Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:21]=[CH:20][C:19]3[C:10](=[C:11]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:12]4[C:17]([C:18]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:34]1[C:42]2[C:41]3[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=3[O:39][C:38]=2[CH:37]=[CH:36][C:35]=1B(O)O.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1.CCCCCC.C(O)C>[C:28]1([C:11]2[C:12]3[C:17]([C:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[C:19]4[C:10]=2[CH:9]=[C:8]([C:4]2[CH:5]=[C:6]([C:35]5[CH:36]=[CH:37][C:38]6[O:39][C:40]7[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=7[C:42]=6[CH:34]=5)[CH:7]=[CH:2][CH:3]=2)[CH:21]=[CH:20]4)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Brc1cccc(-c2ccc3c(-c4ccccc4)c4ccccc4c(-c4ccccc4)c3c2)c1
Reactant: OB(O)c1ccc2oc3ccccc3c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(-c2c3ccccc3c(-c3ccccc3)c3cc(-c4cccc(-c5ccc6oc7ccccc7c6c5)c4)ccc23)cc1
Yield: 29.1 %

Procedure:
In a 50 mL three-neck flask were put 1.2 g (2.4 mmol) of 2-(3-bromophenyl)-9,10-diphenylanthracene, 0.52 g (2.4 mmol) of dibenzofuran-2-boronic acid, and 0.18 g (0.60 mmol) of tri(ortho-tolyl)phosphine. The air in the flask was replaced with nitrogen. To this mixture were added 10 mL of toluene, 3.0 mL of ethanol, and 3.0 mL of an aqueous solution of sodium carbonate (2.0 mol/L). While the pressure was reduced, this mixture was stirred to be degassed. To this mixture was added 27 mg (0.12 mmol) of palladium(II) acetate, and the mixture was stirred at 80° C. for 3 hours. Then, the aqueous layer of the obtained mixture was extracted with toluene, and the toluene solution and the organic layer were combined and washed with saturated brine. The organic layer was dried with magnesium sulfate. Then, this mixture was gravity filtered. The resulting filtrate was concentrated, and the obtained oily substance was purified by silica gel column chromatography to give a yellow oily substance. The chromatography was carried out using a mixed solvent having a 5:1 ratio of hexane to toluene as a developing solvent, whereby an oily substance was obtained. Recrystallization of the oily substance from a mixed solvent of toluene and hexane gave 0.40 g of a yellow powder in 29% yield, which was the substance to be produced.
Reaction SMILES: [CH3:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:15][C:16]1[N:17]=[C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:26]=[CH:27][C:28]([CH3:41])=[C:29]([NH:31][C:32]([C:34]4[N:38]([CH3:39])[N:37]=[C:36]([CH3:40])[CH:35]=4)=[O:33])[CH:30]=3)=[N:20][N:19]2[CH:42]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O.CN(C)C(=O)C.C(OCC)(=O)C.O1CCCC1>[CH3:39][N:38]1[C:34]([C:32]([NH:31][C:29]2[CH:30]=[C:25]([O:24][C:21]3[CH:22]=[CH:23][C:18]4[N:19]([CH:42]=[C:16]([NH:15][C:5]([C:2]5([CH3:1])[CH2:4][CH2:3]5)=[O:7])[N:17]=4)[N:20]=3)[CH:26]=[CH:27][C:28]=2[CH3:41])=[O:33])=[CH:35][C:36]([CH3:40])=[N:37]1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Reactant: CC1(C(=O)O)CC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5(C)CC5)cn4n3)ccc2C)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
To a solution of 1-methylcyclopropanecarboxylic acid (97 mg, 0.97 mmol) in tetrahydrofuran (1.5 mL) were added N,N-dimethylformamide (1 drop) and oxalyl chloride (83 μL, 0.97 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was added to a solution of N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (200 mg, 0.48 mmol) in N,N-dimethylacetamide (5 mL), and the mixture was stirred at room temperature for 1 hr. Ethyl acetate/tetrahydrofuran and saturated aqueous sodium hydrogencarbonate solution were added to the mixture, and the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×4). Combined organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→100/0) to give the title compound (105 mg, 74%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:25]2[CH2:29][CH2:28][CH2:27][S:26]2(=[O:31])=[O:30])[CH:3]=1.[CH3:32][C@@H:33]1[O:37][C:36](=[O:38])[NH:35][CH2:34]1>>[O:30]=[S:26]1(=[O:31])[CH2:27][CH2:28][CH2:29][N:25]1[C:4]1[CH:3]=[C:2]([N:35]2[CH2:34][C@H:33]([CH3:32])[O:37][C:36]2=[O:38])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: C[C@H]1CNC(=O)O1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C[C@H](C)OC4=O)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 82.9 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (507 mg) described in Preparation Example 180 and (S)-5-methyloxazolidin-2-one (121 mg) described in Preparation Example 42, the title compound (437 mg) was obtained.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:11][CH:12]([CH3:44])[C@H:13]([NH:21][CH2:22][C@H:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)[O:34][C:35]=2[CH3:36])[CH2:24]1)[C:14]([O:16]C(C)(C)C)=[O:15]>ClCCl.O>[C:1]([N:21]([CH2:22][C@H:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][CH:42]=3)[O:34][C:35]=2[CH3:36])[CH2:24]1)[C@@H:13]([CH:12]([CH3:44])[CH3:11])[C:14]([OH:16])=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](CN[C@H](C(=O)OC(C)(C)C)C(C)C)C3)c(C)o2)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(C[C@H]1CCC[C@@H](OCc2nc(-c3ccc(C)cc3)oc2C)C1)[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
12 μl of acetyl chloride and 22 μl of pyridine are added to 40 mg of tert-butyl (S)-3-methyl-2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}butyrate in 0.5 ml of dichloromethane, and the mixture is stirred at room temperature for 18 h. The solution is then diluted with water and dichloromethane, the aqueous phase is removed and extracted with dichloromethane and the combined phases are dried over MgSO4 and concentrated. The residue is taken up in 0.5 ml of trifluoroacetic acid and allowed to stand at room temperature overnight. The solvent is distilled off completely and the residue is purified by HPLC, which gives 17 mg of (S)-2-{acetyl-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}-3-methylbutyric acid. C26H36N2O5 (456.59); LCMS (ESI): 457.36 (MH+).
Reaction SMILES: N[C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=[N:4][S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].N(OCCC(C)C)=O>O1CCCC1>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:3]1[CH:2]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:5][N:4]=1
Reactant: CCOC(=O)c1snc(-c2ccc(Cl)cc2Cl)c1N
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2Cl)ns1
Reaction time: 1 h
Yield: 74.8 %

Procedure:
Ethyl 4-amino-3-(2,4-dichlorophenyl)isothiazole-5-carboxylate (3.17 g, 10.0 mmol) prepared in the Step 27-1-3 was dissolved in tetrahydrofuran (50 ml), and isoamyl nitrite (3.20 g) was added thereto. The mixture was heated and stirred for one hour. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give the title compound (2.26 g, 75%).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6]2=[N:8][C:9]([CH2:11][CH3:12])=[CH:10][C:5]2=[C:4]([Cl:13])[N:3]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+]>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([Cl:13])[C:5]2[CH:10]=[C:9]([CH2:11][CH3:12])[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[N:7]=1
Reactant: CCc1cc2c(Cl)nc(C)[nH]c-2n1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cc2c(Cl)nc(C)nc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.2 %

Procedure:
A solution of 500 mg (2.55 mmol) of 2-methyl-4-chloro-6-ethyl-1H-pyrrolo[2,3-d]pyrimidine in 5.0 mL of tetrahydrofuran (THF) was added to a 2° C. slurry of 437 mg (2.55 mmol) of benzylbromide and 60 mg (2.55 mmol) of sodium hydride in 4.0 mL of THF. The reaction was allowed to warm to ambient temperature and stirred for 18 hours. The reaction was quenched by the addition of 7 mL of 2 M sodium hydrogen sulfate and then extracted with 7 mL of ethyl acetate. The organic phase was dried with sodium sulfate and concentrated to 500 mg. The residue was purified by flash chromatography (50 g of silica gel, methylene chloride) to provide 490 mg (67%) of 2-methyl-4-chloro-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidine as a solid. nmr (500 MHz, CDCl3) δ1.29 (t, J=7.5 Hz, 3H), 2.61 (q, J=7.5 Hz, 2H), 2.74 (s, 3H), 5.45 (s, 2H), 6.33 (s, 1H), 7.03 (d, J=7.0 Hz, 2H), 7.28 (m, 3H)
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[C:7]([CH2:9][N:10]([CH3:22])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[C:6]([OH:23])=[C:5]([O:24][CH3:25])[CH:4]=1.C(N(C(C)C)CC)(C)C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[C:36]([O:23][C:6]1[C:7]([CH2:9][N:10]([CH3:22])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[CH:8][C:3]([N:2]([CH3:1])[CH3:26])=[CH:4][C:5]=1[O:24][CH3:25])(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1cc(N(C)C)cc(CN(C)CCc2ccc([N+](=O)[O-])cc2)c1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N(C)C)cc(CN(C)CCc2ccc([N+](=O)[O-])cc2)c1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
0.1 g (0.278 mmol) of 4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]-amino}methyl)phenol (compound of Example 1) are placed in solution in 5 ml of anhydrous dichloromethane in the presence of 49 μl (0.42 mmol; 1.5 eq.) of diisopropylethylamine at 0° C. 30 μl (0.42 mmol; 1.5 eq.) of acetyl chloride are added dropwise to the solution and the medium is stirred for 1 hour at ambient temperature. Then 10 ml of dichloromethane is added to the reaction medium which is then washed with 3 times 10 ml of a saturated solution of sodium chloride. The organic phase is dried over magnesium sulphate, followed by filtering and concentrating under vacuum. The residue is purified on a silica column (eluent: AcOEt/Heptane: 2/1) in order to produce a yellow oil with a yield of 60%.
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][O:15][C:16]1[CH2:21][CH2:20][O:19][CH2:18][CH:17]=1>C(OCC)(=O)C>[OH:1][C:2]1[C:10]([OH:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:13][O:12][C:9]1[C:14]2[O:15][C:16]3([O:1][C:2]=2[C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=1)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3
Reactant: COC1=CCOCC1
Agent: COc1ccc(C(=O)O)c(O)c1O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)O)c2c1OC1(CCOCC1)O2
Reaction time: 72 h
Yield: 28.2 %

Procedure:
A suspension of 2,3-dihydroxy-4-methoxybenzoic acid (6.04 g, 32.8 mmol) in 5,6-dihydro-4-methoxy-2H-pyran (20 mL, 152 mmol) was kept at 140° C. for three days. At room temperature ethyl acetate (200 mL) was added and the organic phase was extracted with saturated aqueous NaHCO3 (2×50 mL). The aqueous phase was washed with Et2O (2×40 mL), acidified to pH=1 with concentrated HCl and extracted with dichloromethane (2×50 mL). The organic phase was dried over MgSO4. Evaporation under reduced pressure afforded traces of 2,3-dihydroxy-4-methoxybenzoic acid along with 7-methoxy-2′,3′,5′,6′-tetrahydro-Spiro[1,3-benzodioxole-2,4′-(4H)-pyran]-4-carboxylic acid (1.23 g, 14%). 13C NMR (DMSO) δ 164.9, 148.2, 146.6, 134.5, 123.7, 117.0, 107.1, 106.8, 64.4, 56.0, 35.3.
Reaction SMILES: [Na].C[O-].[Na+].[N+:5]([NH:8][C:9]([NH2:11])=[NH:10])([O-:7])=[O:6].[CH:12]([CH:14]([CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[C:15](OCC)=O)=[O:13]>CO>[N+:5]([NH:8][C:9]1[NH:11][C:12](=[O:13])[C:14]([CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:15][N:10]=1)([O-:7])=[O:6]
Reactant: N=C(N)N[N+](=O)[O-]
Reactant: CCOC(=O)C(C=O)Cc1ccncc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1ccncc1
Temperature: 0 °C

Procedure:
About 1.77 g. of sodium were dissolved in 75 ml. of anhydrous methanol under a positive nitrogen atmosphere. The sodium methoxide in methanol solution was cooled and 7.28 g. of dried nitroguanidine added thereto. The reaction mixture was heated to reflux temperature briefly after which time 14.5 g. of ethyl 2-formyl-3-(4-pyridyl)propionate (prepared by the method of U.S. Pat. No. 4,216,318) were added thereto. This reaction mixture was then heated to refluxing temperature for about 19 hours. Volatile constituents were removed by evaporation and water was added to the residue. The aqueous mixture was extracted 3 times with chloroform and the chloroform extracts discarded. The aqueous solution was then chilled to about 0° C. and 15.4 ml. of 5N aqueous hydrochloric acid added. 2-Nitroamino-5-(4-pyridyl)methyl-4-pyrimidone formed in the above reaction precipitated and the precipitate was collected by filtration. The filter cake was washed with water and dried. 9.9 g. of product were obtained melting at about 228°-229° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:18][N:19]([CH3:27])[CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:18][N:19]([CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]3[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)[CH2:23][CH2:22]1)[CH3:27]
Reactant: CN(C)CC1CCNCC1
Reactant: COC(=O)c1cc(Br)cc2c1cnn2C(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cc(N2CCC(CN(C)C)CC2)cc2c1cnn2C(C)C
Temperature: 115 °C
Reaction time: 15 h
Yield: 11.6 %

Procedure:
To a 10-mL microwave tube were added methyl 6-bromo-1-(1-methylethyl)-1H-indazole-4-carboxylate (250 mg, 0.841 mmol), N,N-dimethyl-1-(4-piperidinyl)methanamine (132 mg, 0.925 mmol), Toluene (3 mL), and cesium carbonate (411 mg, 1.262 mmol), and the mixture was degassed for 5 min by bubbling N2 through. BINAP (79 mg, 0.126 mmol) and Pd2(dba)3 (38.5 mg, 0.042 mmol) were added. The tube was sealed and the mixture was heated at 115° C. with stirring for 15 h. The mixture was diluted with methanol (5 mL) and filtered. The filtrate was concentrated and the residue was purified using reverse-phase HPLC to give 35 mg of product as a off-white solid. LCMS MH+=359.3
Reaction SMILES: [C:1]1([N: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:13]1([CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=2[O:25][CH2:26][CH:27]2[CH2:29][O:28]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=2[O:25][CH2:26][CH:27]([OH:28])[CH2:29][N:10]2[CH2:11][CH2:12][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: c1ccc(CCCCc2ccccc2OCC2CO2)cc1
Solvent: CC#N
Product: OC(COc1ccccc1CCCCc1ccccc1)CN1CCN(c2ccccc2)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 34.6 %

Procedure:
3.89 g of N-phenylpiperazine were added to a solution of 1.69 g of 2-[2-(4-phenylbutyl)phenoxymethyl]oxirane [prepared as described in Example 1(a)] in 30 ml of acetonitrile, and the resulting mixture was stirred at 50° C. for 3 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 2:3 by volume mixture of ethyl acetate and hexane as the eluent, to give 920 mg (yield 34%) of the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23]O)[CH:19]=[CH:20][C:21]=1[F:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:23][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(F)c(Cl)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(F)c(Cl)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3-chloro-4-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C16H10ClFN4O, 329; Found, 329.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:7].C(P(CCCC)CCCC)CCC.Cl.C(N(CC)CC)C>O1CCCC1>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([N:8]2[CH2:2][CH2:3][NH:4][CH2:5][C:6]2=[O:7])[CH:10]=1
Reactant: O=C(CNCCO)Nc1cccnc1
Agent: CCCCP(CCCC)CCCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CNCCN1c1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.7 %

Procedure:
Bis(1,1-dimethylethyl)diazenedicarboxylate (4.1 g, 18 mmol) in tetrahydrofuran (100 mL) was added dropwise to a stirred, cooled (0° C.) solution of 2-[(2-hydroxyethyl)amino]-N-(3-pyridinyl)acetamide (Description 142, 2.5 g, 13 mmol) and tributylphosphine (4.2 mL, 16.9 mmol) in tetrahydrofuran (300 mL) and the mixture was stirred at room temperature for 16 hours. Ethereal hydrogen chloride (1M, 10 mL) was added and the mixture was stirred at room temperature for 1 hour. Triethylamine (6 mL, 42 mmol) was added the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3(Aq.) (90:10:1), to give the title compound (800 mg, 35%). m/z (ES+) 178 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:29]=[CH:28][C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=3)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH:36]([NH:39][CH:40]([CH3:42])[CH3:41])([CH3:38])[CH3:37]>CN(C=O)C>[CH:36]([N:39]([CH2:2][C:3]1[CH:29]=[CH:28][C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=3)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)[CH:40]([CH3:42])[CH3:41])([CH3:38])[CH3:37]
Reactant: O=C(c1ccc(CCl)cc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reactant: CC(C)NC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N(Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)cc1)C(C)C

Procedure:
A solution of 1-(4-chloromethylbenzoyl)-4-(2-naphthalenesulfonyl)piperazine (300 mg), potassium carbonate (200 mg) and diisopropylamine (4 ml) in DMF (6 ml) was stirred at 100° C. for 10 hours and concentrated. To the residue was added ethyl acetate, and the mixture was washed with water, and extracted with 1 N hydrochloric acid. The extract was made alkaline with sodium hydroxide solution and extracted with dichloromethane. The extract was dried and concentrated. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:2) to give the title compound (70 mg).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:25][CH2:26][O:27][CH3:28].C(=O)(O)[O-].[Na+].[I-].[K+]>C(#N)C>[CH3:28][O:27][CH2:26][CH2:25][N:19]1[CH2:18][CH2:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)([C:22]#[N:23])[CH2:21][CH2:20]1
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCNCC1
Reactant: COCCBr
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CCC(C#N)(c2ccc(OCCCN3CCCC3)cc2)CC1
Yield: 56.3 %

Procedure:
A mixture of 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]piperidine-4-carbonitrile (68 mg, 0.22 mmol), 2-bromoethylmethylether (21 μl, 0.22 mmol), solid sodium bicarbonate (84 mg, 1.0 mmol) and potassium iodide (5 mg, catalytic) was heated at 50° C. in acetonitrile (1 ml) for 18 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between dichloromethane (2×50 ml) and 10% aqueous sodium carbonate (20 ml). The organic layers were combined, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (97:3:0.3 to 95:5:0.5 by volume) to provide the title compound (46 mg, 61%). 1H NMR (400 MHz, CD3OD) 61.83-1.87 (m, 4H), 2.01-2.10 (m, 6H), 2.45-2.52 (m, 2H), 2.65-2.69 (m, 6H), 2.75 (t, 2H), 3.09 (d, 2H), 3.35 (s, 3H), 3.56 (t, 2H), 4.04 (t, 2H), 6.96 (d, 2H), 7.42 (d, 2H). HRMS ESI+ m/z 372.2639 [MH]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].C[CH2:25][O:26]CC.C([Li])(C)(C)C.CN(C)C=O>O1CCCC1.O>[C:12]([O:11][C:9]([NH:8][C:6]1[CH:5]=[CH:4][C:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:2]([CH:25]=[O:26])[CH:7]=1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1ccc(NC(=O)OC(C)(C)C)c(Br)c1
Reactant: CCOCC
Agent: [Li]C(C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)OC(C)(C)C)c(C=O)c1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
3.3 g (0.01 mole) of tert.butyl (2-bromo-4-tert.butoxycarbonylaminophenyl)carbamate from step A was dissolved in 100 mL of anhydrous tetrahydrofuran under argon. Then, 17 mL (0.03 mole) of a 1.6-molar ether solution of methyllitrium was added stepwise. The reaction mixture was cooled to −20° C. and to it was added stepwise 7 mL (0.01 mole) of a 1.5-molar tert.butyllithium solution. At the end of the addition, the solution was allowed to agitate for an additional 30 min at −20° C. Then, 1.2 g (0.02 mole) of dimethylformamide was added, and the reaction mixture was allowed to agitate for one hour at −20° C. The reaction mixture was then slowly warmed up to room temperature, hydrolyzed with water and poured onto diethyl ether. The aqueous phase was then extracted with diethyl ether, and the organic phase was dried with magnesium sulfate. The solvent was distilled off in a rotary evaporator, and the residue was purified on silica gel with petroleum ether/ethyl acetate (9:1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13](/[C:16](/[CH3:20])=[CH:17]/[CH2:18][OH:19])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH2:21]([O:23][C@@H:24]([CH2:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:22]>>[C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13](/[C:16](/[CH3:20])=[CH:17]/[CH2:18][O:19][C:34]3[CH:33]=[CH:32][C:31]([CH2:30][C@H:24]([O:23][CH2:21][CH3:22])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:36][CH:35]=3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(-c2ccc(/C(C)=C/CO)cc2)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cccc(C(C)=O)c3)cc2)cc1)OCC
Yield: 65.8 %

Procedure:
The title compound (0.16 g, 65% yield) was prepared from (E)-3-(3′-acetyl-biphenyl-4-yl)-but-2-en-1-ol (0.133 g, 0.50 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.125 g, 0.525 mmol) by a procedure analogous to that described in example 52 c.