Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[C:32]([Cl:33])=[CH:31][C:30]([C:34](=[O:36])[CH3:35])=[C:29]([OH:37])[C:28]=2[CH2:38][CH2:39][CH3:40])[C:10]=1[CH2:41][CH2:42][CH3:43])C>[OH-].[Na+].CO>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:44])=[O:3])=[C:10]([CH2:41][CH2:42][CH3:43])[C:11]=1[O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[C:32]([Cl:33])=[CH:31][C:30]([C:34](=[O:36])[CH3:35])=[C:29]([OH:37])[C:28]=1[CH2:38][CH2:39][CH3:40])(=[O:17])[CH3:16]
Reactant: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCCOCCCOc1c(C(C)=O)ccc(OCCCC(=O)OCC)c1CCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCCOCCCOc1c(C(C)=O)ccc(OCCCC(=O)O)c1CCC
Yield: 95.3 %

Procedure:
A solution of 0.506 g of 4-[4-acetyl-3-[3-[3-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]butanoic acid ethyl ester in 4.0 ml of 1.0N sodium hydroxide and 20 ml of methanol was stirred at reflux for 2 hours. The methanol was removed in vacuo and the residue was acidified. The product was extracted with ethyl acetate and the dried (magnesium sulfate) extract was concentrated in vacuo to give 0.461 g (95% yield) of 4-[4-acetyl-3-[3-[3-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]butanoic acid as an oil.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[NH:8][C:4]=2[C:3]=1[S:13][CH2:14][CH3:15].[CH3:16][N:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[C:20]2[CH:32]=[CH:33][N:34]([S:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C:19]=2[C:18]1=[O:45]>>[CH2:14]([S:13][C:3]1[C:4]2[NH:8][C:7](=[O:9])[N:6]([CH3:10])[C:5]=2[CH:11]=[CH:12][C:2]=1[C:21]1[C:20]2[CH:32]=[CH:33][N:34]([S:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C:19]=2[C:18](=[O:45])[N:17]([CH3:16])[CH:22]=1)[CH3:15]
Reactant: CCSc1c(Br)ccc2c1[nH]c(=O)n2C
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Product: CCSc1c(-c2cn(C)c(=O)c3c2ccn3S(=O)(=O)c2ccc(C)cc2)ccc2c1[nH]c(=O)n2C

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 5-bromo-4-(ethylthio)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one and 6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as the starting materials. LCMS calculated for C25H25N4O4S2 (M+H)+: m/z=509.1. found: 509.1.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:19]N1C(=O)CCC1=O>CC(C)=O.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([I:19])[CH:10]=[C:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(C)n1Cc1ccccc1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(I)c(C)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 123A (564 mg) in acetone (8 mL) at 0° C. was added N-iodosuccinimide (600 mg). The mixture was stirred at room temperature overnight, and diluted with ethyl acetate and washed with water. The organic layer was concentrated and the residue was purified by flash chromatography, and eluted with 50% dichloromethane in hexane to provide the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11].CO.[BH4-].[Na+].Cl>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:10][OH:11])[CH:12]=[CH:13][CH:14]=1
Reactant: COCCCCc1cccc(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COCCCCc1cccc(CO)c1
Reaction time: 1 h

Procedure:
To a solution of the title D compound, 3-(4-methoxy-butyl)-benzaldehyde (0.1 g, 0.52 mmol) and MeOH (0.063 mL, 1.56 mmol) in 2 mL of THF is added portion wise sodium borohydride (20 mg, 0.52 mmol). The reaction mixture is stirred for 1 hour at room and poured into aqueous 1 M HCl. The aqueous layer is extracted twice with ethyl acetate and the combined organic extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (hexane/EtOAc 3/1) to afford the title compound as a colorless oil: TLC, Rf (hexane/AcOEt 2/1)=0.34. MS 212.1 [M+18].
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[F:16])[N:3]=1.[CH2:17]([CH:24]1[CH2:28][CH2:27][CH2:26][NH:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>O1CCCC1>[CH2:17]([CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[F:16])[N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(CC2CCCN2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCCC2Cc2ccccc2)nc(-c2ccncc2F)cc1=O
Yield: 79.6 %

Procedure:
A solution of 2-chloro-6-(3-fluoropyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (0.24 g, 1.0 mmol), (2RS)-2-benzyl-pyrrolidine (0.20 g, 1.2 mmol) and triethylamine (0.3 g, 3.0 mmol) in tetrahydrofuran (4 ml) was stirred for 5 hours at 40° C. The solution was partitioned between water and ethyl acetate, and the organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform/ethyl acetate=3/2) to afford 2-((2RS)-2-benzyl-pyrrolidin-1-yl)-6-(3-fluoro-pyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (0.29 g, 80%).
Reaction SMILES: [CH2:1](I)[CH3:2].[N+:4]([C:7]1[CH:26]=[CH:25][C:10]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)([O-:6])=[O:5].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([CH2:11][CH2:12][N:13]([CH2:1][CH3:2])[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:25][CH:26]=1)([O-:6])=[O:5]
Reactant: CCI
Reactant: O=[N+]([O-])c1ccc(CCNCCc2ccc([N+](=O)[O-])cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CCc1ccc([N+](=O)[O-])cc1)CCc1ccc([N+](=O)[O-])cc1

Procedure:
Ethyl iodide (0.37 g) was added dropwise to the product of part (A) (0.75 g) and potassium carbonate (0.33 g) in acetonitrile (20 ml) and the reaction mixture was heated under reflux for 18 hours. The reaction mixture was then evaporated to dryness and the residue taken up in methylene chloride, washed twice with aqueous sodium carbonate, twice with brine, then dried (Na2SO4), filtered and evaporated to dryness. The resulting oil was purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 2%). The product-containing fractions were combined and evaporated to dryness to give the title compound as an oil, yield 0.47 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C[O:10][C:11]([C:13]#[C:14][C:15](OC)=[O:16])=[O:12]>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]2[C:3]=1[C:15](=[O:16])[CH:14]=[C:13]([C:11]([OH:12])=[O:10])[NH:5]2
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1cccc(F)c1
Product: O=C(O)c1cc(=O)c2c(F)cccc2[nH]1

Procedure:
Using the method described in Example 15 with 3-fluoroaniline (8.7 ml) and dimethylacetylene dicarboxylate (5.46 ml) gave 5-fluoro-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (0.022 g), m.p. 285°-286° C. (dec), δ (360 MHz, NAOD) 6.86 (1H, s, 3-H), 7.04 (1H, m, 7-H) and 7.52-7.68 (2H. m, 6-H, 8-H).
Reaction SMILES: CS(O[CH:6](C)[C:7](OC)(OC)[C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]=1)(=O)=O.[C:25](=[O:28])(O)[O-:26].[Na+].CO>O>[CH3:19][O:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:7]([CH3:6])[C:25]([OH:26])=[O:28])[CH:17]=[CH:16]2
Reactant: COc1ccc2cc(C(OC)(OC)C(C)OS(C)(=O)=O)ccc2c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Temperature: 70 °C

Procedure:
A mixture is prepared from the oil, 1,1-dimethoxy-1-(6-methoxy-2-naphthyl)prop-2-yl methanesulfonate, from Example 16, 20 g of sodium bicarbonate, 200 ml of methanol and 150 ml of water, and the mixture is heated at 70° C. with reflux for 14 hours. The methanol is removed under reduced pressure on a rotary evaporator and the oil remaining is extracted with ethyl ether. The organic and aqueous phases are separated and the aqueous phase is acidified with hydrochloric acid to afford 12.5 g of 2-(6-methoxy-2-naphthyl)propionic acid.
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][C:5]1[O:6][CH:7]=[CH:8][CH:9]=1.[Cl:10][C:11]1[CH:16]=[C:15]([C:17]([Cl:20])([Cl:19])[Cl:18])[CH:14]=[C:13](Cl)[N:12]=1>O>[Cl:10][C:11]1[CH:16]=[C:15]([C:17]([Cl:18])([Cl:19])[Cl:20])[CH:14]=[C:13]([O:3][CH2:4][C:5]2[O:6][CH:7]=[CH:8][CH:9]=2)[N:12]=1
Reactant: Clc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Reactant: OCc1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1cc(C(Cl)(Cl)Cl)cc(OCc2ccco2)n1
Temperature: 50 °C
Yield: 87 %

Procedure:
To 24 grams (0.6 mole) of sodium hydroxide dissolved in 120 mls of water, was added 300 mls of 2-(hydroxymethyl)furan and the solution warmed to 50° C. In this mixture was added incremently over a 20 minute period, 106.15 grams (0.4 mole) of 2,6-dichloro-4-(trichloromethyl)pyridine. The mixture was heated to ~80° C. for ~3.5 hours and thereafter diluted with water and extracted with hexane. The extract was washed with water and the hexane evaporated off leaving ~114 grams (~87 percent of theoretical) of the desired 2-chloro-6-(2-furanylmethoxy)-4-(trichloromethyl)pyridine product. The product, an oil, had a refractive index of n 25/d = 1.5722 and upon analysis was found to have carbon, hydrogen and nitrogen contents of 40.41, 2.21 and 4.21 percent, respectively, as compared with the theoretical contents of 40.40, 2.16 and 4.28 percent, respectively, as calculated for the above named compound.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH2:15]([C:18]1[C:19]([O:37][CH2:38][CH:39]2[O:41][CH2:40]2)=[CH:20][CH:21]=[C:22]2[C:27]=1[O:26][C:25](=[O:28])[CH:24]=[C:23]2[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:16]=[CH2:17]>C(O)C>[CH2:15]([C:18]1[C:19]([O:37][CH2:38][CH:39]([OH:41])[CH2:40][N:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:8][CH2:9]2)=[CH:20][CH:21]=[C:22]2[C:27]=1[O:26][C:25](=[O:28])[CH:24]=[C:23]2[O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH:16]=[CH2:17]
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: C=CCc1c(OCC2CO2)ccc2c(OCc3ccccc3)cc(=O)oc12
Solvent: CCO
Product: C=CCc1c(OCC(O)CN2CCN(Cc3ccc(Cl)cc3)CC2)ccc2c(OCc3ccccc3)cc(=O)oc12
Yield: 52.5 %

Procedure:
Heating a mixture of 1-(4-chlorobenzyl)piperazine (6.2 g; 0.03 mole) and 8-allyl-4-benzyloxy-7-(2,3-epoxypropyloxy) coumarin (9.47 g; 0.026 mole) in ethanol (50 ml) to reflux for 2 hr and work-up as in Example 2(b) gave 7.85 g (52%) of the title compound of m.p. 155°-157° C., νmax (mull) 3320, 1675, 1615, 1605, 1565 cm-1 ; (Found; C, 69.04; H, 6.20; N, 4.67; Cl, 6.12; C33H35O5N2Cl requires; C, 68.92; H, 6.13; N, 4.87; Cl, 6.17%).
Reaction SMILES: OCC[N:4]1[C:8]2[CH:9]=[C:10]([CH3:14])[C:11]([CH3:13])=[CH:12][C:7]=2[N:6]=[CH:5]1.[NH+]1C=CC=CC=1.C([CH2:23][CH2:24][O:25][P:26](=[O:29])([O-:28])[O-:27])#N.[NH+]1C=CC=CC=1>N1C=CC=CC=1.O>[CH3:14][C:10]1[C:11]([CH3:13])=[CH:12][C:7]2[N:6]=[C:5]([CH2:23][CH2:24][O:25][P:26](=[O:27])([OH:29])[OH:28])[NH:4][C:8]=2[CH:9]=1
Reactant: N#CCCOP(=O)([O-])[O-]
Reactant: Cc1cc2ncn(CCO)c2cc1C
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc2nc(CCOP(=O)(O)O)[nH]c2cc1C
Reaction time: 48 h

Procedure:
A 0.19 g amount of the crude 1-(2-hydroxyethyl)-5,6-dimethylbenzimidazole and 2 ml of 2-cyanoethylphosphoric acid pyridinium salt solution (1 mmol/ml) were dissolved in 20 ml of dry pyridine, and the solution was concentrated to dryness under a reduced pressure. This process was repeated twice more, and further, the dried material was thoroughly dried by a vacuum pump, dissolved in 20 ml of dry pyridine, 1.67 g of dicyclohexylcarbodiimide was added thereto, and the mixture was stored at room temperature for 2 days. After an addition of water to the product, the mixture was concentrated to dryness under a reduced pressure, followed by an addition of 40 ml of an aqueous LiOH solution (0.5 N) to carry out the reaction at 100° C. for 45 minutes. The reaction mixture was filtered to give a filtrate, which was diluted with water, adjusted to a pH of 2.5 to 3, and then the mixture was applied to an ion exchange column (Dowex 50 (hydrogen ion form)). Elution was effected successively with water and 2 N pyridine, and the fractions eluted with the latter were concentrated to dryness under a reduced pressure to give 0.27 g of crude 2-(5,6-dimethylbenzimidazolyl)ethylphosphoric acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:48])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[C:17]([Br:18])=[CH:16][C:15]([C:19](=[O:35])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][C:13]=2[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)=[CH:6][C:5]=1[O:46]C.[K+].[Br-]>>[CH3:1][O:2][C:3](=[O:48])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[C:17]([Br:18])=[CH:16][C:15]([C:19](=[O:35])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:14][C:13]=2[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)=[CH:6][C:5]=1[OH:46]
Reactant: COC(=O)c1ccc(COc2c(Br)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)cc1OC
Agent: [Br-]
Agent: [K+]
Product: COC(=O)c1ccc(COc2c(Br)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)cc1O

Procedure:
The title compound was prepared as a light yellow oil (0.361 g, 37%) from 4-[3-Bromo-5-(8-phenyl-octylcarbamoyl)-3′-trifluoromethyl-biphenyl-2-yloxymethyl]-2-methoxy-benzoic acid methyl ester using a procedure similar to Example 200. 1H NMR (DMSO-d6) δ 10.45 (s, 1H); 8.59 (bt, 1H); 8.18 (d, 1H); 7.90–7.58 (m, 6H); 7.25–7.10 (m, 5H); 6.70–6.60 (m, 2H); 4.60 (s, 2H); 3.88 (s, 3H); 3.24 (dd, 2H); 2.52 (t, 2H); 1.50 (m, 4H); 1.25 (m, 8H); IR (KBr) 3400, 2950, 2850, 1685, 1620, 1550, 1440, 1400, 1180, 1120 cm−1; mass spectrum [(−)APCI], m/z 710 (M−H)−; Anal. Calcd. for C37H37BrF3NO5: C, 61.90; H, 5.05; N, 2.01. Found: C, 60.59; H, 5.09; N, 1.86.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([F:25])[CH:27]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: Fc1cccc(CCl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: Fc1cccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)c1

Procedure:
The title compound (0.01 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C; 0.1 g) using 3-fluorobenzyl chloride (0.5 mL) in place of benzyl chloride. MS (ESI): exact mass calculated for C20H19ClFN3, 355.13; found, m/z 356.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.42-7.37 (m, 2H), 7.35-7.32 (m, 2H), 7.28-7.21 (m, 1H), 6.93-6.88 (m, 1H), 6.84 (d, J=7.7 Hz, 1H), 6.75-6.71 (m, 1H), 5.29 (s, 2H), 2.89-2.85 (m, 4H), 2.79-2.76 (m, 2H), 2.74-2.70 (m, 2H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].N[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]1[CH:30]=[CH:29][CH:28]=[CH:27][C:17]=1[C:18]([N:20](C(C)C)C(C)C)=[O:19]>C1COCC1>[CH:12]1[N:13]=[CH:14][CH:15]=[C:10]2[C:11]=1[C:16]1[CH:30]=[CH:29][CH:28]=[CH:27][C:17]=1[C:18](=[O:19])[NH:20]2
Reactant: CC(C)N(C(=O)c1ccccc1-c1cnccc1N)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1[nH]c2ccncc2c2ccccc12
Temperature: -78 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A solution of lithium diisopropyl amide (LDA, 2.0 M, Aldrich, 10 mL) was dissolved in 90 mL of THF and cooled to −78° C. A solution of amine 3 (2.0 g, 6.73 mmol) in THF (25 mL) was added to the LDA dropwise over a 15 minute period. The reaction was warmed to room temperature and stirred overnight. The reaction was concentrated in vacuo and suspended in 100 mL water. The solid was filtered off and triturated with ethyl acetate (100 mL). The resulting solid was dried to yield 1.24 g (94%) of the desired compound 4. An analytical sample can be obtained by recrystallization with copious amounts of methanol. 1H NMR (DMSO): δ 9.57 (s, 1H), 8.65 (d, 1H), 8.50 (d, 1H), 8.33 (d, 1H), 7.90 (t, 1H), 7.71 (t, 1H), 7.28 (d, 1H). Anal Calcd. for C12H8N2O: C, 73.46; H, 4.11; N, 14.28. Found: C, 73.53; H, 4.26; N, 14.37.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.[C:14]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(/C=C/C(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)/C=C/c1cccc(OC)c1

Procedure:
A mixture of (E)-3-(3-methoxyphenyl)acrylic acid (3.56 g, 20 mmol). K2CO3 (3.1 g, 22 mmol), and iodomethane (4.0 g, 28 mmol) in acetone (20 mL) was heated to 70° C. for 16 hours. The mixture was concentrated and partitioned between water and ethyl acetate to afford the crude title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1([CH2:20][CH:21]=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[C@@H:23]12[NH:30][C@@H:27]([CH2:28][CH2:29]1)[CH2:26][CH:25]([N:31]1[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]1[CH3:40])[CH2:24]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:1][N:2]([CH2:10][C:11]1([CH2:20][CH2:21][N:30]2[C@H:27]3[CH2:28][CH2:29][C@@H:23]2[CH2:24][CH:25]([N:31]2[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=[C:32]2[CH3:40])[CH2:26]3)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2
Reactant: CN(CC1(CC=O)CCc2ccccc21)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(CN(C)C(=O)OC(C)(C)C)CCc2ccccc21
Reaction time: 8 h
Yield: 70.9 %

Procedure:
tert-butyl methyl{[1-(2-oxoethyl)-2,3-dihydro-1H-inden-1-yl]methyl}carbamate (600 mg, 1.98 mmole) and 1-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1H-benzimidazole (622 mg, 1.98 mmole) was dissolved in 50 ml of DCE to which was added sodium triacetoxyborohydride (839 mg, 3.96 mmole) which was stirred overnight. A saturated solution of NaHCO3 was added to quench the remaining hydride. The organic layer was washed with water and evaporated. The resulting residue was absorbed into silica gel and 100% EtOAc was use to remove impurities followed by Methanol to remove the product affording 0.7425 g of tert-butyl methyl[(1-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2,3-dihydro-1H-inden-1-yl)methyl]carbamate (70% yield).
Reaction SMILES: CC(OI1(O[C:20]([CH3:22])=[O:21])(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH:23]1([CH2:26][S:27]([CH2:30][C@H:31]([NH-:43])[C:32](=[O:42])[NH:33][CH:34]2[CH:39](O)[CH2:38][CH2:37][CH2:36][CH:35]2[OH:41])(=[O:29])=[O:28])[CH2:25][CH2:24]1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[CH:23]1([CH2:26][S:27]([CH2:30][C@H:31]([NH:43][C:32]([N:33]2[CH2:22][CH2:20][O:21][CH2:35][CH2:34]2)=[O:42])[C:32](=[O:42])[NH:33][C:34]2[C:35](=[O:41])[CH2:36][CH2:37][CH2:38][CH:39]=2)(=[O:28])=[O:29])[CH2:24][CH2:25]1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: [NH-][C@@H](CS(=O)(=O)CC1CC1)C(=O)NC1C(O)CCCC1O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCCC=C1NC(=O)[C@H](CS(=O)(=O)CC1CC1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dess Martin Periodinane (0.688 g, 1.62 mmol) was added to a solution of the [(R)-2-cyclopropylmethanesulfonyl-1-(2,6-dihydroxy-cyclohexylcarbamoyl)-ethyl]-amide (0.32 g) in DCM (10 mL) and the mixture was stirred at room temperature for 3 hours then treated with resin bound Na2S2O3 (1.5 mmol/g, 1.9 g) and stirred at room temperature for a further 24 hours. The reaction mixture was diluted with DCM (20 mL), then filtered. The filtrate was washed with a solution of 0.25 M Na2S2O3, then with saturated NaHCO3, then dried (MgSO4), and then evaporated under reduced pressure. The residue was subjected to column chromatography eluting with a mixture of ethyl acetate and heptane to give morpholine-4-carboxylic acid [(R)-2-cyclopropylmethanesulfonyl-1-(6-oxo-cyclohex-1-enylcarbamoyl)-ethyl]-amide. 1H NMR (CDCl3): 9.00 (s, 1H), 7.78 (t, 1H), 6.18 (d, 1H), 4.9 (m, 1H), 3.85 (m, 1H), 3.77–3.62 (m, 4H), 3.58–3.45 (dd, 1H), 3.48–3.36 (m, 4H), 3.0 (d, 2H), 2.55–2.42 (m, 4H), 2.08–1.97 (m, 2H), 1.2 (m, 1H), 0.8–0.7 (m, 2H), 0.6–0.4 (m, 2H). MS: 414 (MH+).
Reaction SMILES: O[N:2]=[C:3]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([Br:20])=[CH:16][C:17]=2[Br:19])[NH:12][CH:11]=1)[C:4]([O:6]CC)=[O:5]>C(O)(=O)C.[Zn]>[Br:19][C:17]1[CH:16]=[C:15]([Br:20])[CH:14]=[C:13]2[C:18]=1[C:10]([CH2:9][C@@H:3]([C:4]([OH:6])=[O:5])[NH2:2])=[CH:11][NH:12]2
Reactant: CCOC(=O)C(Cc1c[nH]c2cc(Br)cc(Br)c12)=NO
Agent: [Zn]
Solvent: CC(=O)O
Product: N[C@@H](Cc1c[nH]c2cc(Br)cc(Br)c12)C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Dissolve ethyl 2-(hydroxyimino)-3-(4,6-dibromo-3-indolyl)propanoate (1.47 g, 3.65 mmol) in acetic acid (200 mL) and add activated zinc dust (1.25 g, 19.2 mmol). Stir at room temperature for 72 hours. Evaporate the acetic acid in vacuo and take up in ethyl acetate (200 mL). Treat with saturated sodium hydrogen carbonate (500 mL). Filter the resulting white precipitate and separate the organic phase. Wash with saturated sodium hydrogen carbonate (100 mL) and brine (100 mL). Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: OS(O)(=O)=O.[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[N:12]=[CH:13][NH:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1.O[CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35]>C(O)(=O)CC>[C:26]1(=[O:35])[N:25]([CH2:24][C:10]2[S:6][C:7]([C:11]3[N:12]=[CH:13][NH:14][C:15]=3[C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=[CH:8][CH:9]=2)[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]12
Reactant: O=C1c2ccccc2C(=O)N1CO
Reactant: Cc1ccc(-c2[nH]cnc2-c2cccs2)cc1
Agent: O=S(=O)(O)O
Solvent: CCC(=O)O
Product: Cc1ccc(-c2[nH]cnc2-c2ccc(CN3C(=O)c4ccccc4C3=O)s2)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
375 ml of concentrated H2SO4 are added dropwise to a solution of 240 g of 4-(2-thienyl)-5-p-tolyl imidazole (1 mol) in 1,000 ml of propionic acid at 0° C., and 265 g (1.5 mol) of N-hydroxymethyl-phthalimide are added portionwise. The reaction mixture is left at 25° C. for 24 hours with stirring and the resulting suspension is poured out onto 400 g of ice. The precipitate obtained is suction filtered, washed with water, taken up with ammonia (10%) and again suction-filtered.