Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.FC(F)(F)S(O[C:17]1[CH2:21][CH2:20][CH2:19][C:18]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=O)=O.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:17]1[CH2:21][CH2:20][CH2:19][C:18]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: OB(O)c1ccccc1F
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(c2ccccc2F)CCC1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
2-Fluorobenzeneboronic acid (4.48 g) and tetrakis(triphenylphosphine)palladium (740 mg) were added to a solution of ethyl 2-trifluoromethanesulfonyloxycyclopent-1-enecarboxylate obtained in Preparation Example 3-(1) in toluene. Then, ethanol (100 mL) and a 1 N sodium carbonate solution (32 mL) were added to the reaction solution, followed by replacement of the reaction atmosphere with nitrogen. The reaction solution was heated to 85° C. and stirred overnight. The reaction solution was cooled to room temperature, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (7.60 g).
Reaction SMILES: C([O:3][C:4](=[O:28])/[C:5](=[N:25]\[O:26][CH3:27])/[C:6]1[S:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1)C.[OH-].[Na+]>CO.O1CCCC1>[CH3:27][O:26]/[N:25]=[C:5](/[C:6]1[S:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1)\[C:4]([OH:28])=[O:3]
Reactant: CCOC(=O)/C(=N\OC)c1ccc(OCCOc2ccc3ccccc3c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CO/N=C(\C(=O)O)c1ccc(OCCOc2ccc3ccccc3c2)s1
Temperature: 53 °C
Yield: 76.4 %

Procedure:
As in Example 306, a solution of (E)-alpha-(methoxyimino)-5-[2-(2-naphthalenyloxy) ethoxy]-2-thiopheneacetic acid ethyl ester (0.2 g) in methanol (2 mL) and tetrahydrofuran (1 mL) was treated with 3N sodium hydroxide (0.5 mL) and the stirred mixture was heated at 53° C. for 30 minutes. After the normal work up, the product was crystallized from dichloromethane-hexane to furnish 0.142 g of (E)-alpha-(methoxyimino)-5-[2-(2-naphthalenyloxy)ethoxy]-2-thiopheneacetic acid, mp 118°-120° C.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:30]=[CH:31][CH:32]=[CH:33][C:8]1=2)=[O:6])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:40](OC(=O)C)(=[O:42])[CH3:41].[OH-].[Na+]>ClCCl>[CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:40](=[O:42])[CH3:41])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:27])[F:28])[CH:17]=2)[C:9]2[CH:30]=[CH:31][CH:32]=[CH:33][C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.4 %

Procedure:
A solution of crude 5-(3,5-Bis-trifluoromethyl-benzylamino)-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (200 mg, 0.42 mmol) and pyridine (0.85 ml, 10.5 mmol) in dichloromethane (2 ml) at room temperature was treated with acetic anhydride (0.79 ml, 8.4 mmol) via dropwise addition over 4 minutes. The mixture was stirred at room temperature for 20 hours. The mixture was cooled (0° C.) and treated with 1N NaOH and stirred for 30 minutes. The aqueous layer was extracted with dichloromethane. The combined organic phases were washed with 1N HCl, dried (Na2SO4) and concentrated to an oil. Purification by silica gel chromatography (eluent, 2:1 n-hexanes:ethyl acetate) provided 5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (144 mg).
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([CH2:12][C:13]#[N:14])[CH:3]=1.[H-].[Na+].[C:17](OCC)(=[O:19])[CH3:18].O>C1COCC1>[F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([CH:12]([C:17](=[O:19])[CH3:18])[C:13]#[N:14])[CH:3]=1
Reactant: N#CCc1cc(F)c2c(c1)OCCO2
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)C(C#N)c1cc(F)c2c(c1)OCCO2
Temperature: 60 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of (8-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)acetonitrile (0.40 g, 2.10 mmol) in THF (10 mL) was added sodium hydride (60% dispersion in mineral oil, 0.25 g, 6.3 mmol) and ethyl acetate (2.05 ml, 21.0 mmol) and the mixture was stirred at 60° C. for 2 h. After cooling to 0° C., water was added (25 mL) and the aqueous layer was washed with dichloromethane (3×15 mL), acidified with 1N HCl to pH 3 and extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with brine (30 mL) then dried with sodium sulfate, filtered and concentrated to give 2-(8-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-3-oxobutanenitrile as an orange solid (0.37 g; 75% yield). 1H NMR (400 MHz, d6-DMSO) δ 7.05 (dd, 1H), 6.93 (br. s, 1H), 4.30 (m, 5H), 2.30 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](Cl)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[O:19]=[C:20]1[CH2:25][NH:24][CH2:23][CH2:22][NH:21]1.N1C=CC=CC=1.C(O)(=O)C>[OH-].[Na+]>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:24]3[CH2:23][CH2:22][NH:21][C:20](=[O:19])[CH2:25]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: O=C1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(=O)C3)cc21
Yield: 32.4 %

Procedure:
A mixture of 1-ethyl-7-chloro-1,4-dihydro-6-fluoro-4-oxoquinoline-3-carboxylic acid (0.80 g), 2-oxopiperazine (3.0 g) and 4 ml pyridine was heated for 18 hours. The reaction mixture was evaporated under vacuum, an aqueous solution of caustic soda was added to adjust the pH to 10, ice cooled and the undissolved matter was collected and washed with a small amount of an aqueous solution of NaOH. The filtered product was suspended in water, acidified with acetic acid, filtered and washed. The product obtained was dissolved in an aqueous solution of NaOH and acidified with acetic acid. The precipitate was filtered, washed and dried to obtain 0.32 g (32%) of 1-ethyl-1,4-dihydro-6-fluoro-7-(3-oxo-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: OS(O)(=O)=O.[Cl:6][C:7]1[S:8][C:9]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[C:10]([CH2:12][OH:13])[N:11]=1.C([OH:23])(C)C>CC(C)=O.O.[Na+].[Cl-]>[Cl:6][C:7]1[S:8][C:9]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[C:10]([C:12]([OH:23])=[O:13])[N:11]=1
Reactant: CC(C)OC(=O)c1sc(Cl)nc1CO
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)OC(=O)c1sc(Cl)nc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3 mL H2SO4 and 12 mL water were cooled in an ice water bath, and 2.3 g (23 mmol) CrO3 was added portionwise. The solution was added dropwise to a cooled (ice water bath) solution of 2.74 g (11.6 mmol) of isopropyl 2-chloro-4-(hydroxymethyl)-1,3-thiazole-5-carboxylate (Intermediate 13) in acetone (50 mL) The resulting mixture was stirred 4 hours with warming to room temperature. Isopropanol (2 mL) was added and stirring was continued for 15 min. The solution was diluted with water, saturated with NaCl and extracted 3 times with EtOAc. The EtOAc was washed with brine, dried (MgSO4) and concentrated to give 2.86 g of an oil. NMR: 1.3 (d, 6H), 5.1 (m, 1H), 14.1 (s, 1H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]([C:18]([NH2:20])=[O:19])[CH2:12]2.[C:21](Cl)(=[O:23])[CH3:22]>ClC(Cl)Cl>[C:21]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([Cl:8])=[CH:17][CH:16]=2)[CH2:12][CH:13]1[C:18]([NH2:20])=[O:19])(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: NC(=O)C1Cc2cc(Cl)ccc2N1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N1c2ccc(Cl)cc2CC1C(N)=O
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 85.7 %

Procedure:
Triethylamine (0.02080 mole) was added to intermediate (7) (0.09632 mole) dissolved in trichloromethane (700 ml). The mixture was cooled to 5° C. Acetyl chloride (0.2480 mole) was added over 2 minutes with stirring. After 5 minutes, a precipitate formed. The ice bath was removed, and the container allowed to sit for 15 minutes. Ice water (250 ml) was added, and the mixture was stirred for 10 minutes. The sample was filtered, rinsed with water and trichloromethane. The solid was suspended in water (200 ml), and swirled for 10 minutes. Trichloromethane (200 ml) was added and the mixture was stirred, then filtered and rinsed with water and trichloromethane, and then dried to the air overnight, yielding 19.71 g of 1-acetyl-5-chloro-2,3-dihydro-1H-indole-2-carboxamide (intermediate 8).
Reaction SMILES: I[C:2]1[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:23][C:21]1[C:20]([CH3:24])=[CH:19][C:3]([O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[C:2]([C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)[CH:22]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(C)cc3I)c2cc1OC
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3cc(C)c(C)cc3-c3cccnc3)c2cc1OC
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 24.8 %

Procedure:
4-(2-Iodo-4,5-dimethyl-phenoxy)-6,7-dimethoxyquinoline (compound 164) (59 mg), pyridine-3-boronic acid (33 mg), and tetrakistriphenylphosphine palladium (10 mg) were dissolved in N,N-dimethylformamide (4 ml), a 2 M aqueous potassium carbonate solution (0.5 ml) was added to the reaction system, and the mixture was stirred at 100° C. for 30 min. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (13 mg, yield 25%).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]#[N:13])=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14]N1C(=O)CCC1=O>O1CCCC1>[Cl:14][C:11]1[NH:10][CH:9]=[C:8]([C:12]#[N:13])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1c[nH]cc1-c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: N#Cc1c[nH]c(Cl)c1-c1ccccc1
Reaction time: 48 h
Yield: 97 %

Procedure:
To a solution of 44.3 g (263 mmol) of 4-phenyl-1H-pyrrole-3-carbonitrile (CAS 40167-37-1) in 600 ml of tetrahydrofuran are added portionwise 35.8 g (268 mmol) of N-chlorosuccinimide (CAS 128-09-6) and the mixture is then stirred for 48 hours at reflux. After cooling, the reaction medium is concentrated under reduced pressure and the residue is then taken up in water. The reaction product is extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give a brown solid, which is triturated in diisopropyl ether and then isolated by filtration. The filtrate is concentrated under reduced pressure and the solid residue obtained is triturated in diisopropyl ether and then isolated by filtration. The two batches of solid are combined to give 51.7 g of 5-chloro-4-phenyl-1H-pyrrole-3-carbonitrile in the form of a beige-coloured powder after drying.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:15]#[N:16])(=[O:3])[CH3:2].[CH2:17]([OH:19])[CH3:18].[ClH:20].C(OCC)C>>[ClH:20].[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:15](=[NH:16])[O:19][CH2:17][CH3:18])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)CC(C#N)N2C(C)=O
Reactant: CCO
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)C1Cc2cc(OC)ccc2N1C(C)=O

Procedure:
To a solution of intermediate (23) (0.0154 mole) and ethanol (0.0231 mole) in 1M HCl/diethylether (200 ml), cooled in an ice bath was bubbled HCl (gas) for 60 minutes. The ice bath was maintained for 45 minutes, and the mixture was concentrated at room temperature under vacuum to 200 ml of an oily precipitate. The residue was triturated to a brown solid that became an oil after decanting off the diethylether. The residue was washed with diethylether twice, dissolved in methanol, and used without further purification for further synthesis, yielding ethyl 1-acetyl-2,3-dihydro-5-methoxy-1H-indole-2-carboximidate monohydrochloride (intermediate 24).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]=[CH:11][N+:12]([O-:14])=[O:13])=[CH:4][C:3]=2[O:2]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=1.N12CCCN=C1CCCCC2>C(OCC)(=O)C>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([CH:24]([CH:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[CH2:11][N+:12]([O-:14])=[O:13])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:30])=[CH:21][CH:22]=1
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Reactant: O=[N+]([O-])C=Cc1ccc2c(c1)OCO2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)c1ccc(OC)cc1)C(C[N+](=O)[O-])c1ccc2c(c1)OCO2

Procedure:
Into a 45-L stirred reactor at ambient temperature were charged 5.819 kg (30.1 moles) 3,4-methylenedioxy-1-(2-nitroethenyl)-benzene and 24 L ethyl acetate . A solution of 5.355 kg (24.1 moles) ethyl 3-(4-methoxyphenyl)-3-oxopropionate in 16 L ethyl acetate was added. 280 g (275 ml, 1.84 moles) of 1,8-diaza-bicyclo[5.4.0]undec-7-ene in four equal portions was added over a 2.5 hour period. The reaction mixture was filtered through dicalite and the resulting filtered solution was used in the next step without any further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13].[I-:14].[K+].[N:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1>CC(=O)CC>[I-:14].[CH2:2]([N+:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCC#CCCCCCCCl
Reactant: Cc1cncc(C)c1
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCC#CCCCCCC[n+]1cc(C)cc(C)c1
Temperature: 25 °C
Yield: 78 %

Procedure:
12-Chloro-dodec-5-yne (1 mmol) was mixed with potassium iodide (3 mmol) and 3,5-lutidine (3 mmol) in butanone. The mixture was refluxed for 3 days and cooled to room temperature, filtrated. The butanone was removed in vacuum, and the resulting residue was partitioned between water and ethyl ether. The aqueous layer was washed extensively with ether until no 3,5-lutidine was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (78%). 1HNMR (300 MHz, CDCl3, ppm), 9.06 (s, 2H), 8.00 (s, 1H), 4.86 (t, 3H), 2.48 (s, 3H), 1.98-2.16 (m, 6H), 1.32-1.48 (br, 10H), 0.88 (t, 3H); 13CNMR, 146.12, 141.38, 138.64, 80.43, 79.53, 61.46, 31.70, 31.17, 28.68, 28.07, 25.55, 21.92, 18.57, 18.42, 13.63.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[C:5]#[N:6].[CH2:11](Cl)[O:12][CH3:13].[H-].[Na+]>CN(C)C=O>[I:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[O:1][CH2:11][O:12][CH3:13]
Reactant: COCCl
Reactant: N#Cc1ccc(I)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cc(C#N)ccc1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-hydroxy-4-iodobenzonitrile (500 mg, 2.04 mmol) and MOMCl (350 mg, 4.37 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL) and cooled to 0° C. NaH (100 mg, 60% suspension in mineral oil, 2.5 mmol) is then added. The resulting mixture is allowed to stir at room temperature for 1 h before TLC analysis suggested the consumption of the starting iodide. Ether is then added and washed with H2O (3×20 mL) and brine. After drying over Na2SO4, the ether is removed and the residue is purified through chromatography to afford the desired MOM ether (570 mg, 96%). 1H NMR (300 MHz, CDCl3) δ 7.90 (1H, d, J=8.01 Hz), 7.32 (1H, d, J=1.7 Hz), 7.03 (1H, dd, J=8.01 and 1.71 Hz), 5.27 (2H, s), 3.51 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][CH2:9][CH2:10][OH:11])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:12]N1C(=O)CCC1=O>ClCCl.C(OCC)(=O)C>[Br:12][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([NH:8][CH2:9][CH2:10][OH:11])=[N:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCNc1ncccc1Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: OCCNc1ncc(Br)cc1Cl
Reaction time: 1.5 h
Yield: 103.6 %

Procedure:
2.1 g of 2-(3-chloro-2-pyridinylamino)ethanol was dissolved in 25 mL dichloromethane, and 2.3 g N-bromosuccinimide was added little by little thereto at 0° C. and stirred for 1.5 hours. The reaction mixture was diluted with ethyl acetate and then washed with an aqueous saturated sodium bicarbonate and brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed, whereby 3.17 g of the title compound (yellow oil) was obtained.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH2:13]([O:15][C:16](=[O:38])[CH:17]([O:35][CH2:36][CH3:37])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)=[CH:21][CH:20]=1)[CH3:14].Cl>ClCCl>[CH2:13]([O:15][C:16](=[O:38])[CH:17]([O:35][CH2:36][CH3:37])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([NH:34][S:9]([CH3:8])(=[O:11])=[O:10])=[CH:32][CH:33]=2)=[CH:21][CH:20]=1)[CH3:14]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(N)cc2)cc1)OCC
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(NS(C)(=O)=O)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.9 %

Procedure:
Triethylamine (0.544 g; 2.99 mmole) and thereafter methanesulfonyl chloride (0.392 g; 2.99 mmole) were added to a solution of 3-{4-[2-(4-aminophenyl)ethoxy]phenyl}-2-ethoxypropanoic acid ethyl ester (0.89 g; 2.49 mmole) in dichloromethane (8.9 ml) at 0° C. After stirring at room temperature for 20 hours the reaction mixture was poured onto a mixture of hydrochloric acid and ice. Dichloromethane was added, the phases were separated and the organic phase was washed with water, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo. Purification by chromatography on silica gel using heptane:ethyl acetate (3:2) as eluant gave 0.78 g (yield 72%) of 2-ethoxy-3-{4-[2-(4-methanesulfonylaminophenyl)ethoxy]phenyl}propanoic acid ethyl ester.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][C:31]=1[C:42]1[NH:46][C:45]2[CH:47]=[CH:48][CH:49]=[CH:50][C:44]=2[N:43]=1.CCN(C(C)C)C(C)C>C(#N)C>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH2:22][CH:23]([C:26]([N:39]2[CH2:40][CH2:41][N:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[C:31]([C:42]4[NH:43][C:44]5[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=5[N:46]=4)[CH:32]=3)[CH2:37][CH2:38]2)=[O:28])[CH2:24][CH2:25]1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: Fc1ccc(N2CCNCC2)cc1-c1nc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(c3ccc(F)c(-c4nc5ccccc5[nH]4)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.4 %

Procedure:
CDI (0.047 g, 0.29 mmol) was added to a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (0.07 g, 0.29 mmol) in acetonitrile (2.50 mL). The resulting solution was stirred at room temperature for 5 hours. 2-(2-Fluoro-5-piperazin-1-yl-phenyl)-1H-benzoimidazole (0.10 g, 0.27 mmol) and DIPEA (0.05 mL, 0.26 mmol) were added and reaction was heated at 65° C. overnight. Reaction was cooled to room temperature and solvent was removed under reduced pressure. DCM (2 mL) was added to the crude, organic solution was washed with water (2×4 mL) and with saturated Na2CO3 solution (2×4 mL) and concentrated. The crude reaction mixture was purified by flash chromatography (eluent: cyclohexane:AcOEt gradient from 100% of cyclohexane to 100% AcOEt) to afford 0.08 g of the title compound (60%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].F[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[CH3:9]
Reactant: N#Cc1ccc(F)cc1
Reactant: Cc1cc(O)ccc1F
Product: Cc1cc(Oc2ccc(C#N)cc2)ccc1F

Procedure:
4-Fluoro-3-methylphenol and 4-fluorobenzonitrile were coupled following the procedure outlined in example 28 to give 4-(4-fluoro-3-methylphenoxy)benzonitrile. A mixture of 4-(4-fluoro-3-methylphenoxy)benzonitrile (1.1 g, 4.8 mmol), N-bromosuccinimide (NBS, 1.0 g, 5.6 mmol), dibenzoyl peroxide (90 mg, 0.37 mmol), and CCl4 (20 mL) was heated at reflux under N2. After 1 h, a second aliquot of dibenzoyl peroxide was added. After an additional 3 h, a second aliquot of NBS and a third aliquot of dibenzoyl peroxide were added. After an additional 4 h, a fourth aliquot of dibenzoyl peroxide was added. After an additional 15 h, the reaction was allowed to cool to rt and purified by silica gel chromatography (hexanes:ethyl acetate—1:0→4:1) to give an off-white solid. MS (ESI): 306/308 (M+H). A similar reaction sequence as outlined in example 1 was followed using the above bromide and 1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-ol. 1H NMR (500 MHz, DMSO) δ 8.01 (d, 2H), 7.33 (t, 1H), 7.30-7.24 (m, 2H), 7.21 (d, 1H), 7.21-7.13 (m, 3H), 6.98 (d, 1H), 6.37 (d, 1H), 5.12 (s, 2H), 3.90 (s, 2H), 2.71 (t, 2H), 1.53-1.43 (m, 2H), 0.91 (s, 9H), 0.78 (t, 3H). MS (ESI): 514.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[C:10]([O:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(OC(C)(C)C)=O.O.Cl>N1C=CC=CC=1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[C:21]([O:20][C:18]([O:17][C:10]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[CH:4][CH:3]=1)=[O:19])([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: C=Cc1ccc(O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: C=Cc1ccc(OC(=O)OC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
Poly (p-hydroxystyrene) (VP-8000, manufactured by Nippon Soda Co., Ltd., weight average molecular weight: 11,000) was dissolved in 40 ml of pyridine, and 1.28 g of di-t-butyl dicarbonate was added to the solution with stirring at room temperature. After performing the reaction at room temperature for 3 hours, the reaction solution was poured into 1 liter of ion exchange water containing 20 g of concentrated hydrochloric acid. The powder precipitated was filtered, washed with water, and dried, thereby p-hydroxystyrene/p-(t-butyloxycarbonyloxy)styrene copolymer (60/40) was obtained.