Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.[C:8](Cl)(=[O:10])[NH2:9].CCN(C(C)C)C(C)C.[F:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28]N)=[N:26][CH:27]=1>C(Cl)Cl>[F:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][NH:9][C:8]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]2[CH3:1])=[O:10])=[N:26][CH:27]=1
Reactant: NNc1ccc(F)cn1
Reactant: NC(=O)Cl
Reactant: C[C@H]1COCCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1COCCN1C(=O)NNc1ccc(F)cn1
Temperature: 45 °C
Yield: 57.3 %

Procedure:
Pyridine (1.60 mL, 19.8 mmol) was added dropwise to an ice cold suspension of triphosgene (2.94 g, 9.90 mmol) in DCM (20.0 mL). (S)-3-Methylmorpholine (1.00 mL, 9.90 mmol) was added and the reaction stirred for 3 hours, then quenched by dropwise addition of HCl (1M aqueous, 20 mL). The mixture was extracted into DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give (S)-3-methylmorpholine-carbamoylchloride (1.25 g, 77%). The product was used in the next reaction without purification. (S)-3-Methylmorpholine-carbamoylchloride (766 mg, 4.33 mmol) was dissolved in DCM (35.0 mL) and DIPEA (1.03 mL, 5390 mmol) was added followed by (5-fluoro-pyridin-2-yl)-hydrazine (WO2010022076, 500 mg, 3.94 mmol) and the reaction heated to 45° C. overnight. The reaction was cooled and quenched into water. The mixture was extracted into DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC using 0-10% [2M NH3 in MeOH] in DCM to give the title compound (574 mg, 57%). 1H NMR (300 MHz, CDCl3): 1.36 (3H, d, J=6.9 Hz), 3.30 (1H, td, J=12.5, 3.9 Hz), 3.47-3.74 (4H, m), 3.89-4.03 (2H, m), 6.41 (1H, br s), 6.45 (1H, br s), 6.73 (1H, dd, J=9.0, 3.5 Hz), 7.29 (1H, ddd, J=9.0, 7.9, 2.9 Hz), 8.04 (1H, d, J=2.9 Hz).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13](Cl)=[O:14].[CH2:16]=[CH2:17]>C(Cl)Cl>[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:7]=1[CH2:12][C:13](=[O:14])[CH2:17][CH2:16]2
Reactant: C=C
Reactant: O=C(Cl)Cc1ccccc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCc2cccc(Br)c2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
83.5 g of aluminum chloride (0.63 mmol) were introduced into 1.8 liters of methylene chloride at 0°-+5° C. 105 g (0.49 mole) of 2-bromophenyl-acetyl chloride (dissolved in 200 ml of methylene chloride) were added dropwise at 0°-+5° C. over 30 minutes. After stirring for 30 minutes at 0°-+5° C., 50 g of ethylene were passed in at such a rate that the reaction temperature did not exceed +10° C. The mixture was stirred for a further 2 hours at 20°-+25° C. The aluminum complex was decomposed by careful addition of 500 ml of ice water, the phases were separated, and the aqueous phase was extracted with 250 ml of methylene chloride. The title compound was obtained from the dried methylene chloride phase in a yield of 109 g as a yellow oil (content according to GC 97%) and employed without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2].[CH:26]1([NH2:29])[CH2:28][CH2:27]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:29][CH:26]4[CH2:28][CH2:27]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2]
Reactant: NC1CC1
Reactant: COc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: COc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NC3CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 227 using 6-(4-(4-cyano-2-methoxyphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and cyclopropanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.61 (br. s., 2H) 0.67-0.80 (m, 2H) 2.78-2.93 (m, 1H) 3.96 (s, 3H) 7.37-7.55 (m, 2H) 8.38 (d, J=7.6 Hz, 1H) 8.46 (br. s., 1H) 8.59 (br. s., 1H) 8.68 (br. s., 1H) 8.75 (br. s., 1H) 8.89 (s, 1H) 13.40 (br. s., 1H). MS m/z [M+H]+ 376.4.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>COCCO>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][CH:16]=[C:15]2[CH2:14][CH2:13][CH2:12][OH:11]
Reactant: C1=COCCC1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: COCCO
Product: OCCCc1c[nH]c2ccc(Br)cc12
Yield: 68.8 %

Procedure:
A modification of a procedure reported by Grandberg (Chem. Abstr. 1973, 79,918895) was used. Thus, to a suspension of 4-bromophenylhydrazine hydrochloride (56.0 g, 0.25 mol) in 200 mL of 2-methoxyethanol was added 3,4-dihydro-2H-pyran (25.5 mL, 0.28 mol) over ca. 5 min and the resulting mixture was heated to reflux under Ar for 3.5 h. The cooled reaction mixture was evaporated and the residual oil was poured into 500 mL of cold water. The aqueous mixture was extracted with ether (2×250 mL) and the ethereal extract was washed with H2O (250 mL), 1N HCl (2×250 mL) and brine (250 mL). The organic phase was then dried (Na2SO4) and evaporated to give a dark orange-brown oil. This oil was purified on a 10×15 cm SiO2 pad (elution with CH2Cl2 then CH2Cl2 -ethyl acetate, 1:1) to give the title compound (43.7 g, 69%) as a viscous orange-brown oil: IR (neat) 3570, 3430, 3300 (br), 1460 cm-1 ; 1H NMR (CDCl3, 200 MHz) δ 0.11 (br s, 1H), 7.73 (d, J=1.8 Hz, 1H), 7.30-7.18 (m, 2H), 6.97 (s, 1H), 3.72 (t, J=6.4 Hz, 2H), 2.80 (t, J=7.5 Hz, 2H), 2.03-1.89 (m, 2H), 1.68 (br s, 1H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=3)[C:12](Br)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:24].C(N1C2C(=CC=C([N+]([O-])=O)C=2)C(C2C=CC(C#N)=CC=2)=C1)(C)C>>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=3)[C:12]([C:28]3[CH:29]=[CH:30][C:25]([C:23]#[N:24])=[CH:26][CH:27]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc2c(Br)cn(S(=O)(=O)c3ccccc3)c2c1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: CC(C)n1cc(-c2ccc(C#N)cc2)c2ccc([N+](=O)[O-])cc21
Product: N#Cc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3cc([N+](=O)[O-])ccc23)cc1

Procedure:
Prepare this compound from 1-benzenesulfonyl-3-bromo-6-nitro-1H-indole, 7, and 4-cyanophenylboronic acid using Method C described above for 4-(1-isopropyl-6-nitro-1H-indol-3-yl)-benzonitrile 5. Purify by precipitation from EtOAc/hexanes. 1H NMR (DMSO-d6) δ 8.78 (d, 1H, J=1.8 Hz), 8.73 (s, 1H), 8.17 (dd, 1H, J=2.2, 8.8 Hz), 8.14-8.11 (m, 2H), 8.07 (d, 1H, J=8.8 Hz), 7.97-7.92 (m, 4H), 7.72 (tt, 1H, J=1.3, 7.5 Hz), 7.63-7.59 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:28][O:29][CH2:30][CH:31]=[CH2:32])[C:13](=[O:14])[N:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=3)[C:11](=[O:27])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].[C:33](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:28][O:29][CH2:30][CH:31]=[CH2:32])[C:13](=[O:14])[N:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:24])[F:25])[CH:16]=3)[C:11](=[O:27])[N:10]2[CH3:33])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C([O-])[O-]
Reactant: C=CCOCC1(c2ccc(C#N)cc2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCOCC1(c2ccc(C#N)cc2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 459 mg of 4-[4-(4-cyanophenyl)-2,5-dioxo-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-trifluoromethylbenzonitrile obtained in Step 4 in DMF (1.5 mL), 173 mg of potassium carbonate and 130 μL of methyliodide are added. The mixture is stirred 3 hours at rt, evaporated, washed with brine, extracted with ethyl acetate, dried over magnesium sulfate and concentrated to give the desired compound.
Reaction SMILES: [O:1]([CH:8]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][N:11]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCCC1.CO.O>[O:1]([CH:8]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C(C)Oc2ccccc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(Oc1ccccc1)c1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a solution of methyl 6-(1-phenoxyethyl)nicotinate (400 mg, 1.55 mmol) in tetrahydrofuran (12 mL), methanol (4 mL) and water (4 mL) was added lithium hydroxide (377 mg, 15.7 mmol). The resultant reaction mixture was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure and was treated with aqueous 1N hydrochloric acid (5 mL). Then the mixture was concentrated and the residue was purified by prep-thin layer chromatography to give 6-(1-phenoxyethyl)nicotinic acid (350 mg, 92.5%) as a white solid. LRMS (M+H+) m/z: calcd 244.09. found 244 1H NMR (300 MHz, DMSO) δ 9.08 (d, J=2.1 Hz, 1H), 8.32 (dd, J=8.1 Hz, J2=2.1 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.19 (m, 2H), 6.87 (m, 3H), 5.49 (s, 1H), 1.66 (d, J=6.6 Hz, 3H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[N:12]=[CH:11][C:10]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([CH:22]=3)[C:19]([OH:21])=[O:20])=[CH:9][C:8]=2[CH2:7][CH2:6][CH2:5]1)(=[O:3])[NH2:2].[CH3:23][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[CH3:23][O:20][C:19](=[O:21])[C:18]1[CH:22]=[C:14]([C:10]2[CH:11]=[N:12][C:13]3[N:4]([C:1](=[O:3])[NH2:2])[CH2:5][CH2:6][CH2:7][C:8]=3[CH:9]=2)[CH:15]=[N:16][CH:17]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: NC(=O)N1CCCc2cc(-c3cncc(C(=O)O)c3)cnc21
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
To the solution of 5-(8-Carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-nicotinic acid (100 mg, 0.33 mmol) in 12 mL of toluene/MeOH 3:1 mixture is added 2.0 M trimethylsilyl-diazomethane (0.20 mL, 0.40 mmol) under N2 atmosphere. The reaction solution is stirred at room temperature for 16 hrs. The solvents are removed in vacuo and the residue is purified by preparative HPLC to give 33 mg of the titled product.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O.C(OCC)C>[CH2:1]([C:4]1[C:13]([O:14][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccc2cccnc2c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: C=CCc1ccc2cccnc2c1OCc1ccccc1
Temperature: 25 °C
Yield: 72 %

Procedure:
To a stirring solution of 7-allylquinolin-8-ol (14.56 mmol, 1 eq.) in acetone (50 mL) in a round bottom flask equipped with a reflux condenser was added potassium carbonate (151.94 mmol, 10.44 eq.) followed by benzyl bromide (17.47 mmol, 1.2 eq.) and the resulting solution was stirred and heated to reflux for 20 h. Additional potassium carbonate (151.94 mmol, 10.44 eq.) was added followed by additional benzyl bromide (29.12 mmol, 2 eq.) and the resulting mixture was heated at reflux and stirred 2 h. The reaction mixture was then cooled to room temperature and diluted with 50 mL of diethyl ether. The resulting suspension was filtered and the filtrate concentrated to a yellow oil that was purified by column chromatography using 10% acetone/dichloromethane to give the product as a pale yellow oil (10.48 mmol, 72%). MS (ESI) m/z 276.2; HRMS: calcd for C19H17NO+H+, 276.13829; found (ESI-FTMS, [M+H]1+), 276.13828.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)C.[OH-].[NH4+:27].FC(F)(F)C(O)=O>>[N:11]1([C:9]2[S:10][C:6]([C:4]([NH2:27])=[O:3])=[C:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:8]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1
Reactant: [NH4+]
Reactant: CCOC(=O)c1sc(-n2cnc3ccccc32)nc1-c1ccccc1
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1sc(-n2cnc3ccccc32)nc1-c1ccccc1
Yield: 13 %

Procedure:
2-Benzoimidazol-1-yl-4-phenyl-thiazole-5-carboxylic acid amide was prepared from 2-Benzoimidazol-1-yl-4-phenyl-thiazole-5-carboxylic acid ethyl ester (75 mg, 0.21 mmol) and ammonium hydroxide as described above in the general amide formation procedure. Preparative HPLC with trifluoroacetic acid, 9.1 mg, 13% yield. MS M/z 321 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[CH2:32]([O:31][C:29]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][N:6]1[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=[C:2]1[CH3:1])=[O:30])[CH3:33]
Reactant: CCOC(=O)CCCCCCCBr
Reactant: Cc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CCCCCCCn1c(C)nc(-c2ccccc2)c1-c1ccccc1
Yield: 71.8 %

Procedure:
2-Methyl-4,5-diphenylimidazole (2.5 g) (J. Org. Chem., 1937, 2,328) was reacted with sodium hydride (0.62 g) and ethyl 8-bromooctanoate (3.36 g) in a method similar to Example 12. Chromatography on silica gel eluted with a dichloromethane:ethanol gradient gave 1-(7-ethoxycarbonyl-heptyl)-2-methyl-4,5-diphenylimidazole (3.1 g, 72.1%) as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[CH2:8]([C@@H:12]1[NH:17][CH2:16][CH2:15][N:14]([C:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:13]1)[CH2:9][CH2:10][CH3:11].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:8]([C@H:12]1[CH2:13][N:14]([C:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:15][CH2:16][N:17]1[S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])[CH2:9][CH2:10][CH3:11]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CCCC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CS(=O)(=O)N1CCN(C(=O)c2cccc3ccccc23)C[C@@H]1CCCC
Reaction time: 8 h

Procedure:
Chloroethylsulfonylchloride (0.038 mL, 0.314 mmol) was added to a solution of 3(S)-butyl-1-(1-naphthoyl)piperazine (0.095 g, 0.285 mmol) and diisopropylethylamine (0.119 mL, 0.685 mmol) in dichloromethane (3 mL). The reaction was stirred overnight under nitrogen, quenched with saturated sodium bicarbonate and extracted into ethyl acetate. After drying with magnesium sulfate, the title compound was isolated.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:5]2=[O:17].C([O-])([O-])=O.[K+].[K+].Br.Br[CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>CC#N>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:10][CH:9]=2)[C:5](=[O:17])[N:6]1[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: BrCc1cccnc1
Reactant: COC(=O)CN1C(=O)c2ccc(O)cc2C1=O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CN1C(=O)c2ccc(OCc3cccnc3)cc2C1=O
Temperature: 80 °C
Yield: 55.4 %

Procedure:
To a solution of methyl 2-(5-hydroxy-1,3-dioxoisoindolin-2-yl)acetate (78 mg, 0.332 mmol) in CH3CN (20 mL), K2CO3 (115 mg, 0.829 mmol) and 3-(bromomethyl)-pyridine hydrobromide (126 mg, 0.497 mmol) were added at room temperature. The reaction was heated at 80° C. for 2 hours. The insoluble was filtered off and washed with DCM; the filtrated was evaporated under vacuum; and the crude was partitioned between a saturated solution of Na2CO3 and DCM. The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. The crude was purified by filtration on silica gel cartridge (petroleum ether/EtOAc 1/1 to petroleum ether/EtOAc 2/8) to afford methyl 2-(1,3-dioxo-5-(pyridin-3-ylmethoxy)isoindolin-2-yl)acetate (60 mg, 0.184 mmol, 55.4% yield, MS/ESI+ 327.0 [MH]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].S1C=CN=C1C1C=CC(CNS(C2C=NC=CC=2)(=O)=O)=CC=1.[N:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[C:62]1[CH:69]=[CH:68][C:65]([CH2:66]O)=[CH:64][CH:63]=1>>[C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH2:66][C:65]2[CH:64]=[CH:63][C:62]([C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][N:56]=3)=[CH:69][CH:68]=2)[NH:16][S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:18])=[O:19])[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CNS(=O)(=O)c2cccnc2)n1
Reactant: OCc1ccc(-c2ccccn2)cc1
Agent: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1cccnc1
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2ccc(-c3ccccn3)cc2)NS(=O)(=O)c2cccnc2)n1
Yield: 139.8 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Example 2-(a) except for using tert-butyl(tert-butoxycarbonyl{6-[(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-yl}amino)acetate (934 mg, 1.95 mmol) obtained in Reference Example 12-(d) in place of N-[4-(thiazol-2-yl)benzyl]pyridin-3-ylsulfonamide, and using 4-(pyridin-2-yl)benzyl alcohol (397 mg, 2.14 mmol) in place of tert-butyl [tert-butoxycarbonyl(6-hydroxymethylpyridin-2-yl)amino]acetate to afford the title compound (1.76 g) (pure content 1.26 g) substantially quantitatively as a yellow oil.
Reaction SMILES: C(O[C:4](=O)[CH:5]([O:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])[CH3:6])C.N.ClC1C=CC=C(Cl)C=1OC(C)C(N)=O.CN1CCOCC1.Cl.[NH2:40][CH2:41][CH2:42][NH2:43]>C(O)C.C(Cl)(Cl)Cl>[Cl:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:15])[C:8]=1[O:7][CH:5]([C:4]1[NH:40][CH2:41][CH2:42][N:43]=1)[CH3:6]
Reactant: NCCN
Reactant: CCOC(=O)C(C)Oc1c(Cl)cccc1Cl
Agent: CC(Oc1c(Cl)cccc1Cl)C(N)=O
Agent: Cl
Agent: N
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(Oc1c(Cl)cccc1Cl)C1=NCCN1

Procedure:
In a variation of the present process, the (-)-2-(2,6-dichlorophenoxy)-propionic acid ethylester obtained as above described, is reacted with an ethanolic solution of ammonia at room temperature and is converted into (+)-2-(2,6-dichlorophenoxy)-propionic acid amide which is difficultly soluble in ethanol. This amide is dehydrated at from 0° to 30° C. with a titanium tetrachloride/tetrahydrofurane complex and 4-methyl-morpholine in chloroform into (-)-2-(2,6-dichlorophenoxy)-propionic acid nitrile. By introducing hydrogen chloride at 0° C., the nitrile is then converted with ethanol in chloroform into (-)-2-(2,6-dichlorophenoxy)-propionimido acid ethylester hydrochloride. This compound is dissolved in ethanol and is cyclized by adding 1,2-diaminoethane to produce (-)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-ene. Analogously to the previous process, (-)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-ene hydrochloride is produced from the (-)-base thus obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH:12]=O)=[CH:4][CH:3]=1.[Cl-].[CH2:15]([N:19]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:20](=[O:22])[CH3:21])[CH:16]([CH3:18])[CH3:17]>>[CH2:15]([NH:19][C:20](=[O:22])/[CH:21]=[CH:12]/[CH2:11][CH2:10][C:9]#[C:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: O=CCCC#Cc1ccc(Br)cc1
Reactant: CC(=O)N(CC(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Product: CC(C)CNC(=O)/C=C/CCC#Cc1ccc(Br)cc1

Procedure:
N-isobutyl 7-(4'-bromophenyl)-(2E)-hepten-6-ynamide was prepared from 5-(4'-bromophenyl)-4-pentyn-1-al and N-isobutyl acetamidotriphenylphosphonium chloride as in Example 9 and semi-hydrogenated as in Example 9 to give N-isobutyl 7-(4'-bromophenyl)-(2E,6Z)-hepta-dienamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.C([Li])CCC.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH:24]=[O:25])[CH3:19].C(O)(C)C>C1COCC1.O>[CH2:11]([O:10][C:4]1[CH:3]=[C:2]([CH:24]([C:23]2[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:21]([O:20][CH2:18][CH3:19])[CH:22]=2)[OH:25])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[CH3:12]
Reactant: CCOc1cc(Br)ccc1OC
Reactant: CCOc1cc(C=O)ccc1OC
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C(O)c2ccc(OC)c(OCC)c2)ccc1OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 103.6 %

Procedure:
A stirred mixture of 4-bromo-2-ethoxy-1-methoxy-benzene (6.52 g, 28.2 mmol) and dry THF (40 mL) was cooled to −78° C., evacuated and refilled with nitrogen for 10 cycles. To this clear solution was slowly added n-butyllithium (11.3 mL, 28.2 mmol) and stirred for 30 min. Then a mixture of 3-ethoxy-4-methoxy-benzaldehyde (4.62 g, 25.7 mmol) in dry THF (60 mL) was added and stirred for 1 h at −78° C. The mixture was quenched with isopropanol (11.7 mL, 154 mmol) and added water (30 mL). It was extracted with ether (3×50 mL). The combined organic phases were washed with water (2×50 mL), dried over MgSO4 and concentrated to an oil, which was purified by flash column chromatography (EtOAc/Hexane) to give bis-(3-ethoxy-4-methoxy-phenyl)-methanol as an oil (8.85 g, 100% yield): 1H NMR (CDCl3) δ 1.44 (t, J=7 Hz, 6H, 2CH2CH3), 2.12 (d, J=4 Hz, 1H, OH), 3-0.86 (s 6H, 2OCH3), 4.06 (q, J=7 Hz, 4H, 2CH2CH3), 5.74 (d, J=4 Hz, 1H, CH), 6.81-6.91 (m, 6H, Ar). The product was used in the next step without further purification.
Reaction SMILES: [C:1]1(=[O:14])[C:9]2[C:8]3[CH:10]=[CH:11][CH2:12][O:13][C:7]=3[CH:6]=[CH:5][C:4]=2[CH2:3][NH:2]1.[N:15]([O-:17])=[O:16].[Na+].II>CN1CCCC1.O>[N+:15]([C:11]1[CH2:12][O:13][C:7]2[CH:6]=[CH:5][C:4]3[CH2:3][NH:2][C:1](=[O:14])[C:9]=3[C:8]=2[CH:10]=1)([O-:17])=[O:16]
Reactant: O=C1NCc2ccc3c(c21)C=CCO3
Reactant: O=N[O-]
Agent: CN1CCCC1
Agent: II
Agent: [Na+]
Solvent: O
Product: O=C1NCc2ccc3c(c21)C=C([N+](=O)[O-])CO3
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
To a mixture of 2,3-dihydropyrano[3,2-e]isoindol-1(7H)-one ((71) 2.3 g, 12.3 mmol) in N-methylpyrrolidine (150 ml) and H2O (3 ml) was added NaNO2 (3.4 g, 49.2 mmol) in portions. To the mixture cooled at 0° C. was added iodine (9.4 g, 36.9 mmol). The reaction mixture was stirred for 3 hr, then quenched with 58% NaHSO3 (12 ml), H2O (12 ml), followed by addition of another 30 ml of 58% NaHSO3 solution. The solid was participated, filtered, and washed with H2O. The desired compound was air-dried under vacuum to give the title compound (2.41 g, 84%) as a yellow solid. MS (ES) m/z 233.2.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[C:13]2[CH:14]=[C:15]([CH2:18][N:19]3[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:22]([CH3:29])[N:21]=[C:20]3[CH2:30][CH3:31])[CH:16]=[CH:17][C:12]=2[O:11][C:10]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([O:40]C(C)(C)C)=[O:39]>ClCCl>[Br:8][C:9]1[C:13]2[CH:14]=[C:15]([CH2:18][N:19]3[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:22]([CH3:29])[N:21]=[C:20]3[CH2:30][CH3:31])[CH:16]=[CH:17][C:12]=2[O:11][C:10]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([OH:40])=[O:39]
Reactant: CCOC(=O)c1c(C)nc(CC)n1Cc1ccc2oc(-c3ccccc3C(=O)OC(C)(C)C)c(Br)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(C)nc(CC)n1Cc1ccc2oc(-c3ccccc3C(=O)O)c(Br)c2c1
Temperature: 0 °C
Yield: 24.9 %

Procedure:
Trifluoroacetic acid (7 ml) was added dropwise to a stirred solution of the product of Example 144 (0.892 g) in dichloromethane (30 ml)cooled to 0° C. After 21/2 h the solvent was removed in vacuo to yield an orange oil. The oil was diluted with dichloromethane, washed with hydrochloric acid, dried and the solvent removed in vacuo. The residue was purified by flash column chromatography eluting with dichloromethane/methanol (30:1) to give the title compound as a white solid (200 mg).