Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:20]2[CH2:19][CH2:18][N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:22][CH2:21]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 4-bromobenzyl bromide (5 g, 20 mmol) and N-Boc piperazine (4.47 g, 24 mmol) in DMF (25 mL), K2CO3 (5.52 g, 40 mmol) was added and the reaction mixture was stirred for 16 h at room temperature. After completion of reaction (monitored by TLC), the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude product, V-1-I. This compound was used for next step without purification.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[C:21]1([NH:27]N)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[C:21]1([N:27]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccnc2)ccc1=O
Reactant: NNc1ccccc1
Solvent: CO
Product: O=c1ccn(-c2cccnc2)nc1-c1ccnn1-c1ccccc1
Yield: 19 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-pyridin-3-ylpyridazin-4(1H)-one (crude 260 mg, 0.98 mmol) in 20 mL of methanol was added phenylhydrazine (423 mg, 3.92 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 3-(1-phenyl-1H-pyrazol-5-yl)-1-pyridin-3-ylpyridazin-4(1H)-one (60 mg, 19% for two steps) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:23]=1[N:24]([CH2:29][CH:30]1[CH2:32][CH2:31]1)[CH2:25][CH:26]1[CH2:28][CH2:27]1)=[CH:21][C:20]([CH3:33])=[CH:19][CH:18]=2)[C:8]1[N:9]=[N:10][NH:11][N:12]=1.[H-].[Na+].[CH3:45]I>CN(C=O)C.CCOC(C)=O>[F:38][C:37]([F:40])([F:39])[C:35]1[CH:34]=[C:5]([CH:4]=[C:3]([C:2]([F:41])([F:1])[F:42])[CH:36]=1)[CH2:6][N:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:23]=1[N:24]([CH2:29][CH:30]1[CH2:31][CH2:32]1)[CH2:25][CH:26]1[CH2:27][CH2:28]1)=[CH:21][C:20]([CH3:33])=[CH:19][CH:18]=2)[C:8]1[N:9]=[N:10][N:11]([CH3:45])[N:12]=1
Reactant: Cc1ccc2ncc(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nn[nH]n3)c(N(CC3CC3)CC3CC3)c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc2ncc(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c(N(CC3CC3)CC3CC3)c2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 28.63 %

Procedure:
A mixture of (3-{[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-6-methyl-quinolin-4-yl)-bis-cyclopropylmethyl-amine (700 mg, 1.18 mmol) and sodium hydride (60%) (61 mg, 1.5 mmol) in DMF (25 mL) was stirred at 0° C. for 5 min. To this, methyl iodide (337 g, 2 mmol) was then added and stirring was continued for another 30 min. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (200 mL×4) and finally with brine (100 mL). The organic layer was separated, dried over sodium sulphate and concentrated under vacuum. The crude product was purified by column chromatography (silica gel 230-400 mesh). Elution with 1.5% EtOAc in hexane afforded 0.205 gm of gummy mass (yield: 28.63%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH:16][CH:15]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc(CCl)cc1
Product: CCOC(=O)C(Cc1ccc(OC)cc1)C(=O)OCC
Yield: 55.9 %

Procedure:
In the same manner as in Example 6 (1), a crude product was obtained using diethyl malonate (25.6 g) and 4-methoxybenzyl chloride (25.0 g). This was purified by silica gel column chromatography to give the title compound (25.0 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([O:8][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(O)CCCCC1
Solvent: CCN(CC)CC
Product: CC(=O)OC1(C)CCCCC1
Yield: 90 %

Procedure:
The procedure given in a product publication, "POLYDMAP(tm) POLYMER, A Guide to Its Successful Use", Reilly Industries, 1990, for testing the activity of polystyrene bound BMAP, was followed. A sample (7.0 gm) of the above silica bound catalyst was mixed with 8.2 gm (0.07 mol) 1-methylcyclohexanol. To this suspension was added 11.6 gm (0.12 mol) triethylamine and 12.8 gm (0.13 mol) acetic anhydride. The mixture was heated at reflux for 5 hours, then filtered to remove the catalyst. The catalyst was washed with 50 ml dichloromethane. The combined filtrate and washes were treated with three 50 ml portions of 9% aqueous HCl, then with three 50 ml portions of saturated aqueous sodium bicarbonate. The organic layer was then dried over anhydrous magnesium sulfate, filtered and the volatile components were removed using a rotary evaporator. The crude product was purified by vacuum distillation through a short Vigreux column. Analysis of the distilled fractions by vapor phase chromatography showed that the desired 1-methylcyclohexyl acetate was obtained in 90 % yield.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[Na].[CH3:20][SH:21]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH3:20][S:21][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]1
Reactant: CS
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na]
Solvent: C1CCOC1
Product: CSC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of tert-butyl 4-(methylsulfonyl)oxypiperidine-1-carboxylate (12.5 g), methylmercaptan sodium salt (3.31 g), tetra-n-butylammonium iodide (1.66 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 72 hrs. The insoluble material was filtered through celite and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and tert-butyl 4-(methylthio)piperidine-1-carboxylate was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio) (6.89 g, yield 67%).
Reaction SMILES: C(OCC)(=O)C.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[C:24]3C(=O)OC(C)(C)[O:26][C:25]3=[O:33])=[CH:19][CH:18]=2)=[CH:11][CH:10]=1.[BH4-].[Na+]>CCO>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:33])=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(COc2ccc(C=C3C(=O)OC(C)(C)OC3=O)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(COc2ccc(CCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirring ethyl acetate (100 mL) solution of 5-[[4-[(4-methoxyphenyl)methoxy]phenyl]-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (200 mg, 0.543 mmol) was added EtOH (4 mL), followed by NaBH4 (62 mg, 1.63 mmol). The reaction mixture was stirred at room temperature for 15 minutes, quenched with water (5 mL), extracted with EtOAc (10 mL). The extract was washed with brine, dried over MgSO4, filtered, and concentrated to a white solid. A solution of this white solid in 3:1 pyridine-water (5 mL) was heated at 100° C. for 24 h. The reaction mixture was cooled to room temperature and put in an ice-water bath. Concentrated HCl was carefully added to pH ˜2. The resulting suspension was extracted with ethyl acetate (10 mL×3), dried over MgSO4, filtered, and concentrated to an off-white solid. Preparative HPLC gave compound 37 as a white solid. MS ESI (neg.) m/e: 285.0 (M−1).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.O>C1(C)C=CC=CC=1>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([C:1]2([C:14]3[CH:15]=[CH:16][C:11]([OH:17])=[CH:12][CH:13]=3)[CH2:3][CH2:2][CH:1]([CH2:4][CH2:5][CH3:6])[CH2:3][CH2:2]2)=[CH:5][CH:6]=1
Reactant: CCCC1CCC(=O)CC1
Reactant: Oc1ccccc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC1CCC(c2ccc(O)cc2)(c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 50 h
Yield: 91.5 %

Procedure:
1st stage 4-n-Propylcyclohexanone 650 g and phenol 1550 g were mixed, and hydrochloric acid gas was blown to the mixture with vigorously stirring at room temperature. The mixture was vigorously stirred for three hours and then left for 50 hours at room temperature. Meantime, the reaction solution was solidified. Warm water 1,000 ml and toluene 3,000 ml were added to the solid. The solid was heated and dissolved completely. The crystals deposited from the solution after cooling were filtered and washed with water and with toluene. After drying the crystals, white crystals 658 g of 1,1-bis(4-hydroxyphenyl)-4-n-propylcyclohexane was obtained by recrystallization from acetone.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[NH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[N:16]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH3:13])(=[N:12][C:22]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:23])=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=NC(=O)N1CCOCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
100 mg (0.5 mmol) (RS)—S-(4-nitrophenyl)-S-methylsulphoximide in 4 ml dimethylformamide are treated at room temperature with 23.97 mg sodium hydride (55%, 0.55 mmol). The mixture is stirred for 30 minutes at room temperature and for 30 minutes at 50° C. After cooling to room temperature 0.063 ml (0.55 mmol) 4-morpholinylcarbonyl chloride are added. The mixture is stirred for 30 minutes at room temperature and for 2 hours at 50° C. and finally quenched with methanol. After chromatographic purification (silica gel, hexane/ethyl acetate (0-50% ethyl acetate)), 87 mg (0.28 mmol, corresponding to 56% of theor.) of the desired product is obtained.
Reaction SMILES: CO[C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([S:16][CH3:17])[C:4]=1C(O)=O.FC(F)(F)C1C=CC=CC=1[C:22]([OH:24])=[O:23].CSSC>>[CH3:17][S:16][C:8]1[CH:4]=[CH:3][CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[C:9]=1[C:22]([OH:24])=[O:23]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)O
Reactant: O=C(O)c1ccccc1C(F)(F)F
Solvent: CSSC
Product: CSc1cccc(C(F)(F)F)c1C(=O)O

Procedure:
The title compound, white solid, MS: m/e=235.0 [(M−H)−], was prepared in accordance with the general method of intermediate A from 2-(trifluoromethyl)benzoic acid and dimethyl disulfide.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH:8]3[CH2:10][C:4]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:21][CH2:20][CH2:19][C:18]5=[O:22])=[CH:13][CH:12]=4)([CH2:5][CH:6]1[CH2:7]3)[CH2:3]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][C:31]([N:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[C:38]#[N:39])=[O:32]>CS(C)=O.CCOC(C)=O>[O:22]=[C:18]1[CH2:19][CH2:20][CH2:21][N:17]1[C:14]1[CH:15]=[CH:16][C:11]([C:4]23[CH2:10][CH:8]4[CH2:9][C:2]([NH:1][CH2:30][C:31]([N:33]5[CH2:37][CH2:36][CH2:35][C@H:34]5[C:38]#[N:39])=[O:32])([CH2:3]2)[CH:6]([CH2:7]4)[CH2:5]3)=[CH:12][CH:13]=1
Reactant: NC12CC3CC1CC(c1ccc(N4CCCC4=O)cc1)(C3)C2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(c1ccc(N4CCCC4=O)cc1)(C3)C2
Reaction time: 3 h
Yield: 50.1 %

Procedure:
To a stirred solution of 1-[4-(3-aminotricyclo[3.3.1.03,7]non-1-yl)phenyl]pyrrolidin-2-one obtained in step II (0.36 g, 1.2 mmol) in DMSO (4.8 mL) at an ice bath temperature under nitrogen atmosphere was added K2CO3 (0.48 g, 3.6 mmol) followed by addition of (2S)-1-(chloroacetyl)pyrrolidine-2-carbonitrile (0.21 g, 1.2 mmol). After stirring the reaction mixture at r.t for 3 h, it was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain the title compound (2S)-1-{N-[2-[4-(2-oxopyrrolidin-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as a white solid (0.26 g) in 50% yield. M.R: 254-256° C.; m/z (M+1) 433; 1H NMR (300 MHz, CDCl3) δ: 7.54 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 4.30-4.20 (m, 1H), 4.06-4.18 (m, 2H), 3.87 (t, J=7.0 Hz, 1H), 3.80-3.50 (m, 4H), 2.64 (t, J=7.8 Hz, 2H), 2.58-1.60 (m, 18H).
Reaction SMILES: [CH:1]1([NH:7][N:8]2[NH:12][CH:11]=[C:10]([C:13]3[N:14]([CH3:21])[C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=3)[S:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:22](N)[CH2:23]CCCCCC.C1(N)CCCCC1>>[CH2:1]([NH:7][N:8]1[NH:12][CH:11]=[C:10]([C:13]2[N:14]([CH3:21])[C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=2)[S:9]1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:22][CH3:23]
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(NC2CCCCC2)S1
Reactant: CCCCCCCCN
Solvent: NC1CCCCC1
Product: CCCCCCCCNN1NC=C(c2ncc([N+](=O)[O-])n2C)S1

Procedure:
The preparation of the above compound is carried out essentially as described for the 2-cyclohexylamino derivative (Example 38), an equivalent of n-octylamine replacing the cyclohexylamine. The crude product is purified by recrystallization from aqueous 2-methoxyethanol and then melts at 130°-132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]=3Br)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[I-].[C:34]1([Zn+])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[C:17]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:18][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: [Zn+]c1ccccc1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2ccccc2)c1
Reaction time: 2 h
Yield: 63.4 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-bromophenyl)acetate (Example 46 step C; 24 mg, 0.046 mmol) was diluted with THF (1 mL) followed by the addition of bis(tri-t-butylphosphine)palladium (0) (2.4 mg, 0.0046 mmol) and phenylzinc iodide (0.23 ml, 0.12 mmol). After stirring for 2 hours, the reaction was loaded directly onto a silica gel column and eluted with hexanes:ethyl acetate (3:1) to yield Ethyl 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)biphenyl-3-yl)acetate (15 mg, 63% yield) as a clear oil.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][NH:21][C:22]4=[O:25])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Cl>>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][N:21]([CH2:37][C:36]5[CH:39]=[CH:40][CH:41]=[C:34]([O:33][CH3:32])[CH:35]=5)[C:22]4=[O:25])=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1NCc2ccc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)cc21
Reactant: COc1cccc(CCl)c1
Product: COc1cccc(CN2Cc3ccc(N4CCN(CCC(c5ccccc5)c5ccccc5)CC4)cc3C2=O)c1
Yield: 60.6 %

Procedure:
In the same manner as in Example 51, the title compound (35 mg) was prepared from the compound (50 mg) obtained in Example 50 and 3-methoxybenzyl chloride (17 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[CH:7]=1.[CH3:27][N:28]1[CH:32]=[C:31]([S:33](Cl)(=[O:35])=[O:34])[N:30]=[CH:29]1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:33]([C:31]2[N:30]=[CH:29][N:28]([CH3:27])[CH:32]=2)(=[O:35])=[O:34])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2cn(C)cn2)c1

Procedure:
The title compound of Step A was prepared from 3-{3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, of Step A of Example 11o, and 1-methyl-1H-imidazole-4-sulfonyl chloride following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, 1H), 7.70 (s, 1H), 7.54 (m, 3H), 7.39 (d, 1H), 7.24 (m, 2H), 7.14 (m, 1H), 7.04-6.97 (m, 3H), 6.45 (m, 1H), 4.43 (s, 2H), 4.40 (s, 2H), 3.74 (s, 3H), 3.65 ), 2.83 (t, 2H), 2.53 (t, 2H); MS 494 (M+1).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:18][C:17](=O)[CH2:16][C@H:15]1[C:20]([OH:22])=[O:21])=[O:13])([CH3:10])([CH3:9])[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC1CCCO1>[C:7]([O:11][C:12]([N:14]1[CH2:18][C:17](=[CH2:1])[CH2:16][C@H:15]1[C:20]([OH:22])=[O:21])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CC1CCCO1
Product: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of methyltriphenylphosphonium bromide (2.2 eq.) in 2-methyl tetrahydrofuran (3 vol) was added rapidly solid potassium tert-butoxide (2.3 eq.) maintaining the temperature around 0° C. The temperature was kept at +20° C. for 2 hours (a suspension remained) and re-cooled to 0° C. Keeping the temperature below 6° C., (S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (1 eq.) was added over 40 minutes. The reaction was warmed to room temperature and stirred for 16 h and then cooled to 0° C. The reaction was quenched with saturated NaHCO3 (5 vol) and water (2 vol) and the aqueous layer was separated. The organic layer was extracted with saturated NaHCO3/water (1.8 vol/1.8 vol) and the combined aqueous layers were filtered through Celite®. The aqueous layer was acidified with 6 N HCl (2.6 vol) at ambient temperature and extracted twice with isopropyl acetate (16 vol, then 8 vol). The organic phase was dried (MgSO4) and the solvent removed. The crude product was dissolved in isopropyl acetate (10 vol) and extracted with 0.5 M NaOH (10 vol, then 1 vol). The combined aqueous layers were acidified at ambient temperature with 6 N HCl to pH=3, and extracted twice with ethyl acetate (10 vol, then 8 vol). The combined extracts were dried (Na2SO4), the solvent removed and the crude product was recrystallized from cyclohexane (5 vol) to afford the title compound. 1H-NMR (400 MHz, DMSO): δ 12.9, (broad, 1H); 5.00 (m, 2H); 4.24 (dt, J=1.9H, J=7.3 Hz, 1H), 3.91 (m, 2H); 2.98 (m, 1H); 2.50 (m, 1H, coincides with DMSO); 1.41 and 1.36 (2 s rotamers, 9H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[CH:17][NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>CN(C=O)C>[CH3:23][CH:22]([CH3:24])[C:21]([N:16]1[CH:17]=[CH:18][C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)=[N:15]1)=[O:25]
Reactant: CC(C)C(=O)Cl
Reactant: c1ccc(Oc2ccc(-c3cc[nH]n3)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)n1ccc(-c2ccc(Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
A mixture of 3-(4-phenoxyphenyl)-1H-pyrazole (123 mg, 0.52 mmol) and NaH (28 mg, 0.70 mmol) in 5 mL of DMF was stirred at room temperature for 30 minutes. Neat isobutyryl chloride (80 μL, 0.75 mmol) was added and the reaction was stirred at room temperature. The reaction was then partitioned between water and EtOAc. The aqueous layer was extracted twice with EtOAc and the pooled organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Column chromatography (5% EtOAc/hexane) gave 127 mg (80%) of the title compound as a white solid, mp 49-51° C. 1H NMR (CDCl3): δ 8.30 (d, J=3.0 Hz, 1H), 7.88 (d, J=8.7 Hz, 2H), 7.39 (t, J=8.0 Hz, 2H), 7.17 (t, J=7.2 Hz, 2H), 7.12-7.08 (m, 4H), 6.75 (d, J=3.0 Hz, 1H), 4.03 (m, 1H), 1.78 (d, J=6.9 Hz, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Cl.[CH2:13](N(CC)CC)C>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1ccc(O)cc1
Temperature: 25 °C

Procedure:
4-Hydroxyphenylacetic acid (1.75 g) was dissolved in methanol (30 ml) and 10M aqueous hydrochloric acid (0.15 ml) was added and heated to reflux for 15 hours. After cooling to room temperature, triethylamine (1 ml) was added, the mixture concentrated, purified by flash chromatography using silica gel (30 g) and eluted with ethyl acetate-hexane (2:8 volume by volume) to give Methyl 4-Hydroxyphenylacetate (4) (1.693 g). This was confirmed by spectroscopy--1H NMR (CDCl3) δ 3.58 (s, 2 H), 3.73 (s, 3 H), 6.75 (d, 2 H), 7.10 (d, 2 H).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[CH:7]=[C:8]([CH:13]=[C:14](Br)[C:15]=1[C:16]([O:18][CH3:19])=[O:17])[C:9]([O:11][CH3:12])=[O:10]>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:4][CH2:1][C:2]#[C:3][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([C:3]#[C:2][CH2:1][OH:4])[C:15]=1[C:16]([O:18][CH3:19])=[O:17])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc(Br)c(C(=O)OC)c(Br)c1
Reactant: C#CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#CCO)c(C(=O)OC)c(C#CCO)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.3 %

Procedure:
Pd(Ph3P)4 (0.27 g), CuBrSMe2 (0.11 g) and propargyl alcohol (0.72 g, 12.9 mmol) are added successively to a solution of dimethyl 3,5-dibromoterephthalate (Al 15, 2.0 g, 5.7 mmol) in triethylamine (40 ml), and the mixture is stirred at RT for 10 min and then under reflux at 80° C. for 3.5 h. After cooling, the reaction mixture is filtered off with suction through kieselguhr and washed with ethyl acetate (20 ml). The organic phase is concentrated under reduced pressure. Further purification is carried out by chromatography [toluene/acetone (8:2)] on a silica gel column. This gives the title compound (1.4 g) as a colorless solid. TLC, silica gel (glass plates), [toluene/acetone (8:2)], Rf=0.20.