Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1)=[O:6].[F:15][C:16]1[C:17](=[O:50])[NH:18][C:19](=[O:49])[N:20]([CH:48]=1)[C@@H:21]1[O:47][C@H:25]([CH2:26][O:27]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:23]([OH:24])[CH2:22]1>O1CCOCC1>[F:15][C:16]1[C:17](=[O:50])[NH:18][C:19](=[O:49])[N:20]([CH:48]=1)[C@@H:21]1[O:47][C@H:25]([CH2:26][OH:27])[C@@H:23]([O:24][CH2:11][C:10]2[CH:13]=[CH:14][C:7]([C:5]([OH:4])=[O:6])=[CH:8][CH:9]=2)[CH2:22]1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(CO[C@H]2C[C@H](n3cc(F)c(=O)[nH]c3=O)O[C@@H]2CO)cc1
Temperature: 25 °C
Yield: 27.8 %

Procedure:
Potassium hydroxide (4.30 g) and 1.70 g of 4-methoxycarbonylbenzyl bromide were added to a solution of 3.00 g of 2'-deoxy-5-fluoro-5'-O-trityluridine in 200 ml of dioxane. The mixture was stirred at room temperature for a day. The reaction mixture was concentrated under a reduced pressure. To the concentrate was added 200 ml of water and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was rendered acidic with acetic acid, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under a reduced pressure. The concentrate was dissolved in 50 ml of a 80% aqueous solution of acetic acid. The solution was heated to 100° C. for 2 hours. The solvent was distilled off and the residue was applied to silica gel column chromatography using 3% methanol-chloroform as an eluent, affording 650 mg of the title compound in a yield of 28%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([CH3:30])[CH:3]=1.Cl.[NH2:32][OH:33].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:9]/[C:10](=[N:32]\[OH:33])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(S(N)(=O)=O)cc1

Procedure:
In analogy to example 151, step 3, 4-(1-(4-chloro-2-methylphenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)benzenesulfonamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid, MS (ESI+): m/z=460.2 [M+H]+.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1[CH:36]=[CH:35][C:15]([CH2:16][C:17]2([C:30](OCC)=[O:31])[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]2)=[CH:14][CH:13]=1>C1COCC1.CCOCC>[OH:31][CH2:30][C:17]1([CH2:16][C:15]2[CH:35]=[CH:36][C:12]([CH3:11])=[CH:13][CH:14]=2)[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:18]1
Reactant: CCOC(=O)C1(Cc2ccc(C)cc2)CCCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(CC2(CO)CCCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
A solution of diisobutylaluminum hydride (12.0 ml, 12.0 mmol, 1M in THF) was added dropwise to a solution of the product from STEP 2 (1.5 g, 6.0 mmol) in 15 ml THF at −20° C. The resulting mixture was stirred at −20° C. for 20 min and allowed to warm to room temperature. After 3 h, the reaction was diluted with ether (70 ml) and washed with 50 ml of aqueous 1M tartaric acid. The organic extracts were dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (SiO2, ethyl acetate/hexane=1/3) to afford 0.58 g of a viscous. The 1H NMR spectrum of the product was consistent for the proposed structure.
Reaction SMILES: [Na].[O:2]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH:17]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(N)=O>C(O)C>[O:2]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:17]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)C(Br)C1CCCCC1
Agent: [Na]
Solvent: CCO
Solvent: NC=O
Product: CCOC(=O)C(Oc1ccc(Oc2ccccc2)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
Into 15 ml of anhydrous ethanol, 205 mg (0.0089 mole) of methallic sodium was dissolved and then, 1.8 g (0.0089 mole) of p-phenoxyphenol was added. The mixture was stirred at room temperature for about 30 minutes. Ethanol was distilled off under a reduced pressure and 5 ml of dimethyl formamide was added to the residue and dimethyl formamide was distilled off under a reduced pressure and then, 15 ml of dimethyl formamide was added to the residue to dissolve it. Into the solution, 2.5 g (0.010 mole) of ethyl α-bromo-α-cyclohexylacetate was added. The mixture was refluxed for 8 hours and then diemethyl formamide was distilled off under a reduced pressure. The residue was admixed with 50 ml of water and extracted twice with 50 ml of benzene. The benzene layers were combined and washed three times with 30 ml of 5% NaOH aq.sol. and then with water and dehydrated over sodium sulfate and distilled in vacuum to obtain 1.4 g of ethyl α-(p-phenoxyphenoxy)α-cyclohexylacetate (yield: 42.6%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7](=[O:21])[N:8]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:9]=[CH:10][C:11]=1[C:12](OCC)=[O:13])[CH:2]([CH3:4])[CH3:3].S(Cl)([Cl:24])=O>>[CH2:1]([O:5][C:6]1[C:7](=[O:21])[N:8]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:9]=[CH:10][C:11]=1[C:12]([Cl:24])=[O:13])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1ccn(CC(C)C)c(=O)c1OCC(C)C
Reactant: O=S(Cl)Cl
Product: CC(C)COc1c(C(=O)Cl)ccn(CC(C)C)c1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a solution of ethyl 3-isobutoxy-1-isobutyl-2-oxo-1,2-dihydropyridine-4-carboxylate (Intermediate 8) (100 mg, 0.339 mmol) was added thionyl chloride (24.71 μL, 0.3390 mmol). The reaction mixture was stirred at 80° C. for 3 h. The solvent was evaporated under reduced pressure to give Example 52A which was used without further purification (90 mg, 0.315 mmol, 93% yield). LCMS RT=1.89 min [M+MeO+1]=282 {(MeOH/H2O/TFA) Phenom. Luna C18; 50×4.6 mm; 4 min Grad}.
Reaction SMILES: [CH2:1]([N:3]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1)[CH2:4][CH2:5][NH:6]C(=O)OC(C)(C)C)[CH3:2].[ClH:21]>C(Cl)Cl>[ClH:21].[ClH:21].[CH2:1]([N:3]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1)[CH2:4][CH2:5][NH2:6])[CH3:2]
Reactant: CCN(CCNC(=O)OC(C)(C)C)c1cc(C)ccn1
Agent: Cl
Solvent: ClCCl
Product: CCN(CCN)c1cc(C)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl N-[2-[ethyl-(4-methyl-2-pyridyl)amino]ethyl]carbamate (130 mg, 0.465 mmol) was dissolved in DCM (10 ml) and flushed with nitrogen. Hydrochloric acid (4N in dioxane, 9.31 mmol, 2.33 ml) was added and the mixture was stirred at room temperature overnight. The product was filtered off, dissolved in a mixture of acetonitrile and water and obtained by evaporation under reduced pressure to yield 58 mg (0.229 mmol, 49%) MS(ESI) m/z=180.2 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>[Ni].CO>[NH2:1][C:4]1[C:5]([O:10][C@H:11]2[CH2:12][CH2:13][C@H:14]([OH:17])[CH2:15][CH2:16]2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccnc1O[C@H]1CC[C@H](O)CC1
Agent: [Ni]
Solvent: CO
Product: Nc1cccnc1O[C@H]1CC[C@H](O)CC1
Reaction time: 4.5 h

Procedure:
A mixture of 0.29 g trans-4-(3-nitro-pyridin-2-yloxy)-cyclohexanol and 0.05 g Raney nickel in 50 ml methanol was hydrogenated at 5 bar and rt for 4.5 hours. The reaction mixture was filtered and the filtrate concentrated.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][C:15]2[CH:25]=[CH:24][C:18]3[O:19][C:20]([F:23])([F:22])[O:21][C:17]=3[CH:16]=2)[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl>[F:23][C:20]1([F:22])[O:19][C:18]2[CH:24]=[CH:25][C:15]([CH2:14][CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[CH:16][C:17]=2[O:21]1
Reactant: CC(C)(C)OC(=O)N1CCCC(Cc2ccc3c(c2)OC(F)(F)O3)C1
Agent: Cl
Solvent: ClCCl
Product: FC1(F)Oc2ccc(CC3CCCNC3)cc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.8 mmol) in CH2Cl2 (11 mL) was added HCl (4 M in dioxane, 4.2 mL, 16.9 mmol). The reaction mixture was stirred at r.t. overnight and then concentrated to give 3-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]-piperidine as the hydrochloride salt (791 mg, 96%). The crude product was used without further purification.
Reaction SMILES: C12BC(CCC1)CCC2.C(O[CH:13]([O:16]CC)[CH:14]=[CH2:15])C.Br[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[N:26]1[C:27]2[C:22](=[CH:21][C:20]([CH2:16][CH2:13][CH:14]=[O:15])=[CH:29][CH:28]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: C=CC(OCC)OCC
Reactant: Brc1ccc2ncccc2c1
Agent: [Pd+2]
Agent: B1C2CCCC1CCC2
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: C1CCOC1
Solvent: O
Product: O=CCCc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 52.1 %

Procedure:
A 22 L flask charged with 0.5 M solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (9-BBN, 5.75 L, 2.89 mol, 2.0 equiv) and tetrahydrofuran (THF, 6 L) was treated with 3,3-diethoxy-1-propene (393 g, 3.02 mol, 2.10 equiv) at 0-5° C. and the resulting reaction mixture was subsequently warmed to room temperature and stirred at room temperature for 14 h. 6-Bromoquinoline (8, 300 g, 1.44 mol, 1.0 equiv), palladium acetate (Pd(OAc)2, 16.1 g, 0.072 mol, 0.05 equiv), potassium carbonate (K2CO3, 398 g, 2.89 mol, 2.0 equiv), tricyclohexylphosphine (22.3 g, 0.079 mol, 0.055 equiv), and water (52 g, 2.8 mol) were added to the reaction mixture at room temperature before being degassed with nitrogen for 1 h. The resulting reaction mixture was heated to 75° C. for 1 h. When TLC and LC/MS showed the reaction was deemed complete, the reaction mixture was cooled to room temperature and water (2 L) was added to dissolve the salts. The resulting mixture was then concentrated under the reduced pressure to a volume of approximately 4 L before being filtered through a plug of Celite. The Celite plug was washed with ethyl acetate (EtOAc, 2 L). The filtrate was concentrated under the reduced pressure to a volume of approximately 2 L and this residual solution was then added slowly over 5 min to a flask containing a 2.0 M aqueous hydrochloric acid (HCl) solution (2 L) at 0-5° C. The resulting solution was stirred at 0-5° C. for 14 h before being quenched with saturated aqueous sodium bicarbonate (NaHCO3) solution at 0° C. until the pH was between 8 to 9. The layers were separated and the aqueous layer was extracted with ethyl acetate (EtOAc, 2 L). The combined organic layers were washed with brine (1 L), dried with sodium sulfate (Na2SO4), and concentrated under the reduced pressure. The residue, which contains the crude 3-(quinolin-6-yl)propanal (9) was purified by flash column chromatography (SiO2, 20-80% ethyl acetate in heptane gradient elution) to afford 3-(quinolin-6-yl)propanal (9, 139 g, 266.7 g theoretical, 52.1%) as a yellow oil, which was found to be identical to the material obtained from Methods 1 and 2.
Reaction SMILES: [CH2:1]([N:8]1[N:12]=[N:11][C:10]([C:13]2[C:14]([NH:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[N:15][C:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:34])(=[N:28]C(OCC)=O)=[O:27])=[CH:22][CH:21]=3)=[N:17][CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])C.[Na+].[Na+].[Cl-]>C(O)C>[CH2:1]([N:8]1[N:12]=[N:11][C:10]([C:13]2[C:14]([NH:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[N:15][C:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:34])(=[NH:28])=[O:27])=[CH:22][CH:21]=3)=[N:17][CH:18]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3nnn(Cc4ccccc4)n3)c(NC3CCCCC3)n2)cc1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CS(=N)(=O)c1ccc(Nc2ncc(-c3nnn(Cc4ccccc4)n3)c(NC3CCCCC3)n2)cc1
Temperature: 60 °C
Reaction time: 22 h

Procedure:
28 mg (0.048 mmol) (RS)—S-(4-{[5-(2-benzyl-2H-tetrazol-5-yl)-4-(cyclohexyl-amino)pyrimidine-2-yl]amino}phenyl)-N-(ethoxycarbonyl)-S-methylsulfoximide in 0.4 ml ethanol are treated with 78 μL (0.119 mmol) of a freshly prepared 1.53 molar sodium ethanolate solution and stirred for 22 hours at 60° C. Next, a further 0.15 ml (0.229 mmol) of the 1.53 molar sodium ethanolate solution is added, and the mixture stirred for a further 22 hours at 60° C. The mixture is treated with saturated NaCl solution and extracted with ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated. 24 mg (0.048 mmol, corresponding to 100% of theor.) of the product is obtained.
Reaction SMILES: [O:1]1[CH2:6][C:5](=[O:7])[NH:4][C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[H-].[Na+].[CH3:14]I.[Cl-].[NH4+]>CN(C=O)C>[CH3:14][N:4]1[C:5](=[O:7])[CH2:6][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[N:8][C:3]1=2
Reactant: CI
Reactant: O=C1COc2cccnc2N1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN1C(=O)COc2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,3-Dihydro-4H-pyrido[3,2-b][1,4]oxazin-3-one (U.S. Pat. No. 3,854,926; 1.5 g) was added portionwise to a stirred suspension of sodium hydride (60% w/w dispersion in mineral oil; 0.4 g) in DMF (30 ml) which had been cooled in an ice-bath. The mixture was allowed to warm to ambient temperature and was stirred for 30 minutes. Methyl iodide (0.65 ml) was added and the mixture was stirred at ambient temperature for 16 hours. The mixture was poured into a saturated aqeuous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and with brine, dried (MgSO4) and evaporated to give 4-methyl-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-3-one (1.58 g) which was used without further purification.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH3:5].[Mg].Cl[SiH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH2:11][CH2:10]1>O1CCCC1>[CH2:1]([Si@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Fc1ccc(-c2ccc(-c3ccc(CCC4CC[SiH](Cl)CC4)cc3)cc2)cc1
Reactant: CCCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H](CCc2ccc(-c3ccc(-c4ccc(F)cc4)cc3)cc2)CC1

Procedure:
15.1 g (100 mmol) of n-pentyl bromide was dripped into a mixture of 2.4 g of magnesium (100 mmol) and 60 ml of tetrahydrofuran (hereafter referred to as "THF") to obtain a Grignard's reagent. This solution was then dripped into a 300 ml THF solution of 40.9 g of 4-(2-(4-chloro-4-silacyclohexyl)ethyl)-4'-(4-fluorophenyl)biphenyl. The reaction mixture thus obtained was a mixture of trans isomers and cis isomers with respect to the silacyclohexane ring. After a conventional after treatment, they were separated by means of chromatography to obtain 38.1 g (yield 93%) of the target product.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:12](O)[CH2:13][OH:14].C(OCC)(OCC)OCC>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][C:2]1([CH2:9][CH2:10][CH3:11])[O:14][CH2:13][CH2:12][O:1]1)[CH3:8]
Reactant: OCCO
Reactant: CCCC(=O)CC(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(OCC)OCC
Product: CCCC1(CC(=O)OCC)OCCO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
A mixture of ethyl 3-oxohexanoate (5 g, 31.6 mmol), ethylene glycol (3.92 g, 63.2 mmol) and triethyl orthoformate (4.68 g, 31.6 mmol), and p-toluenesulfonic acid monohydrate (544 mg, 2.86 mmol) was stirred at room temperature for 29 hours and 10 minutes. To the reaction mixture, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced press-re to obtain the title compound (6.2 g, 97%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:3]([O:16][CH2:17][CH:18]2[CH:23]([CH3:24])[CH2:22][CH2:21][CH2:20][CH:19]2[CH3:25])=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH:26]1(B(O)O)[CH2:28][CH2:27]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:26]1([C:2]2[C:3]([O:16][CH2:17][CH:18]3[CH:23]([CH3:24])[CH2:22][CH2:21][CH2:20][CH:19]3[CH3:25])=[CH:4][C:5]([F:15])=[C:6]([CH:14]=2)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:28][CH2:27]1
Reactant: OB(O)C1CC1
Reactant: CC1CCCC(C)C1COc1cc(F)c(C(=O)OC(C)(C)C)cc1Cl
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1CCCC(C)C1COc1cc(F)c(C(=O)OC(C)(C)C)cc1C1CC1
Temperature: 130 °C
Yield: 100 %

Procedure:
To a solution of tert-butyl 5-chloro-4-((2,6-dimethylcyclohexyl)-methoxy)-2-fluorobenzoate (0.43 g, 1.16 mmol), cyclopropylboronic acid (0.14 g, 1.74 mmol), potassium phosphate (1.48 g, 7.00 mmol) and tricyclohexylphosphine tetrafluoroborate (0.085 g, 0.230 mmol) in toluene (5 mL) and water (0.5 mL) under a nitrogen atmosphere was added palladium acetate (0.04 g, 0.12 mmol). The reaction mixture was heated at 130° C. for 30 minutes in the microwave then cooled to ambient temperature. Water (20 mL) was added and the mixture extracted with ethyl acetate (3×10 mL), the combined organics were washed with brine; dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography (5% ethyl acetate in hexanes) afforded tert-butyl 5-cyclopropyl-4-((2,6-dimethylcyclohexyl)methoxy)-2-fluorobenzoate (0.43 g, 1.16 mmol) which was used directly into the next step. To a solution of this compound (0.43 g, 1.16 mmol) in dichloromethane (2 mL), was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at 0° C. for 1 hour and then concentrated in vacuo. The residue was purified by column chromatography (0 to 30% ethyl acetate in hexanes) to afford the title compound (0.142 g, 38%). MS (ES−) m/z 319.2 (M−1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1)=O.[CH2:14]([C:18]1[N:19]([CH2:32][CH2:33][CH2:34][NH:35][CH:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:20]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[C:22]([NH2:30])[C:21]=2[N:31]=1)[CH2:15][CH2:16][CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN1C(=O)CCC1.CO>[NH2:30][C:22]1[C:21]2[N:31]=[C:18]([CH2:14][CH2:15][CH2:16][CH3:17])[N:19]([CH2:32][CH2:33][CH2:34][N:35]([CH2:1][C:3]3[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=3)[CH:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)[C:20]=2[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:23]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC1CCN(C)CC1
Reactant: COC(=O)Cc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(Cc1cccc(CC(=O)OC)c1)C1CCN(C)CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of methyl 2-(3-formylphenyl)acetate (0.15 g) dissolved in NMP (10 mL) was added to a stirred solution of the product from step (i) (0.36 g) in NMP (10 mL) at rt. Sodium triacetoxyborohydride (0.90 g) was added to the mixture, the temperature was increased to 50° C. and the reaction mixture stirred for 24 h. The resulting solution was dissolved in methanol (0.5 mL), acidified with acetic acid (0.5 mL) and purified by SCX. The crude product was further purified by RPHPLC to give the title product, yield 22 mg.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[C:19](#N)[CH3:20]>>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([CH2:12][CH2:7][CH2:8][CH2:9][C:20]3[CH:19]=[CH:3][CH:2]=[CH:1][CH:6]=3)[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(CCCCN2CCC(c3ccccc3)CC2)cc1

Procedure:
4-Phenylpiperidine (1 eq) was reacted with 4-phenylbromobutyl (1 eq) in the presence of K2CO3 in acetonitrile at reflux overnight. The product obtained was treated and purified on a silica column. The 1H NMR at 500 MHz is in accordance with the expected structure.
Reaction SMILES: I.I.[N:3]1([C:10]2[N:14]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[N:11]=2)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[CH:28][C:27]=1[C:37]([N:39]1[CH2:43][CH2:42][C@:41]([CH2:50][CH2:51]OS(C)(=O)=O)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)=[O:38].C(N(CC)CC)C>C(#N)C>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[CH:28][C:27]=1[C:37]([N:39]1[CH2:43][CH2:42][C@@:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([CH2:50][CH2:51][N:6]2[CH2:7][CH2:8][CH2:9][N:3]([C:10]3[N:14]([CH2:15][C:16]([F:19])([F:17])[F:18])[C:13]4[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=4[N:11]=3)[CH2:4][CH2:5]2)[CH2:40]1)=[O:38]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: FC(F)(F)Cn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCN2CCCN(c3nc4ccccc4n3CC(F)(F)F)CC2)(c2ccccc2)C1
Yield: 77 %

Procedure:
Reflux a stirred solution of 2-[1,4]diazepan-1-yl-1-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole dihydroiodide (0.44 g, 0.79 mmol), methanesulfonic acid 2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethyl ester (0.38 g, 0.79 mmol, example 47.2), triethylamine (2.54 mmol) and acetonitrile (11 mL) under argon for 20 hours. Cool and concentrate in vacuo. Dilute with dichloromethane (100 mL), wash the organic phase with NaHCO3 solution (2×20 mL), dry (Na2SO4) the organic phase, filter and evaporate in vacuo. Purify the residue by flash chromatography (silica gel, 7×15 cm) eluting with 10% methanol/0.1% ammonium hydroxide solution in dichloromethane, concentrate the appropriate fractions, and dry the resultant material in vacuo (0.2 Torr) for 2 hours to afford 0.41 g of the title compound as a beige colored foam, Rf=0.39 (silica gel, 10% methanol/0.1% ammonium hydroxide solution in dichloromethane). The compound may be converted to the dihydrochloride salt by methods well known in the art.
Reaction SMILES: [Br:1][C:2]1[C:14]([CH3:15])=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9])=[CH:4][C:3]=1[CH3:16].C(N1C=CN=C1)([N:19]1C=CN=C1)=O.O.[OH-].[NH4+]>O1CCCC1>[Br:1][C:2]1[C:14]([CH3:15])=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([NH2:19])=[O:9])=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc(OC(C)(C)C(=O)O)cc(C)c1Br
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OC(C)(C)C(N)=O)cc(C)c1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(4-Bromo-3,5-dimethyl-phenoxy)-2-methyl-propionic acid (500 mg) is dissolved in 10 mL of tetrahydrofurane, 1,1′-carbonyldimidazole (217 mg) and 30% ammonium hydroxide water solution are added and the reaction mixture is stirred at room temperature for 3 h. The reaction mixture is concentrated under vacuum, ethyl acetate is added and the organic solution is washed with a 10% HCl water solution. The organic phase is separated, dried over sodium sulfate and concentrated under vacuum to give the title compound. Yield: 300 mg.