Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:21])[CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:22](Cl)(=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(Cl)(Cl)Cl>[CH3:21][N:9]([CH3:8])[CH2:10][CH2:11][CH2:12][N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=[C:37]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: CN(C)CCCNc1ccccc1N
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCc1nc2ccccc2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Triethylamine (0.80 ml) was added to a solution containing N-[3-(dimethylamino)propyl]-1,2-benzenediamine (1.00 g) in chloroform (10 ml) and then palmitoyl chloride (1.58 ml) was added thereto while being cooled with ice. After being stirred for 2.5 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium bydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (4.3 ml) was added to a solution containing the residue (2.25 g) in ethanol (23 ml). After being stirred for 1.5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (2.21 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=30:1), thereby yielding the entitled compound (1.44 g) as yellow syrup.
Reaction SMILES: [CH2:1]1[C:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[NH:8][C:7]=3[CH:6]=[CH:5][C:4]=2[C:3](=[O:17])[CH2:2]1.Br[CH2:19][CH2:20][CH2:21][N:22]([CH2:35][CH2:36][CH3:37])[S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33])(=[O:25])=[O:24].[H-].[Na+].CCCCCC.C(OCC)(=O)C>C(Cl)Cl>[N+:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[S:23]([N:22]([CH2:35][CH2:36][CH2:37][N:8]1[C:7]2[CH:6]=[CH:5][C:4]3[C:3](=[O:17])[CH2:2][CH2:1][C:16]=3[C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)[CH2:21][CH2:20][CH3:19])(=[O:25])=[O:24])([O-:34])=[O:33]
Reactant: O=C1CCc2c1ccc1[nH]c3ccccc3c21
Reactant: CCCN(CCCBr)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCN(CCCn1c2ccccc2c2c3c(ccc21)C(=O)CC3)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
Compound 46 (0.538 g, 2.43 mmol) and bromide 50 (0.9 g, 2.46 mmol) were dissolved in CH2Cl2 (30 mL). Then NaH (0.15 g, 3.75 mmol, 1.5 eq.) was added. The reaction mixture was stirred for 20 min (TLC monitoring, eluent: hexane-ethyl acetate, 1:1). Then, the mixture was poured onto ice. The product was extracted with ethyl acetate, and the extract was evaporated in a rotary evaporator. The residue of CH2Cl2 was removed in high vacuum. Methanol was added to the hardened precipitate. The product was triturated; the precipitate was filtered off. Yield of 47: 0.638 g (52%).
Reaction SMILES: C(O)(O)CC.[Br:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([C:14]2C=[CH:21][CH:20]=[CH:19][C:15]=2C(Cl)=O)=[CH:9][C:8]=1[F:23].[OH:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26].C(OC(=O)C)(=O)C>C(OCC)C>[O-:27][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:26])=[O:24].[Br:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([C+:14]2[CH2:15][CH2:19][CH2:20][CH2:21][S:25]2)=[CH:9][C:8]=1[F:23]
Reactant: O=C(Cl)c1ccccc1-c1cc(F)c(Br)c(F)c1
Reactant: O=S(=O)(O)C(F)(F)F
Agent: CCC(O)O
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: Fc1cc([C+]2CCCCS2)cc(F)c1Br
Product: O=S(=O)([O-])C(F)(F)F
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Propanediol (0.3 mole) is cooled under a nitrogen atmosphere to a temperature of 0° C. Then 4-bromo-3,5-difluorophenylbenzoylchloride (0.3 mole) are swiftly added with continuous stirring. The reaction mixture is then cooled to −10° C. and triflic acid (0.45 mole) is added. The reaction mixture is stirred further for 1 hour, then acetic anhydride (2 mole) is added maintaining the temperature below 5° C. After adding diethyl ether and stirring for 1 more hour at −10° C., 4-bromo-3,5-difluorophenyl-thianylium triflate is filtered off and washed with cold ether.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)=[N:8][C:7]=2[N:6]([CH2:27][CH2:28][CH3:29])[C:5]1=[O:30])[CH2:2][CH3:3].[CH:31]([C:34]1[CH:39]=[CH:38][C:37]([N:40]2[C:44](=[O:45])[CH2:43][CH:42]([CH2:46]OS(C)(=O)=O)[CH2:41]2)=[CH:36][CH:35]=1)([CH3:33])[CH3:32].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH:31]([C:34]1[CH:39]=[CH:38][C:37]([N:40]2[C:44](=[O:45])[CH2:43][CH:42]([CH2:46][N:25]3[CH:26]=[C:22]([C:9]4[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:21])[CH3:19])[C:11]5[C:12](=[O:13])[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:30])[N:6]([CH2:27][CH2:28][CH3:29])[C:7]=5[N:8]=4)[CH:23]=[N:24]3)[CH2:41]2)=[CH:36][CH:35]=1)([CH3:33])[CH3:32]
Reactant: CCCn1c(=O)c2c(nc(-c3cn[nH]c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Reactant: CC(C)c1ccc(N2CC(COS(C)(=O)=O)CC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(=O)c2c(nc(-c3cnn(CC4CC(=O)N(c5ccc(C(C)C)cc5)C4)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Temperature: 77.5 °C
Yield: 80.5 %

Procedure:
A mixture of 1,3-dipropyl-8-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.100 g, 0.23 mmol), methanesulfonic acid 1-(4-isopropyl-phenyl)-5-oxo-pyrrolidin-3-ylmethyl ester (0.107 g, 0.34 mmol), K2CO3 (0.048 g, 0.34 mmol) and DMF (1 ml) were heated at 75-80° C. for 16 hrs. Reaction mixture was cooled to 20-25° C. and water was added (10 ml). The aqueous layer was extracted with ethyl acetate, washed with saturated brine solution. The organic layer was dried over Na2SO4 and evaporated to obtain crude product (0.2 g). The crude product was purified by preparative TLC to obtain pure 8-{1-[1-(4-isopropyl-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazol-4-yl}-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.12 g, 80%) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:20][C:21]1([CH3:29])[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23][CH2:22]1)(=O)=O>CN(C)C=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:20][C:21]2([CH3:29])[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23][CH2:22]2)=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)nc1
Reactant: CC1(COS(C)(=O)=O)COC(C)(C)OC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(COc2cnc(Cl)nc2)COC(C)(C)OC1
Temperature: 90 °C
Reaction time: 24 h
Yield: 30.2 %

Procedure:
To a solution of 9.50 g (72.8 mmol) of 2-chloro-5-hydroxypyrimidine in 100 ml of N,N-dimethylformamide, 26.1 g (80.1 mmol) of cesium carbonate and 24.3 g (102 mmol) of 5-(methanesulfonyloxymethyl)-2,2,5-trimethyl-1,3-dioxane, which was synthesized by the method described in V. W. Gash, Journal of Organic Chemistry, 1972, Vol. 37, pp. 2197-2201, were added, and the reaction solution was stirred at 90° C. for 24 hours. After completion of the reaction, the insoluble material was filtered off and washed with ethyl acetate, and then 0.5 N sodium hydroxide aqueous solution was added to the filtrate and separation was performed. The obtained aqueous layer was further extracted with ethyl acetate. The obtained organic layers were combined, washed with water and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Toluene was added to the obtained residue, and the precipitate was obtained by filtration and washed with toluene and n-heptane to provide 6.00 g of the title compound as a white solid (yield: 30%).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:14]([Br:15])=[CH:13][C:12]([Br:16])=[C:11]([C:17](=[O:19])[NH2:18])[C:10]=1[Br:20])C.[OH-].[Na+]>O>[C:17]([C:11]1[C:10]([Br:20])=[C:9]([C:14]([Br:15])=[CH:13][C:12]=1[Br:16])[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:21])=[O:3])(=[O:19])[NH2:18]
Reactant: CCOC(=O)CCCOc1c(Br)cc(Br)c(C(N)=O)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1c(Br)cc(Br)c(OCCCC(=O)O)c1Br
Reaction time: 3 h

Procedure:
18 g (36.9mmol) of 4-(3-carbamoyl-2,4,6-tribromophenoxy)butyric acid ethyl ester is suspended in 180 ml of water and, after adding 10 ml of concentrated sodium hydroxide solution, saponified at 60° C. within three hours. The solution is filtered over active carbon and brought to pH 1 by the dropwise addition of concentrated hydrochloric acid. After several hours of agitation in an ice bath, the resultant precipitate is vacuum-filtered, washed with water, and dried at 60° C. Yield: 15 g (88% of theory) of 4-(3-carbamoyl-2,4,6-tribromophenoxy)butyric acid as a white powder, mp 193°-194° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:2]2[N:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]3)=[N:15][CH:16]=1
Reactant: Nc1ccc(F)cn1
Reactant: Cc1ccc2ccnc(Cl)c2n1
Product: Cc1ccc2ccnc(Nc3ccc(F)cn3)c2n1

Procedure:
The title compound, MS: m/e=255.3 (M+H+), was prepared in accordance with the general method of example 1 from 8-chloro-2-methyl-[1,7]naphthyridine (Example E) and 2-amino-5-fluoropyridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:26](Br)[CH:27]=[CH2:28]>CN(C)C=O.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:28][CH:27]=[CH2:26])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 75 °C
Reaction time: 4 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.79 g, 2.50 mmol) and sodium hydride (0.13 g, 60% n in oil, 3.254 mmol) in dimethylformamide (10 mL). After 30 minutes add allyl bromide (0.35 mL, 3.25 mmol). Heat to 75° C. After 4 hours, cool the reaction mixture, dilute with dichloromethane, and extract with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 1-(t-butoxycarbonyl)-4-(1-allyl-1H-benzimidazol-2-yl)[1,4]diazepane: Rf=0.83 (silica gel, dichloromethane/methanol/concentrated ammonium hydroxide 90/10/0.1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.C(N(CC)CC)C.[C:26]12([NH2:36])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:36][C:26]34[CH2:27][CH:28]5[CH2:34][CH:32]([CH2:31][CH:30]([CH2:29]5)[CH2:35]3)[CH2:33]4)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2cc(NC34CC5CC(CC(C5)C3)C4)ncn2)cc1

Procedure:
To a solution of 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (prepared as in Example 59: 0.078 mmol) in 1.5 mL of ethanol is added 10 L of triethylamine and 1-Adamantanamine (12 mg, 0.078 mmol). The mixture can be microwaved at 120 degrees until formation of the desired compound. The reaction mixture can then be filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH:10](O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(Cl)(=O)=O.[C:19]1([CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:26]#[N:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na]>C(N(CC)CC)C>[C:28]1([C:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([CH:10]2[CH2:11][CH2:12][N:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:9]2)[C:26]#[N:27])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: OC1CCN(Cc2ccccc2)C1
Reactant: N#CC(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [Na]
Solvent: CCN(CC)CC
Product: N#CC(c1ccccc1)(c1ccccc1)C1CCN(Cc2ccccc2)C1

Procedure:
The title compound was prepared from 1-(phenylmethyl)-3-pyrrolidinol, methanesulfonylchloride, triethylamine and sodium diphenylacetonitrile by the procedure of U.S. Pat. No. 3,192,210, b.p. 215-218/0.01 mm.
Reaction SMILES: [N+](=[CH2:3])=[N-].[Cl-:4].[CH2:5]([O:7][C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=O)C>>[CH3:5][O:7][C:8](=[O:14])[CH2:9][CH2:10][C:11]([CH2:3][Cl:4])=[O:13]
Reactant: CCOC(=O)CCC(=O)O
Reactant: [Cl-]
Reactant: C=[N+]=[N-]
Product: COC(=O)CCC(=O)CCl

Procedure:
In EP 58392 a procedure for the production of 5-chlorolevulinic acid ethyl ester is described that starts from succinic acid mono ethyl ester mono chloride. This compound is converted with diazo methane at −5° C. and is after that worked up by passing in hydrogen chloride. You receive so the desired compound in pure form and in a high yield but the difficult handling of explosive diazo methane makes this method for the large-scale use not suitable. The same procedure is described in PL 136454. Instead of the succinic acid mono ethyl ester mono chloride the respective methyl ester derivative is used and results in the formation of 5-chlorolevulinic acid methyl ester.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH2:11])[CH2:8]2.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[C:21]([CH3:28])([CH3:27])[C:22](OCC)=[O:23].Cl>C(O)C.[Zn]>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:21]([CH3:28])([CH3:27])[C:22]1=[O:23])[CH2:8]2
Reactant: CCOC(=O)C(C)(C)Br
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: CCO
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)C1c1ccccc1
Reaction time: 1.5 h
Yield: 64 %

Procedure:
A solution of 2-adamantylamine (50.0 mg, 0.330 mmol) in ethanol (2 mL) was added with benzaldehyde (56.3 mg, 0.330 mmol) at room temperature, and the resultant was stirred at the same temperature for 1.5 hours. The reaction solution was concentrated in vacuo. The obtained residue was dissolved in toluene (5 mL), and sequentially added with ethyl 2-bromoisobutyrate (109 mg, 0.660 mmol) and zinc (432 mg, 6.60 mmol) at room temperature. The reaction solution was stirred at 130° C. for 5 hours, and added with hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using preparative thin-layer chromatography (hexane:ethyl acetate=3:1), and 1-(adamantan-2-yl)-3,3-dimethyl-4-phenylazetidin-2-one (65.4 mg, 64.0%) was obtained as a white crystalline powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]2[C:24]3[N:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[C:27]([CH:33]=O)=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:33][C:27]2[C:26]([CH3:25])=[CH:31][C:30]([CH3:32])=[CH:29][N:28]=2)[CH:15]2[C:24]3[N:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17][CH2:16]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CCCc3cccnc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(C2CCN(C(=O)OC(C)(C)C)CC2)C2CCCc3cccnc32)c(C)c1

Procedure:
Using General Procedure B: Reaction of 4-(5,6,7,8-Tetrahydro-quinolin-8-ylamino)-piperidine-1-carboxylic acid tert-butyl ester and 3,5-dimethyl-pyridine-2-carbaldehyde with NaBH(OAc)3 in CH2Cl2 gave 4-[(3,5-Dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid. Deprotection with TFA using General Procedure F gave (3,5-dimethyl-pyridin-2-ylmethyl)-piperidin-4-yl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine as a yellow oil.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH2:24][NH2:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH2:24][NH:25][C:27]5[N:32]=[CH:31][CH:30]=[CH:29][N:28]=5)[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: NCC1(c2ccc(OC3CCN(C4CCC4)CC3)cc2)CCOCC1
Reactant: Clc1ncccn1
Product: c1cnc(NCC2(c3ccc(OC4CCN(C5CCC5)CC4)cc3)CCOCC2)nc1
Yield: 25 %

Procedure:
The title compound (31 mg, 25%) was prepared from 1-(4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methanamine and 2-chloropyrimidine similarly to the procedure used for example 145. 1H NMR (400 MHz, CDCl3) δ 1.66-1.73 (m, 2H), 1.83-1.95 (m, 6H), 1.98-2.15 (m, 8H), 2.60-2.66 (m, 2H), 2.75 (m, 1H), 3.57-3.62 (m, 2H), 3.66 (d, 2H), 3.81-3.85 (m, 2H), 4.31 (m, 1H), 4.68 (t, 1H), 6.47 (t, 1H), 6.90 (d, 2H), 7.23 (d, 2H), 8.20 (d, 2H). LRMS APCI+ m/z 423 [MH]+.
Reaction SMILES: [N:1]1([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:4][CH2:3][CH:2]1[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].IC.[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Na+].N>C1COCC1>[CH3:27][C:2]1([C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])[CH2:3][CH2:4][N:1]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: O=C(OCc1ccccc1)C1CCN1C(=O)OCc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C(=O)OCc2ccccc2)CCN1C(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A solution of Example 22A (325 mg, 1 mmol) and iodomethane (0.12 ml, 2.0 mmol) in THF (5 mL) was treated with NaN(TMS)2 in THF (1.0 M, 2 mL, 2.0 mmol) at −70° C. under nitrogen. The temperature of the cooling bath was slowly raised to −20° C. within 1 h and the mixture was stirred at the same temperature for additional 2 h. After quenching with water, the mixture was partitioned between water and EtOAc. The organic phase was washed with water and concentrated. The residue was purified on flash column chromatograph to give Example 22B. (250 mg, 77% yield). MS (DCI/NH3) m/z 340 (M+H)+.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([OH:20])=O)[CH:14]=[CH:13][C:11]=2[N:12]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:55][C:56]1[CH:61]=[CH:60][C:59]([C@H:62]([CH3:69])[CH2:63][C:64]([O:66]CC)=[O:65])=[CH:58][CH:57]=1>CN(C)C=O>[C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([NH:55][C:56]3[CH:57]=[CH:58][C:59]([C@H:62]([CH3:69])[CH2:63][C:64]([OH:66])=[O:65])=[CH:60][CH:61]=3)=[O:20])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Reactant: CCOC(=O)C[C@@H](C)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)Nc3ccc([C@H](C)CC(=O)O)cc3)cc2o1
Yield: 30.6 %

Procedure:
A solution of 2-(o-tolylaminobenzoxazol-6-yl)acetic acid (1.0 g, Reference Example 4) in dimethylformamide (75 mL) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.35 g), then with diisopropylethylamine (1.2 mL) and then with ethyl (R)-3-(4-aminophenyl)butanoate (0.74 g, Reference Example 1). The mixture was kept at room temperature for an hour and then evaporated to low bulk. The residue was partitioned between hydrochloric acid (1M) and dichloromethane. The organic phase was washed with aqueous bicarbonate solution (5%) then with water, then dried, and then evaporated. The residue was suspended in ethanol (about 50 mL). The mixture was treated with aqueous sodium hydroxide (about 5 mL, 1M), then refluxed for 2 hours, then evaporated. The residue was triturated with aqueous hydrochloric acid (1M) then filtered. The insoluble material was washed with water, and then dried to give the title compound (0.48 g) as a white powder. MS: accurate mass=444.1936 (calculated 444.1923 MH+). LC-MS: RT=3.19 minutes (100% by ELSD); MS (ES+), 444 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][CH2:13][NH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O.O>[C:26]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:27]=[CH:28][C:29]([CH2:32][C:33]([NH:14][CH2:13][CH2:12][C:11]2[CH:15]=[CH:16][C:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)=[O:34])=[CH:30][CH:31]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(-c2ccccc2)cc1)NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reaction time: 22 h

Procedure:
The intermediate 2-biphenyl-4-yl-N-[2-(3,4-bis-benzyloxy-phenyl)-ethyl]-acetamide (1) was prepared as follows: To a stirred solution of 2.85 g (7.7 mmol) of 3,4-dibenzyloxyphenethyl amine and 1.49 g (7 mmol) of 4-biphenylacetic acid in 20 ml of anhydrous dimethylformamide at 0° C., 2.5 ml (17.7 mmoles) of triethyl amine was added dropwise and then 1.4 ml (7.7 mmol) of diethyl cyanophosphonate (90% purity) was added dropwise. The reaction mixture was stirred for 22 hours and allowed to reach room temperature, and then it was poured into 300 ml of water. The precipitated solid was separated on a glass filter funnel, washed with water (3×70 ml), and air-dried overnight. This solid was recrystallized using hexanes/ethanol mixture to provide 3.1 g (84%) of grayish crystals, mp 142-144° C.