Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.Cl.[CH3:6][NH2:7].C([O:10][C:11]([C:13]1[O:14][C:15]2[C:21]([F:22])=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19]([CH3:29])=[C:18]([C:30]#[N:31])[C:16]=2[N:17]=1)=O)C.Cl>ClCCl>[C:30]([C:18]1[C:16]2[N:17]=[C:13]([C:11]([NH:7][CH3:6])=[O:10])[O:14][C:15]=2[C:21]([F:22])=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]=1[CH3:29])#[N:31]
Reactant: CN
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reaction time: 0.67 h
Yield: 64 %

Procedure:
Under nitrogen atmosphere, trimethylaluminium (1.03 M n-hexane solution, 1.80 ml, 1.85 mmol) was dropwise added to a dichloromethane (2 ml) solution of methylamine hydrochloride (125 mg, 1.85 mmol) at room temperature, and stirred for 40 minutes. Subsequently, a dichloromethane (2 ml) solution of ethyl-4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carboxylate (I-111) (200 mg, 617 μl) was dropwise added and stirred for 63 hours. After the reaction, aqueous 1 N hydrochloric acid solution was added to the reaction liquid with cooling with ice, followed by stirring at room temperature. The reaction liquid was extracted with chloroform. Next, the obtained organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with dichloromethane/methanol (100:1, v/v) gave the entitled compound (122 mg, 64%) as a pale green solid.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[Br:6][C:7]1[C:8]([OH:17])=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:11][C:12]=1[F:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Br:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[C:8]=1[O:17][CH2:2][C:3](=[O:5])[CH3:4]
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1O
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1c([N+](=O)[O-])ccc(F)c1Br
Temperature: 25 °C

Procedure:
Chloroacetone (3.8 g, 3.3 ml, 41 mmol) was added dropwise to a solution of 3-bromo-4-fluoro-2-hydroxy-1-nitrobenzene (4.3 g, 18.2 mmol) in acetone (54 ml) with stirring at ambient temperature. Potassium carbonate (5.8 g, 42 mmol) and potassium iodide (6.0 g, 36.4 mmol), were added and the reaction mixture was heated to reflux temperature for 2 hours. The reaction mixture was then cooled to room temperature, poured onto water (100 ml), and extracted three times with ethyl acetate (150 ml). The combined organic layers were dried over magnesium sulfate, treated with decolorizing charcoal and filtered through diatomaceous earth. Solvent was removed in vacuo to afford a dark brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2.[C:13]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:14].N1C=CN=C1>ClCCl>[Si:17]([O:12][CH:9]1[CH2:10][C:11]2[C:2]([NH2:1])=[CH:3][CH:4]=[CH:5][C:6]=2[CH2:7][CH2:8]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1cccc2c1CC(O)CC2
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCc2cccc(N)c2C1

Procedure:
A mixture of the product of Example 18A (2.33 g, 14.3 mmol), tert-butylchlorodimethylsilane (2.6 g, 17.2 mmol), and imidazole (2.9 g, 42.3 mmol) was stirred in 40 mL of dichloromethane at rt overnight. The mixture was then washed several times with water and once with brine. Drying over Na2SO4, filtered and evaporation afforded the product as a dark purple oil, 2.6 g (65%). 1H NMR (DMSO-d6) δ 6.77 (dd, J=7.8, 7.4 Hz, 1H), 6.42 (d, J=7.8 Hz, 1H), 6.28 (d, J=7.4 Hz, 1H), 4.7 (br s, 2H), 4.11 (m, 1H), 2.75 (m, 3H), 2.24 (m, 1H), 1.82 (m, 1H), 1.63 (m, 1H), 0.88 (s, 9H), 0.09 (s, 6H); MS (ESI+) m/z 278 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[S:11][C:10]=1C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N1C2C(=CC=CC=2)C=CC=1>[CH2:1]([O:8][C:9]1[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[S:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1cc(OCc2ccccc2)c(C(=O)O)s1
Solvent: c1ccc2ncccc2c1
Product: CS(=O)(=O)c1cc(OCc2ccccc2)cs1
Temperature: 165 °C
Yield: 86 %

Procedure:
A solution of 3-benzyloxy-5-(methylsulfonyl)-2-thiopenecarboxylic acid (13.6 g, 43.6 mmol) in 50 ml quinoline is treated with Cu powder (4.15 g, 65.4 mmol) at room temperature, heated to 165° C. for 15 minutes, cooled to room temperature and filtered. (The filtercake is washed with water.) The combined filtrate is acidified to pH 1 with 6N HCl and filtered. This filtercake is washed with water and dried to afford the title product as a dark grey powder, 10.1 g (86% yield), mp 108-109° C., identified by 1HNMR, 13CNMR and mass spectral analyses.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH2:16][C:9]1(CC1C=CC=CC=1)[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH:9]2[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:12][NH:11][CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1C2CCCC1(Cc1ccccc1)CNC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C2CCCC1CNC2
Yield: 49.7 %

Procedure:
A mixture of benzyl-3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (477 mg, 1.51 mmol, 1.0 eq) and palladium hydroxide on carbon (466 mg) in ethanol (10 mL) was stirred with hydrogenation under balloon pressure until no more hydrogen uptake. The reaction was then filtered through celite and concentrated under reduced pressure. The crude was purified using chromatography (MeOH/Ethyl Acetate) which gave 3,9-Diaza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (170 mg) in 47% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 11H) 1.57-1.70 (m, 1H) 1.70-1.79 (m, 2H) 1.79-2.01 (m, 2H) 2.43-2.58 (m, J=19.14, 12.69, 6.32, 6.32 Hz, 1H) 2.93-3.05 (m, 2H) 3.05-3.18 (m, 2H) 3.99 (br. s., 1H) 4.11 (br. s., 1H)
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([CH:11]1[O:13][CH2:12]1)[Br:10].O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CCOCC.CC(C)=O>[Br:10][CH2:9][C:11]([CH2:12][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:13]
Reactant: Br[Mg]c1ccccc1
Reactant: BrCC1CO1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: O
Product: O=C(CBr)Cc1ccccc1
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a suspension of CuBr (0.143 g, 0.997 mmol) in 25 mL dry ether was slowly added 1M phenylmagnesium bromide (10 mL, 10 mmol). Epibromohydrin (0.87 mL, 10.5 mmol) was then added dropwise. The reaction mixture was allowed to stir at −78° C. to room temperature overnight, poured into H2O and extracted with ether. The extracts were washed with H2O and brine, dried over Na2SO4, filtered and evaporated in vacuo. The crude alcohol thus obtained was dissolved in acetone (400 mL) and chilled in ice, and to this solution was added dropwise 6 mL of Jones reagent (prepared by dissolution of 2.67 g CrO3 in 2.5 mL H2SO4, followed by dilution with H2O to 10 mL). The reaction mixture was stirred at 0° C. for 15 min and was then evaporated in vacuo. The residue was taken up in ethyl acetate, washed repeatedly with water and once with brine, dried over Na2SO4, filtered and evaporated to afford the ketone product as a brown oil (1.6 g, 75%). 1H NMR (DMSO-d6) δ 7.17-7.35 (m, 5H), 4.45 (s, 2H), 3.94 (s, 2H); MS (DCI+) m/z 230 (M+NH4+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH:5]=[C:6]1[C:10](=[O:11])O[C:8]([CH3:12])=[N:7]1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH:5]=[C:6]1[N:7]=[C:8]([CH3:12])[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]1=[O:11]
Reactant: COc1ccccc1C=C1N=C(C)OC1=O
Reactant: Nc1ccccc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COc1ccccc1C=C1N=C(C)N(c2ccccc2)C1=O
Temperature: 100 °C
Yield: 27.5 %

Procedure:
4-(2′-Methoxybenzylidene)-2-methyl-4H-oxazol-5-one (5 g) was dissolved in acetic acid (100 ml), and aniline (2.33 g) and sodium acetate (1.8 g) were added. The mixture was heated at 100° C. for 5 hr. The reaction mixture was poured into ice-water, neutralized with potassium carbonate and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.85 g) as yellow crystals.
Reaction SMILES: [C:1]([C:9]1[C:14]2[NH:15][CH2:16][CH2:17][O:18][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Br:25][CH2:26][C:27](Br)=[O:28].O>C(Cl)Cl>[Br:25][CH2:26][C:27]([N:15]1[C:14]2[C:9]([C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=[CH:12][C:13]=2[O:18][CH2:17][CH2:16]1)=[O:28]
Reactant: O=C(Br)CBr
Reactant: O=C(c1ccccc1)c1cccc2c1NCCO2
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cccc2c1N(C(=O)CBr)CCO2
Yield: 69.4 %

Procedure:
To a solution of 5-benzoyl-3,4-dihydro-2H-1,4-benzoxazine (5.74 g), pyridine (1.9 g) and methylene chloride (100 ml) was dropwise added a solution of bromoacetyl bromide (5.82 g) in methylene chloride (5 ml) at room temperature. After the mixture was stirred for 1.0 hour at the same temperature, water (100 ml) was added thereto under stirring. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated. The residue was crystallized with a mixture of diisopropyl ether and ethyl acetate. The crystals were collected by filtration to give 4-bromoacetyl-5-benzoyl-3,4-dihydro-2H-1,4-benzoxazine (6.0 g).
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4].[N+](=[CH:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N-].C(OCC)(=O)C.O>C(Cl)Cl.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]#[N:36])=[CH:27][CH:28]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ccnn12
Reaction time: 3 h

Procedure:
To a solution of 4′-{[7-butyl-4-(trans-4-hydroxycyclohexyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (2.9 g) and rhodium acetate (dimer, 0.070 g) in methylene chloride (15 mL) was added dropwise a solution of ethyl diazoacetate (3.1 mL) in methylene chloride (3 mL), and the mixture was stirred for 3 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (2.1 g, 61%).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[S:23][C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[N:21][C:20]=2[CH3:34])=[CH:13][C:12]=1[CH3:35])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[OH-].[Na+]>>[CH3:35][C:12]1[CH:13]=[C:14]([O:17][CH2:18][C:19]2[S:23][C:22]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=3)=[N:21][C:20]=2[CH3:34])[CH:15]=[CH:16][C:11]=1[CH2:10][CH:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:36])=[O:2]
Reactant: CCCCCC(Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: CCCCCC(Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-2-{2-methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzyl}-heptanoic acid methyl ester was treated with 3 N NaOH to obtain [rac]-2-{2-methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzyl}-heptanoic acid as yellow crystals.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([CH:27]5[CH2:31][CH2:30][NH:29][C:28]5=[O:32])=[O:26])=[CH:20][C:19]=4[F:33])=[C:11]3[C:10]([CH3:34])=[N:9]2)=CC=1.FC(F)(F)C(O)=O>>[F:33][C:19]1[CH:20]=[C:21]([NH:24][C:25]([CH:27]2[CH2:31][CH2:30][NH:29][C:28]2=[O:32])=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([CH3:34])[C:11]=12
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc(NC(=O)C5CCNC5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2nccc(Oc3ccc(NC(=O)C4CCNC4=O)cc3F)c12
Temperature: 60 °C
Yield: 87.7 %

Procedure:
A 100 mL round-bottomed flask was charged with N-(4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-oxopyrrolidine-3-carboxamide (22.3 mg, 0.046 mmol) and 2,2,2-trifluoroacetic acid (259.7 mg, 2.28 mmol). The reaction mixture was stirred at 60° C. until LC-MS showed that the starting material was consumed (8 hour). The CF3COOH was removed under reduced pressure and the residue purified by column (Silica gel, DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to give the desired product (14.9 mg, 88.6%). HPLC: >99% purity, 1.91 min (254 nm); LRMS (APCI neg) m/e 368 (M−1). 1H NMR (400 MHz, CD3OD) δ 8.25 (d, J=5.6 Hz, 1H), 7.85 (dd, J=12.4, 2.4 Hz, 1H), 7.43 (m, 1H), 7.37 (t, J=8.8 Hz, 1H), 6.25 (dd, J=5.6, 0.8 Hz, 1H), 3.52-3.38 (m, 2H), 3.31 (m, 1H), 2.71 (s, 3H), 2.52-2.59 (m, 1H), 2.38-2.44 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6]C(=O)C)=[C:4]([F:12])[CH:3]=1.Cl>C(O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([NH2:6])=[C:4]([F:12])[CH:3]=1
Reactant: CC(=O)Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CCO
Product: Nc1ccc(Cl)cc1F

Procedure:
A mixture of 119 parts of 4'-chloro-2'-fluoroacetanilide in 475 parts of ethanol and 200 parts of 37% hydrochloric acid was refluxed for 17 hours and the solvent removed under a reduced pressure of 300 mm.Hg to yield the moist, solid hydrochloride salt of 4-chloro-2-fluoro-aniline.
Reaction SMILES: Cl.C([NH:10][C:11](=[S:25])[N:12]([CH:16]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[Cl:24])[CH3:17])[CH2:13][CH2:14][CH3:15])(=O)C1C=CC=CC=1>O>[Cl:24][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:18]=1[CH:16]([N:12]([CH2:13][CH2:14][CH3:15])[C:11]([NH2:10])=[S:25])[CH3:17]
Reactant: CCCN(C(=S)NC(=O)c1ccccc1)C(C)c1ccncc1Cl
Agent: Cl
Solvent: O
Product: CCCN(C(N)=S)C(C)c1ccncc1Cl
Reaction time: 1 h

Procedure:
Add 6 ml of 32% hydrochloric acid to 1.18 g of the compound obtained in Step A. Bring the reaction medium to 80° C. for one hour, then cool and add water. Extract with methylene chloride and discard the organic phase. Alkanilise the aqueous phase with sodium carbonate and extract with methylene chloride. Dry the organic phase and evaporate under vacuum. Purify the residue by chromatography on a silica column, using a mixture of methylene chloride and methanol (98:2 V/V) as eluent.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][C:13]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=2[F:29])[CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16]>>[F:29][C:23]1[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]1[CH:19]=[CH:18][C:14]([C:15]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)=[O:16])=[C:13]([CH3:12])[N:21]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: Cc1nc(-c2cccc(F)c2F)ccc1C(=O)O
Product: Cc1nc(-c2cccc(F)c2F)ccc1C(=O)Nc1ccc2cccnc2c1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (28 mg, 0.20 mmol) and 6-(2,3-difluorophenyl)-2-methyl-nicotinic acid (D26) (54 mg, 0.33 mmol), as a brown solid. MS(ES): MH+ 376, M-H+ 374.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:21])[CH:4]=[C:3]1[CH3:22].[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.CO>CN(C=O)C.O>[CH3:28][O:27][C:23](=[O:26])[CH2:24][CH2:25][N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:12]([CH2:11][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:2]([CH3:1])[C:3]([CH3:22])=[CH:4]3)[C:13]1=[O:21]
Reactant: C=CC(=O)OC
Reactant: Cc1cc2cccc(Cn3c(=O)[nH]c4ccccc43)c2n1C
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCn1c(=O)n(Cc2cccc3cc(C)n(C)c23)c2ccccc21
Yield: 41.1 %

Procedure:
To a solution of 1-(1,2-dimethyl-1H-indol-7-ylmethyl)-1,3-dihydro-benzimidazol-2-one (170 mg, 0.58 mmol) in DMF (3.0 mL) are added methyl acrylate (0.06 mL, 0.6 mmol) and 40% benzyltrimethyl ammonium hydroxide in MeOH (0.06 mL, 0.15 mmol). The resulting mixture is stirred at room temperature for 18 h after which time water (20 mL) was added. The mixture is extracted with EtOAc (3×50 mL) and the organic layers are combined, dried over MgSO4 and concentrated to give crude product. Purification by flash column chromatography using 20-50% EtOAc in Hexanes affords 90 mg (41%) of 3-[3-(1,2-dimethyl-1H-indol-7-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid methyl ester.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][CH2:11]2.CS(C)=O.[Br:26]N1C(=O)CCC1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([Br:26])[CH2:11]2
Reactant: O=C1CCC(=O)N1Br
Reactant: C1=Cc2c(cccc2-c2ccccc2-c2ccccc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: O
Product: BrC1=Cc2c(cccc2-c2ccccc2-c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
A cold solution (5° C.) of compound 8 (40 g, 149 mmol, 1 equiv), dimethyl sulfoxide (400 mL) and water (5 mL) was treated in one portion with N-bromosuccinimide (39.8 g, 224 mmol, 1.5 equiv). The bath was removed and the reaction allowed to stir at room temperature overnight. The reaction was poured into water (1 L) and extracted with ethyl acetate (2×500 mL). The combined organic layers were washed with saturated brine (1 L), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in 500 mL of toluene and p-toluenesulfonic acid (5.6 g, 29.4 mmol, 0.2 equiv) was added. This mixture was refluxed for 20 h while removing water with a Dean-Stark trap. The reaction was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified over silica gel (1 Kg), eluting with heptanes to give compound 9 (39 g, 75% yield) as a light yellow solid.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][C:5]([CH3:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].Cl>CC(C)=O>[CH:8]1([C:6](=[O:7])[C:5]([CH3:20])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:4][CH:3]=[O:2])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(CC(C)(C(=O)C1CCCCC1)c1ccccc1)OC
Agent: Cl
Solvent: CC(C)=O
Product: CC(CC=O)(C(=O)C1CCCCC1)c1ccccc1
Yield: 97.6 %

Procedure:
To a solution of 82.65 g (66.29 g, 0.2177 mol) of 4cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde dimethyl acetal in 539 mL of acetone was added 539 mL of 3 N HCl (aq) at RT. After reaction completion (2 h), the mixture was concentrated to 426.5 g (or ⅓ volume) of residue (RT−40° C.). The residue contained mostly water (pH=0) and was extracted twice with 300 mL of MTBE. The MTBE extract was washed with 300 mL of 25% NaCl (aq), dried over MgSO4, gravity filtered and concentrated to afford 54.92 g (97.65%) of title compound as a pink oil: 1H NMR (d6-DMSO): δ 9.54 (t, J=2.0 Hz, 1H, —CHO), 7.36-7.45 (m, 2H, phenyl CH), 7.28-7.35 (m, 3H, phenyl CH), 2.95 (dd, J=16.6 Hz, J=1.9 Hz, 1H, CH2CHO), 2.85 (dd, J=16.6 Hz, J=1.7 Hz, 1H, CH2CHO), 2.41-2.49 (m, 1H, cyclohexyl CH), 1.72 (s, 3H, R2C(CH3)Ph), 0.85-1.66 (m, 10H, cyclohexyl —CH2).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([C:9]([OH:18])([C:14]([F:17])([F:16])[Cl:15])[C:10]([F:13])([F:12])[Cl:11])[CH:6]=[C:5]([CH3:19])[C:3]=1[NH2:4].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].[I-].[K+].C([O-])(O)=O.[Na+]>CC#N>[CH2:25]([O:24][C:22]([CH2:21][NH:4][C:3]1[C:2]([CH3:1])=[CH:8][C:7]([C:9]([OH:18])([C:10]([F:12])([F:13])[Cl:11])[C:14]([F:16])([F:17])[Cl:15])=[CH:6][C:5]=1[CH3:19])=[O:23])[CH3:26]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(C(O)(C(F)(F)Cl)C(F)(F)Cl)cc(C)c1N
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CNc1c(C)cc(C(O)(C(F)(F)Cl)C(F)(F)Cl)cc1C

Procedure:
Combine 2,6-dimethyl-4-(tetrafluoro-1,3-dichloro-2-hydroxy-2-propyl)aniline [Gilbert, et. al., J. Org. Chem., 30, 1001 (1965)] (26 g=0.08 mol) with ethyl bromoacetate (22 g=0.13 mol) and potassium iodide (22 g=0.13 mol) in 150 ml CH3CN. Heat to reflux and add NaHCO3 (13.4 g=0.16 mol). Heat at reflux 20 hours, allow to cool, pour onto water, and extract with Et2O. Wash the Et2O with 10% Na2CO3, then 1 N HCl. Dry over MgSO4 and filter. Add 4 N HCl/Et2O and dilute with an equal volume of hexane. Decant and wash the solid with benzene. Partition the solid between 10% Na2CO3 and Et2O. Dry and concentrate the Et2O. Recrystallize the residue from hexane to obtain the title product as a white solid, melting at about 102°-104° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:13])([CH3:12])[CH2:5][N:6]1[CH:10]=[C:9]([I:11])[CH:8]=[N:7]1.CC(C[AlH]CC(C)C)C.[OH-].[NH4+]>C1COCC1>[I:11][C:9]1[CH:8]=[N:7][N:6]([CH2:5][C:4]([CH3:13])([CH3:12])[CH2:3][OH:2])[CH:10]=1
Reactant: COC(=O)C(C)(C)Cn1cc(I)cn1
Agent: CC(C)C[AlH]CC(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(CO)Cn1cc(I)cn1
Temperature: 25 °C

Procedure:
A cold (−20° C.) solution of 3-(4-Iodopyrazol-1-yl)-2,2-dimethylpropionic acid methyl ester (Compound 47F, 6.0 g, 19.48 mmol) in THF (80 mL) was treated with DIBAL (42.85 mL, 42.85 mmol, 1M solution in toluene) and allowed to warm to RT over a period of 2 h. The reaction mixture was treated with aq. ammonium hydroxide (20 mL) and the solids were filtered through celite. The filtrate was diluted with ethyl acetate (50 mL) and washed with brine (2×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give 4.9 g (90%) as an oil which crystallized upon standing. 1H NMR (500 MHz, CDCl3) δ 7.50 (s, 1H), 7.41 (s, 1H), 4.0 (s, 2H), 3.17 (s, 3H), 0.9 (s, 6H).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:23][NH2:24]>CO>[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[O:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([NH:23][NH2:24])=[O:2])[CH2:6][CH2:7]1
Reactant: COC(=O)[C@H]1CC[C@H](Oc2ccc3ccccc3c2)CC1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)[C@H]1CC[C@H](Oc2ccc3ccccc3c2)CC1
Temperature: 80 °C

Procedure:
A mixture of trans-4-(naphthalen-2-yloxy)-cyclohexanecarboxylic acid methyl ester (0.130 g, 0.457 mmol) and hydrazine hydrate (0.02 ml, 0.45 mmol) in methanol (0.5 ml) was heated at 80° C. for 16 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.112 g, 86%) as yellow solid, which was used in the next step without further purification. MS m/e: 285 (M+H+)