69 (d, J=8.1 Hz, 2H), 7.67 (tb, 1H), 7.34 (t, J=5.7 Hz, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 6.93 (s, 1H), 6.74 (d, J=8.4 Hz, 2H), 6.37 (d, J=2.5 Hz, 1H), 4.41 (d, J=5.8 Hz, 2H); 13C-NMR (126 MHz, δ ppm, DMSO-d6) 164.0, 161.2, 156.3, 143.6, 142.6, 138.5, 131.2, 129.9, 127.4; 127.1, 126.8, 125.9, 121.3, 118.2, 115.1, 108.7, 108.3, 42.0.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][O: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.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:30][C@H:31]1[CH2:35][CH2:34][CH2:33][NH:32]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:32]2[CH2:33][CH2:34][CH2:35][C@@H:31]2[CH3:30])[C:5]2[CH2:10][O: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: Fc1ccc(C2OCc3c(Cl)nc(Cl)nc32)cc1
Reactant: C[C@H]1CCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C[C@H]1CCCN1c1nc(Cl)nc2c1COC2c1ccc(F)cc1

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine (Preparation M) was reacted as described in Preparation Hp1 and Hp2 with (S)-2-methylpyrrolidine p-toluenesulfonate salt to afford 2-chloro-7-(4-fluorophenyl)-4-((S)-2-methylpyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidine (Preparation Me) as a mixture of 2 diasteriomers. LC-MS (M+H)+=334.1.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[N:14]=[CH:15][C:8]=12.[H-].[Na+].[S:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[NH:35][C:36]([C:38]1[CH:39]=[CH:40][CH:41]=[C:42]2[C:47]=1[CH2:46][N:45]([C:48]1[S:49][C:50]([CH2:58][CH2:59][CH2:60]I)=[C:51]([C:53]([O:55]CC)=[O:54])[N:52]=1)[CH2:44][CH2:43]2)=[O:37].[OH-].[Na+].C(O)(C(F)(F)F)=O>CN(C=O)C.O.CO>[S:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[NH:35][C:36]([C:38]1[CH:39]=[CH:40][CH:41]=[C:42]2[C:47]=1[CH2:46][N:45]([C:48]1[S:49][C:50]([CH2:58][CH2:59][CH2:60][O:22][C:19]3[CH:18]=[CH:17][C:16]([N:13]4[C:9]5=[N:10][CH:11]=[N:12][C:7]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:23])=[C:8]5[CH:15]=[N:14]4)=[CH:21][CH:20]=3)=[C:51]([C:53]([OH:55])=[O:54])[N:52]=1)[CH2:44][CH2:43]2)=[O:37]
Reactant: CN(C)CCCNc1ncnc2c1cnn2-c1ccc(O)cc1
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCI
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCCNc1ncnc2c1cnn2-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Reaction time: 0.17 h

Procedure:
To a solution of compound 54A (160 mg, 0.512 mmol) in DMF (5 ml) was added sodium hydride (102 mg, 2.56 mmol)(60%). The reaction mixture was stirred for 10 min and Example 2C (194 mg, 0.307 mmol) was added. The resulting mixture was stirred for 1 hour and methanol (3 ml), 10% NaOH (3 ml) and water (1 ml) were added. The resulting mixture was stirred overnight, acidified with TFA and concentrated. The residue was dissolved in a mixture of DMSO-methanol and purified by reverse phase HPLC (mobile phase: 0%-55% acetonitrile in 0.1% TFA aqueous solution during 60 min) to provide the title compound: 1H NMR (400 MHz, DMSO-D6) δ ppm 12.84 (1H, s), 9.34 (1H, s), 8.53 (1H, t), 8.36 (1H, s), 8.32 (1H, s), 7.96-8.03 (3H, m), 7.78 (1H, d), 7.67 (1H, d), 7.42-7.49 (2H, m), 7.32-7.41 (2H, m), 7.05-7.10 (2H, m), 4.84 (2H, s), 4.04 (2H, t), 3.73 (2H, t), 3.60 (2H, q), 3.12-3.26 (4H, m), 3.03 (2H, t), 2.80 (6H, s), 1.93-2.08 (4H, m). LCMS (APCI) m/e 789 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]=[C:5]1[CH2:8][CH:7]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]1[CH2:6][CH:7]([NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:8]1
Reactant: COC(=O)C=C1CC(NC(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC1CC(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To a solution of (3-tert-Butoxycarbonylamino-cyclobutylidene)-acetic acid methyl ester (7 g, 29 mmol) in methanol (100 mL) was added Pd/C (5 g) and stirred at room temperature under H2 balloon overnight. After TLC showed the reaction was completed, the mixture was filtered over Celite. The filtrate was concentrated under reduced pressure to give the title compound (7 g, yield 99%) as a white solid, which was used for the next step directly without further purification.
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=3)[C:33]2=[O:48])[S:27][C:28]=1[C:29]([OH:31])=O.[NH2:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1>>[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:45])([F:46])[F:47])[CH:39]=3)[C:33]2=[O:48])[S:27][C:28]=1[C:29]([NH:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1)=[O:31]
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3cccc(C(F)(F)F)c3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3cccc(C(F)(F)F)c3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 81 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(3-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 81% yield: mp 175-176° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) 8.58 (s, 1H), 8.50 (d, J=4.8 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.61-7.54 (m, 1H), 7.53-7.44 (m, 3H), 7.29-7.21 (m, 1H), 6.21 (t, J=5.6 Hz, 1H), 4.57 (d, J=5.6 Hz, 2H), 4.51 (s, 2H), 4.14-4.02 (m, 2H), 3.52-3.41 (m, 2H), 2.59 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.6, 157.2, 155.5, 153.7, 149.3, 149.0, 136.7, 135.6, 133.9, 131.6, 131.5, 131.1, 129.5, 125.0, 124.9, 123.6, 117.1, 47.7, 42.0, 41.9, 41.4, 17.3; MS (ES+) m/z 476.4 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:20][CH2:19][C:18]([CH:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[OH:22])=[CH:17][CH2:16]2)=[CH:10][CH:9]=1.[F:33][C:34]1[CH:35]=[C:36]([N:41]=[C:42]=[O:43])[CH:37]=[C:38]([F:40])[CH:39]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:33][C:34]1[CH:35]=[C:36]([NH:41][C:42]([O:22][CH:21]([C:18]2[CH2:19][CH2:20][N:15]([CH2:14][C:11]3[CH:12]=[CH:13][C:8]([O:7][C:2]4[N:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:9][CH:10]=3)[CH2:16][CH:17]=2)[C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=2)=[O:43])[CH:37]=[C:38]([F:40])[CH:39]=1
Reactant: O=C=Nc1cc(F)cc(F)c1
Reactant: OC(C1=CCN(Cc2ccc(Oc3ncccn3)cc2)CC1)c1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cc(F)cc(F)c1)OC(C1=CCN(Cc2ccc(Oc3ncccn3)cc2)CC1)c1ccc(C(F)(F)F)cc1
Yield: 30.2 %

Procedure:
This compound was prepared in a manner analogous to that of Step F of Example 2, using 0.44 gram (0.0010 mole) of {1-[(4-pyrimidin-2-yloxyphenyl)methyl](4-1,2,5,6-tetrahydropyridyl)}[4-(trifluoromethyl)phenyl]methanol, 0.21 gram (0.0014 mole) of 3,5-difluorophenylisocyanate, 0.14 gram (0.0014 mole) of triethylamine, and 0.05 gram (catalyst) of 4-dimethylaminopyridine in 15 mL of methylene chloride. The reaction product was purified with column chromatography on silica gel using 10% to 25% acetone/methylene chloride mixtures as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.18 gram of Compound 786, mp 85–92° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C([Cl:15])=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([Cl:15])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(F)cc(Cl)c1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(F)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3-Chloro-5-fluorobenzoic acid (400 mg, 2.3 mmol) was treated with a solution of oxalyl chloride (4.6 mL of 2.5 M in dichloromethane, 11.5 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred at ambient temperature for 2.5 hours. The excess oxalyl chloride was removed in vacuo to afford 3-chloro-5-fluorobenzoyl chloride.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:16][Si:17](Cl)([CH3:19])[CH3:18]>>[CH2:1]([NH:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Si:17]([CH3:19])([CH3:18])[CH3:16])=[O:5])[CH3:2]
Reactant: CCNC(=O)c1cccc2ccccc12
Reactant: C[Si](C)(C)Cl
Product: CCNC(=O)c1c([Si](C)(C)C)ccc2ccccc12
Yield: 58 %

Procedure:
N-Ethyl-1-naphthalenecarboxamide was reacted with 2 eq TMSCl according to General Method C. The resulting reaction mixture was worked up in the usual manner, then purified by recrystallization from cold ethyl acetate/hexanes to afford 1.6 g of desired compound as a white solid, a 58% yield. m.p. 141-143° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:21][C:22](O)=[O:23])[CH:18]=2)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30]>>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:21][C:22]([NH:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:23])[CH:18]=2)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCCN
Reactant: O=C(O)Cc1ccc2c(c1)CC(NC(=O)OCc1ccccc1)C2
Product: COC(=O)CCCNC(=O)Cc1ccc2c(c1)CC(NC(=O)OCc1ccccc1)C2

Procedure:
In the same manner as described in Example 1-(1), 2-(benzyloxycarbonylamino)indan-5-acetic acid and methyl γ-aminobutyrate are reacted to give methyl 4-[(2-benzyloxycarbonylaminoindan-5-yl)acetylamino]-n-butyrate.