Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[NH:21][C:22]([C:24]2[CH:32]=[C:31]([Cl:33])[C:30]([Cl:34])=[CH:29][C:25]=2[C:26]([OH:28])=[O:27])=[O:23])=[CH:6][CH:5]=1.[N:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.CCN(CC)CC>C1COCC1>[Cl:33][C:31]1[C:30]([Cl:34])=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([C:22]([NH:21][C:12]2[CH:13]=[C:14]([C:17]([F:19])([F:20])[F:18])[CH:15]=[CH:16][C:11]=2[NH:10][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:41]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:42])=[CH:9][CH:8]=2)=[O:23])[CH:32]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: NCc1ccc(Nc2ccc(C(F)(F)F)cc2NC(=O)c2cc(Cl)c(Cl)cc2C(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)c(Cl)cc1C(=O)Nc1cc(C(F)(F)F)ccc1Nc1ccc(CNC(=O)N2CCOCC2)cc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
Into a vial are placed 2-({[2-{[4-(aminomethyl)phenyl]amino}-5-(trifluoromethyl)phenyl]amino}carbonyl)-4,5-dichlorobenzoic acid hydrochloride (100 mg, 0.187 mmol), 4-morpholine-carbonylchloride (28 mg, 0.187 mmol), Et3N (0.08 mL, 0.573 mmol), and THF (10 mL). The mixture is heated with efficient stirring at 40° C. for 4 h. The solution is concentrated and purified by preparative thin layer chromatography. The yield is 31 mg of 4,5-dichloro-2-({[2-[(4{[(morpholin-4-ylcarbonyl)amino]methyl}phenyl)amino]-5-(trifluoromethyl)phenyl]amino}carbonyl)benzoic acid, 27%. 1H NMR (400 MHz, DMSO-d6): □ 13.88 (s, 1 H), 10.14 (s, 1 H), 8.09 (s, 2 H), 7.77 (s, 1 H), 7.70 (s, 1 H), 7.44-7.42 (m, 1 H), 7.26-7.23 (m, 3 H), 7.14-7.09 (m, 3 H), 4.22-4.21 (m, 2 H), 3.56-3.54 (m, 4 H), 3.30-3.28 (m, 4 H) 7.44-7.42 (m, 1 H), 7.26-7.23 (m, 3 H), 7.14-7.09 (m, 3 H), 4.22-4.21 (m, 2 H), 3.56-3.54 (m, 4 H), 3.30-3.28 (m, 4 H). HRMS for C27H23Cl2F3N4O5 m/z 611.1071 M+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][C:9](=[O:10])[C:5](=[C:6]([CH3:8])[CH3:7])[CH2:4][CH2:3]1.[CH:12]([N-]C1CCCCC1)(C)C.[Li+].CI>>[CH3:12][CH:11]1[CH:2]([CH3:1])[CH2:3][CH2:4][C:5](=[C:6]([CH3:7])[CH3:8])[C:9]1=[O:10]
Reactant: CC(C)=C1CC[C@@H](C)CC1=O
Reactant: CC(C)[N-]C1CCCCC1
Agent: [Li+]
Solvent: CI
Product: CC(C)=C1CCC(C)C(C)C1=O
Yield: 72 %

Procedure:
The regioisomeric problem upon fragmentation of the tosylhydrazone (i.e., production of mix 74/75) was overcome by increased substitution for increased selectivity. Therefore 3R-pulegone was used as a starting material for synthesis (Scheme VIII). The enolate of pulegone was generated with lithium isopropylcyclohexylamide (LICA) and alkylated with methyl iodide to furnish mainly 2,3-dimethyl-6-isopropylidene cyclohexanone 78 along with by-product 79, ##STR51## which was previously observed by Reusch et al., (Lee, R. A., McAndrews, C., Patel, K. M., and Reusch, W. Tetrahedron Lett. 965 (1973)) but 79 did not react in the following conversion of crude material. When the mixture containing the isopropylidene 78 was placed in acid and submitted to prolonged heating, acetone distilled prior to the water azeotrope of the epimeric mix of 80:81 (1:1.96, as determined by NMR) in 72% yield. The corresponding tosylhydrazone mix 82 from the mix of 80:81 was made as before and underwent n-butyllithium-effected fragmentation in TMEDA to a regioisomerically pure cyclohexenyl anion, which was capped with dimethylformamide to afford isomeric aldehydes 83 in 76% yield. The mix was treated with tris(trimethylsilyl)aluminum (III) etherate (L. Rosch and G. Altman, J. Organomet. Chem., 195, 47 (1980).It should be noted that this procedure has failed to work in our hands, as well as others: See B. Trost, J. Yoshida, and M. Lautens, J. Amer. Chem. Soc., 105, 4494 (1983). However, a procedure which works is provided in the experimental. The reagent can be titrated as described or by reaction with peperonal: L. Rosch, G. Altman, and W. Otto, Angew. Chem. Int. Ed. Engl., 20 581 (1981)) and followed by acetylation to provide a mixture of all possible diastereomers of 84. The lack of selectivity was surprising in contrast to the total synthesis of QHS, in which a synthetic intermediate substrate differs in the presence of a 6'-methyl instead of a larger alkyl chain. Regardless, the mixture 84 upon exposure to lithium diethylamide rearranged to a mixture of diastereomeric cyclohexylacetic acids, which upon rigorous chromatographic separation furnished geometric isomers of acid 85 in a 1:1 ratio by NMR, in 28% yield. The acid 85 was submitted to single-pot exposure to ozone and acidification to give trioxane 30 in 22% yield. Alternatively the acid 85 was methylated via the corresponding LDA-generated dianion to the propionic acid 86, which was subsequently reacted with ozone and acidified to provide trioxane 31. The two optically active trioxanes 30 and 31 have been assessed for their antimalarial activity. In addition, all three optically active trioxanes, 29, 30 and 31, display temperature-dependent NMR behavior. ##STR52##
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.[H][H]>CO.[Pd]>[CH3:11][C:10]1[CH:9]=[CH:8][C:7]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:2]=1[OH:1]
Reactant: [H][H]
Reactant: Cc1ccc2c(c1O)CCC2=O
Agent: [Pd]
Solvent: CO
Product: Cc1ccc2c(c1O)CCC2
Reaction time: 5 h
Yield: 82.1 %

Procedure:
To a suspension of 4-Hydroxy-5-methyl-indan-1-one (8 gm) in Methanol (80 ml), added 10% w/w Pd—C. Hydrogenation was carried out for 5 hours at 55-60° C. in an autoclave at 200-250 psi using Hydrogen gas. The reaction mixture was filtered through hyflow bed and filtrate was distilled under vacuum to give a 6.0 gm of desired product as white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([O:10][CH2:11][CH3:12])=[CH:5][N:4]=1.[NH2-].[Na+].[CH2:15]([OH:18])[C:16]#[CH:17].O>C1C=CC=CC=1>[CH3:1][S:2][C:3]1[N:8]=[C:7]([O:18][CH2:15][C:16]#[CH:17])[C:6]([O:10][CH2:11][CH3:12])=[CH:5][N:4]=1
Reactant: C#CCO
Reactant: CCOc1cnc(SC)nc1Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: C#CCOc1nc(SC)ncc1OCC
Reaction time: 5 h

Procedure:
A solution comprising 3 grams of 2-methylthio-4-chloro-5 ethoxy pyrimidine in 30 milliliters of benzene was treated with 1 gram of sodium amide and 1.5 ml of propargyl alcohol. The reaction mixture was refluxed with stirring for 5 hours. Upon cooling, the unreacted sodium amide was decomposed with water, the benzene layer separated and the solvent evaporated under reduced pressure. Crystallization of the residue from ethanol yielded 2.8 grams of 2-methylthio-4-propargyloxy-5-ethoxy pyrimidine having a melting point ranging from 84°-85° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH2:7]2.Cl.Cl[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH2:7]1[C:8]2[C:3](=[C:2]([N:1]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][CH2:6]1
Reactant: ClCCNCCCl
Reactant: Nc1cccc2c1CCCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: c1cc2c(c(N3CCNCC3)c1)CCCC2
Yield: 49.5 %

Procedure:
14.7 g (0.1 mol) of 5-aminotetralin were refluxed with 18 g (0.11 mol) of bis(β-chloroethyl)amine hydrochloride in 300 ml of n-butanol for 48 h and, after cooling, 5.4 g of sodium carbonate were added and the mixture was refluxed for a further 20 h. The precipitate which formed on cooling was filtered off with suction and taken up in water, and 2N sodium hydroxide solution was added. The aqueous phase was extracted with ethyl acetate, and washing with water and drying over sodium sulfate were followed by evaporation under reduced pressure. It was possible in this way to isolate 10.7 g (50%) of the product as an oil.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]I)=[CH:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][N:16]1[C:21](=[N:22][N+:23]([O-:25])=[O:24])[NH:20][CH2:19][O:18][CH2:17]1>CN(C)C=O>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:20]2[CH2:19][O:18][CH2:17][N:16]([CH3:15])[C:21]2=[N:22][N+:23]([O-:25])=[O:24])=[CH:5][N:6]=1
Reactant: CN1COCNC1=N[N+](=O)[O-]
Reactant: Clc1ncc(CI)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1COCN(Cc2cnc(Cl)s2)C1=N[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of 2.0 g of 2-chloro-5-iodomethyl-thiazole, 20 ml of dimethylformamide, 2.66 g of potassium carbonate and 1.23 g of 3-methyl-4-nitroimino-perhydro-1,3,5-oxadiazine is stirred for 16 hours at 50° C., cooled to room temperature and filtered; the filtrate is concentrated to dryness by evaporation. The residue is purified by column chromatography on silica gel using dichloromethane/methanol (9:1), yielding the title compound having a melting point of 132-134° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([SH:11])[N:4]=1.[OH-].[K+].[N+]([N:17]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([CH3:25])=[N:18]1)([O-])=O>O.C(O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([S:11][C:21]2[NH:17][N:18]=[C:19]([CH3:25])[C:20]=2[N+:22]([O-:24])=[O:23])[N:6]=1
Reactant: Cc1nn([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: COc1cc(OC)nc(S)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(OC)nc(Sc2[nH]nc(C)c2[N+](=O)[O-])n1
Reaction time: 0.75 h
Yield: 78.5 %

Procedure:
4,6-Dimethoxy-2-mercaptopyrimidine (4.65 g) was dissolved in water containing potassium hydroxide (1.7 g in 75 mls of water). 1,4-Dinitro-3-methylpyrazole (4.65 g) dissolved in the minimum of ethanol was then added dropwise. After the exothermic reaction had subsided, the mixture was stirred for 45 minutes. The precipitated solid was filtered off, washed with fresh water, and dried to give 6.3 g of the desired product, mp 175°-6° C.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.C([Mg]Cl)(C)C.[Br:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[NH:24][C:23](=[O:26])[C:22]2=[O:27]>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>[Br:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[NH:24][C:23](=[O:26])[C:22]2([OH:27])[C:8]1[C:7]([OH:10])=[CH:6][C:4]2[O:5][CH2:1][O:2][C:3]=2[CH:9]=1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: O=C1Nc2c(Br)cccc2C1=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1Nc2c(Br)cccc2C1(O)c1cc2c(cc1O)OCO2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a solution of sesamol (7.32 g, 53.1 mmol) in anhydrous tetrahydrofuran (150 mL) were added a solution of isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 30.1 mL, 60.2 mmol) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 30 min, followed by the addition of 7-bromo isatin (8.0 g, 35.4 mmol). The suspended mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with a saturated aqueous solution of ammonium chloride (300 mL) and ethyl acetate (250 mL), and the phases were separated. The aqueous phase was extracted with ethyl acetate (200 mL), and the combined organic solution was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude solid was triturated with diethyl ether, filtered and dried under the reduced pressure to afford 7-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (9.8 g, 77%) as a light yellow solid: 1H NMR (300 MHz, DMSO-d6) δ10.64 (s, 1H), 9.18 (s, 1H), 7.33 (dd, J=7.8, 1.4 Hz, 1H), 7.21 (s, 1H), 6.84-6.75 (m, 2H), 6.54 (s, 1H), 6.21 (s, 1H), 5.92 (dd, J=6.1, 0.8 Hz, 2H); MS (ES+) m/z 363.8 (M+1), 365.8 (M+1).
Reaction SMILES: C([O:3][C:4](=O)[CH:5](Br)[CH2:6][CH3:7])C.[OH:10][CH:11]([CH2:21][OH:22])[CH2:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].[H-].[Na+]>CN(C)C=O.C(Cl)(Cl)Cl>[CH2:6]([CH:5]1[C:4](=[O:3])[N:13]([CH2:12][CH:11]([OH:10])[CH2:21][OH:22])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20]1)[CH3:7]
Reactant: OCC(O)CNc1ccccc1O
Reactant: CCOC(=O)C(Br)CC
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCC1Oc2ccccc2N(CC(O)CO)C1=O
Yield: 55 %

Procedure:
This same compound is prepared in a yield of 55 % by the action of ethyl-2-bromobutyrate on 2-(2,3-dihydroxypropylamino) -phenol (Method D): 4.8 g of a suspension of sodium hydride in oil are slowly added to a solution of 18 g of 2-(2,3-dihydroxypropylamino)-phenol in dimethylformamide, followed by the addition 30 minutes afterwards of 20 g of ethyl-2-bromobutyrate. The mixture is then heated for 2 hours to 60°C and then kept for a few hours at the reflux temperature of the solvent. The solvent is then eliminated under reduced pressure, the residue dissolved in chloroform and the organic phase washed with a normal aqueous solution of soda and then with water. After drying over magnesium sulphate, the chloroform is eliminated under reduced pressure and the crude product obtained is purified by recrystallisation from cyclohexane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH2:10].[C:11](Cl)(=[O:13])[CH3:12].CCN(CC)CC>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)Cl
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
A solution of 2,4,6-trimethyl-phenylamine (1) (50 g, 0.370 moles) in CH2Cl2 (500 mL) was cooled to 0° C. (ice-water bath). To this was added acetyl chloride (29.8 g, 27 mL, 380 mmol) during 5 minutes via an addition funnel; this was followed by portion-wise addition of Et3N (38.5 g, 53 mL, 380 mmol). The ice-bath was removed and the solution was allowed to warm to room temperature and stir for 2 h. The resultant ivory colored solid was collected by filtration and dried in vacuo. To remove residual Et3N.HCl, the solid was suspended H2O (600 mL) stirred for 0.5 h, collected by filtration and dried to a constant weight. The original organic filtrate was washed with H2O (3×100 mL) and brine (1×100 mL), dried (MgSO4), filtered and concentrated providing additional product. Combined with material collected from the water afforded 60.2 g (99% yield) of the desired acetamide. RP-HPLC Method: 2-100 B in 2 minutes.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:17]([OH:21])([CH2:19][CH3:20])[CH3:18])[N:8]2C2CCCCO2)=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:17]([OH:21])([CH2:19][CH3:20])[CH3:18])[NH:8]2)=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=1
Reactant: CCC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CCC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2[nH]1
Temperature: 50 °C

Procedure:
A suspension of 2-(2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)butan-2-ol (3.87 g, 9.8 mmol) in methanol (110 mL) was treated with p-toluenesulfonic acid (170 mg, 0.98 mmol) and heated overnight at 50° C. The solvent was removed in vacuo to afford 2-(2-chloro-6-morpholino-9H-purin-8-yl)butan-2-ol as a white solid, which was used in the next step without any further purification (3.0 g, quant). LC/MS (ESI+): m/z 312 (M+H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([N+:29]([O-])=O)[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)[CH:14]=2)[NH:9][CH:8]=1)[CH3:2]>C(Cl)(Cl)Cl.CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH2:29])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:18][CH:17]=3)[CH:14]=2)[NH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1c[nH]c2ccc(-c3ccc(Oc4ccccc4)cc3)cc12)[N+](=O)[O-]
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)C(N)Cc1c[nH]c2ccc(-c3ccc(Oc4ccccc4)cc3)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
2-Amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester (7) was prepared as follows. Compound 6 (0.5 g) was dissolved in a mixture of CHCl3 (5 mL) and EtOH (15 mL). Palladium on carbon (10% wet, 0.25 g) was added to this solution, and shaken under hydrogen (50 PSI) for 24 hours at room temperature. After filtration over Celite, HCl (4N in 1,4-dioxane, 2 mL) was added to the mixture. The solvents were evaporated under vacuum to afford 2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester (7) as a white solid (0.4 g, 80%): 1H-NMR (400 MHz, CD3OD) δ: 7.75 (s, 1H), 7.65-7.71 (m, 2H), 7.35-7.51 (m, 4H), 7.05-7.15 (m, 5H), 4.2-4.4 (m, 3H), 3.4-3.5 (m, 2H), 1.2 (t, 3H, 7.2 Hz); LC/MS: m/z=401.5 [M+H]+ (Calc: 400.5).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:21][CH2:22][N:23]3[C@H:28]4[CH2:29][CH2:30][C@@H:24]3[CH2:25][CH:26]([N:31]3[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[N:33]=[C:32]3[CH3:40])[CH2:27]4)[CH2:13][CH2:12][N:11]([C:14](=[O:20])[C@@H:15]3[CH2:19][CH2:18][CH2:17][NH:16]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:41][CH:42]([Cl:46])[C:43](Cl)=[O:44].CCN(C(C)C)C(C)C>>[Cl:41][CH:42]([Cl:46])[C:43]([N:16]1[CH2:17][CH2:18][CH2:19][C@H:15]1[C:14]([N:11]1[CH2:12][CH2:13][C:8]([CH2:21][CH2:22][N:23]2[C@H:28]3[CH2:29][CH2:30][C@@H:24]2[CH2:25][CH:26]([N:31]2[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=[C:32]2[CH3:40])[CH2:27]3)([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:9][CH2:10]1)=[O:20])=[O:44]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H]2CCCN2)CC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H]2CCCN2C(=O)C(Cl)Cl)CC1
Yield: 49.2 %

Procedure:
1-((1R,5S)-8-{2-[1-[1-(dichloroacetyl)-L-prolyl]-4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole was obtained from treating 1,1-dimethylethyl (2S)-2-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1-pyrrolidinecarboxylate (0.645 g, 1.01 mmol) with HCl as outlined in the procedure for Example 890 to form 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)-1-L-prolyl-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole (0.545 g, 99%). 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)-1-L-prolyl-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole (0.050 g, 0.09 mmol), Dichloro-acetyl chloride (0.013 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 1-((1R,5S)-8-{2-[1-[1-(dichloroacetyl)-L-prolyl]-4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole (0.029 g, 49%) as an oil. ES-LCMS m/z 654 (M+1).
Reaction SMILES: [C-:1]#[N:2].[K+].[F:4][CH:5]([F:15])[O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:4][CH:5]([F:15])[O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][C:1]#[N:2])=[CH:9][CH:8]=1
Reactant: [C-]#N
Reactant: FC(F)Oc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: N#CCc1ccc(OC(F)F)cc1
Temperature: 100 °C
Yield: 81.6 %

Procedure:
100 g of potassium cyanide were dissolved in 160 ml of water, and 15 g of tetrabutylammonium bromide and 230 g of 4-difluoromethoxy-benzyl bromide were then added. The mixture was then heated to 100° C. for 1 hour and, after cooling, was extracted twice with methylene chloride. After drying over sodium sulphate, the organic phase was first freed from solvent and then distilled. 145 g of 4-difluoromethoxy-benzyl cyanide were obtained. Boiling point=106°-8° C./0.3 mm Hg; nD20 =1.4822.
Reaction SMILES: C[O-:2].[Na+].[CH3:4][C:5]([C:8]1[C:9](O)=[C:10]([CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=1)[C:11]([NH:13][NH:14][C:15](=[S:17])[NH2:16])=O)([CH3:7])[CH3:6]>CO>[CH3:4][C:5]([C:8]1[CH:9]=[C:10]([C:11]2[NH:16][C:15](=[S:17])[NH:14][N:13]=2)[CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:20]=1[OH:2])([CH3:7])[CH3:6]
Reactant: C[O-]
Reactant: CC(C)(C)c1cc(C(=O)NNC(N)=S)c(O)c(C(C)(C)C)c1
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1cc(-c2n[nH]c(=S)[nH]2)cc(C(C)(C)C)c1O
Yield: 60.7 %

Procedure:
Sodium methoxide (2.2 g, 0.041 mole) is added to a solution of 2-[3,5-bis(1,1-dimethylethyl)-hydroxybenzoyl]-hydrazinecarbothioamide (4.0 g, 0.0124 mole) in methanol (50 ml). The resulting mixture is stirred at reflux under an atmosphere of nitrogen for 24 hours. The solution is cooled and concentrated in vacuo. The residue is dissolved in water (25 ml) and washed with ether (2×20 ml). The aqueous layer is acidified with cold aqueous 2M HCl (25 ml) and the product extracted out with a 1:1 mixture of ethyl acetate/ether (2×30 ml). The combined organic extracts are washed with saturated aqueous NaCl and dried over MgSO4. Filtration and concentration gives a residue which is purified by flash chromatography (SiO2, 30% ethyl acetate/hexane eluent). The solid product is recrystallized from ethyl acetate/hexane to give 2.3 g of 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione. (3.8 g theor., 61%): mp 271 ° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14].CO[CH2:17][N:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][Si](C)(C)C>C(Cl)Cl>[CH2:24]([N:18]1[CH2:19][CH:10]2[C:9](=[O:14])[NH:8][C:12](=[O:13])[CH:11]2[CH2:17]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CC(=O)N1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NC(=O)C2CN(Cc3ccccc3)CC12
Temperature: 25 °C
Reaction time: 5 h
Yield: 42 %

Procedure:
To a suspension of TFA (1.02 g) and 1H-Pyrrole-2,5-dione (10.22 g) in CH2Cl2 (250 mL) at −5° C. was added a solution of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (29.99 g) in CH2Cl2 (20 mL) dropwise over 1 h. The reaction mixture was stirred at room temperature for another 5 h and evaporated in vacuo. The residue was stirred in the mixed solvent (EA: PE=3:7) at −10° C. for 1 h, and the mixture was filtered to afford the title compound as a white solid (10.18 g, 42.00%).
Reaction SMILES: C[O:2][CH2:3][C@@:4]([CH3:10])([CH:8]=[CH2:9])[C:5]([OH:7])=[O:6].B(Br)(Br)Br.[CH3:15]O>ClCCl>[CH3:15][O:7][C:5](=[O:6])[C@:4]([CH2:3][OH:2])([CH3:10])[CH:8]=[CH2:9]
Reactant: CO
Reactant: C=C[C@](C)(COC)C(=O)O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C=C[C@](C)(CO)C(=O)OC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
A solution of (R)-2-methoxymethyl-2-methyl-but-3-enoic acid (600 mg, 4.2 mmol) in dichloromethane (40 mL) was stirred at 0° C. under nitrogen. Boron tribromide (1 M in dichloromethane, 16.8 mL, 16.8 mmol) was added and the reaction mixture was stirred at 0° C. for 90 minutes. Methanol (20 mL) was cautiously added and the reaction mixture was warmed to room temperature over 30 minutes and then stirred at room temperature for 30 minutes. The solvent was evaporated and the residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 3:1 to 1:1 to afford the title compound (540 mg, 90%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.35 (s, 3H), 2.33 (m, 1H), 3.62 (m, 1H), 3.75 (s, 3H), 3.75-3.80 (m, 1H), 5.21 (dd, J=17.4, 0.5 Hz, 1H), 5.24 (dd, J=10.7, 0.5 Hz, 1H), 5.98 (dd, J=17.4, 10.7 Hz, 1H). LCMS (m/z) 145.1 [M+H], Tr=1.16 min.