Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]1.[C:19]([N:27]=[C:28]=S)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[C:19](/[N:27]=[C:28]1/[N:8]([C@@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][CH2:14]2)[C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[NH:1]/1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COC(=O)[C@H]1CC[C@@H](Nc2ccncc2N)CC1
Solvent: CC#N
Product: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccccc3)[nH]c3cnccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.9 %

Procedure:
To a solution of cis-methyl 4-(3-aminopyridin-4-ylamino)cyclohexanecarboxylate (70 mg, 0.281 mmol) in ACN (5.6 mL) under nitrogen was added benzoyl isothiocyanate (0.045 mL, 0.337 mmol). The reaction mixture was stirred for 30 minutes at RT. To the mixture was added polymer-supported-carbodiimide (936 mg, 1.123 mmol; Loading: 1.2 mmol/g;), and the resulting mixture was stirred at 70° C. for 16 hours. The reaction mixture was cooled to RT and filtered, and the resin was washed with 1% MeOH/DCM. The filtrate was concentrated and purified by silica gel chromatography (1-4% MeOH/DCM) to afford cis-methyl 4-((E)-2-(benzoylimino)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate as an off-white solid (18 mg, 17% yield). MS m/z=379.2 [M+H]. Calc'd for C21H22N4O3: 378.2.
Reaction SMILES: C(N)C1C=CC=CC=1.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:13][NH2:14].[F:19][C:20]1[CH:42]=[CH:41][C:23]([CH2:24][N:25]2[CH2:29][CH2:28][N:27]([C:30]3[CH:31]=[C:32]([CH:37]=[CH:38][N:39]=3)[C:33](OC)=[O:34])[C:26]2=[O:40])=[CH:22][CH:21]=1>>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:13][NH:14][C:33](=[O:34])[C:32]1[CH:37]=[CH:38][N:39]=[C:30]([N:27]2[CH2:28][CH2:29][N:25]([CH2:24][C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:42][CH:41]=3)[C:26]2=[O:40])[CH:31]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Solvent: NCc1ccccc1
Product: O=C(NCc1ccc(F)c(F)c1)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 34 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace benzylamine with 3,4-difluorobenzylamine to react with methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate, N-(3,4-difluorobenzyl)-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinamide was obtained as a colorless solid in 34% yield: mp 182-183° C.; 1H NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 8.37 (d, J=5.1 Hz, 1H), 7.24-6.99 (m, 9H), 4.55 (d, J=5.7 Hz, 2H), 4.42 (s, 2H), 4.04 (t, J=8.1 Hz, 2H), 3.37 (t, J=8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 165.7, 157.0, 153.0, 148.4, 142.6, 131.9, 129.9, 129.7, 123.9, 117.6, 117.4, 117.0, 116.8, 116.1, 115.9, 115.6, 108.9, 47.2, 43.1, 41.3, 41.1; MS (ES+) m/z 440.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])=[C:5]([CH3:23])[CH:4]=1.[CH3:24][C:25]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[C:26]=1[C:27](Cl)=[O:28].ClC(Cl)C>C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][N:19]([CH:20]([CH3:21])[CH3:22])[C:27]([C:26]2[C:25]([CH3:24])=[CH:33][C:32]([CH3:34])=[CH:31][C:30]=2[CH3:35])=[O:28])=[C:5]([CH3:23])[CH:4]=1
Reactant: COc1ccc(-n2c(CNC(C)C)nc3ccccc32)c(C)c1
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1ccc(-n2c(CN(C(=O)c3c(C)cc(C)cc3C)C(C)C)nc3ccccc32)c(C)c1
Yield: 92 %

Procedure:
A solution of 3 g (10.5 mmole) 1-[2-(chloromethyl)benzimidazolyl]-4-methoxy-2-methylbenzene in 20 mL of dry acetonitrile is treated with 5 mL of isopropylamine for 1 hour in a sealed reaction vessel at 50° C. The solvent is removed in vacuo and the residue is partitioned between 30 mL of ethyl acetate and 10 mL of 1 N NaOH. The ethyl acetate layer is dried over anhydrous Na2SO4 and solvent removed in vacuo to afford 3.1 g (98%) {[1-(4-methoxy-2-methylphenyl)benzimidazol-2-yl]methyl}(methylethyl)amine. The latter amine is then vigorously stirred with 2.6 mL of 2,4,6-trimethylbenzoylchloride in a 1:1 mixture of dichloroethane and saturated aqueous sodium carbonate (30 mL) at room temperature for 1 hour. The mixture is partitioned, the organic layer is dried with Na2SO4 and the solvent removed in vacuo. The crystallized product is triturated in ethyl ether, filtered and dried to afford 4.4 g (92%) of white solid N-{[1-(4-methoxy-2-methylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide: Mass Spec. 456 (M+H); (Compound 1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([P:22](=[O:29])([O:26]CC)[O:23]CC)[P:14](=[O:21])([O:18]CC)[O:15]CC.[ClH:30]>>[ClH:30].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([P:22](=[O:23])([OH:26])[OH:29])[P:14](=[O:15])([OH:18])[OH:21]
Reactant: CCOP(=O)(OCC)C(NCCCCSc1ccccn1)P(=O)(OCC)OCC
Agent: Cl
Product: O=P(O)(O)C(NCCCCSc1ccccn1)P(=O)(O)O
Yield: 70 %

Procedure:
A solution of tetraethyl 4-(2-pyridylthio)butylaminomethylenebisphosphonate (2.50 g) in hydrochloric acid (40 ml) was stirred for 3 hours under reflux. The reaction mixture was concentrated under reduced pressure. Acetone was added to the residue and the separated white precipitate was collected by filtration and recrystallized from water-methanol to obtain 4-(2-pyridylthio)butylaminomethylenebisphosphonic acid hydrochloride (1.46 g, 70%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1I)[NH2:5].[CH2:10](C([Sn])=C(CCCC)CCCC)[CH2:11]CC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:5])[CH:6]=[CH:7][C:8]=1[CH:10]=[CH2:11]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Nc1ccc(I)c(Cl)c1
Solvent: C1CCOC1
Product: C=Cc1ccc(N)cc1Cl
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a deoxygenated solution of 3-chloro-4-iodo-aniline (6.95 g) triphenyl arsine (0.67 g), and tris(dibenzylideneacetone)palladium(0) (0.50 g) in tetrahydrofuran (120 mL) at 50° C. is added tributylvinyltin (10 g) and the mixture is stirred for approximately 15 hours at 50° C. under an atmosphere of argon. The reaction is then cooled, filtered through diatomaceous earth, and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in hexanes and then extracted three times with 5% aqueous hydrochloric acid. These aqueous acidic extracts are then basified with solid potassium carbonate and extracted three times with ethyl acetate. These pooled organic extracts are then washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent is removed under reduced pressure. The resulting residue is chromatographed over silica gel (hexanes and then 10% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an amber oil.
Reaction SMILES: [Na].Cl.[N:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O>C(O)C>[F:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:9]([C:6]2[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=2)[C:10]#[N:11])[CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1cccc(F)c1
Reactant: N#CCc1ccncc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: N#CC(=Cc1cccc(F)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.3 %

Procedure:
After sodium (3.0 g, 130 mmol) was dissolved in ethanol (150 mL), 4-pyridyl acetonitrile hydrochloride (33 g, 121 mmol) was added thereto and stirred at room temperature. After 10 minutes, 3-fluorobenzaldehyde (8 g, 65 mmol) was added thereto and stirred as such for 30 minutes. The resulting precipitates were collected by filtration and washed with a small amount of water, to give the title compound (8.2 g, 56%) as a colorless solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:7]=1[CH3:20].[CH2:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:21]([N:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][S:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[C:7]=2[CH3:20])[CH2:30][CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1c(SCCCCl)ccnc1CSc1ccncc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(SCCCN2CCN(Cc3ccccc3)CC2)ccnc1CSc1ccncc1
Yield: 57 %

Procedure:
According to the procedure indicated in Example 7, reaction of 4-(3-chloropropylthio)-3-methyl-2-[(4-pyridinylthio)methyl]pyridine with 1-benzylpiperazine and potassium carbonate in acetonitrile, after chromatography on silica gel and crystallization of the concentrated pure fraction from diisopropyl ether, gives the title compound as a colorless solid; m.p. 79-81° C.; yield 57% of theory. A hydrated hydrochloride can be prepared from isopropanol; m.p. 165° C. (dec.); yield 87% of theory.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22](I)=[N:23][C:24]=2[Cl:28])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH:37]#[C:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([C:37]#[C:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[N:23][C:24]=2[Cl:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C#CCCCCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCCCCCC#Cc1nc(Cl)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Yield: 89 %

Procedure:
In 12 ml of 1,4-dioxane were suspended 2.15 g (4 mmole) of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-2-iodopurine, 56 mg (0.08 mmole) of bis(triphenylphosphine)palladium dichloride and 15 mg (0.08 mmole) of cuprous iodide, and 1.2 ml of triethylamine and 0.75 ml of 1-nonyne were added to the suspension. The mixture was stirred and caused to react at room temperature (25° C.) for 12 hours. The reaction solution at this time had a transparent pale brown color, which was paler than those in the aforementioned (i) or (ii). After the reaction, the solution was concentrated, and 200 ml of ethyl acetate was added to the residue to obtain a solution, which was distributed and washed several times with an aqueous EDTA.2 Na solution and a saturated brine solution, respectively to remove copper ions. The organic layer was subjected to silica gel column chromatography in the same manner as in (i) to remove colored materials and other by-products and to produce 1.90 g (yield 89%) of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-2-(1-nonynyl)purine as a viscous material.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:6]=[C:5]2B(O)O.[CH3:21][N:22]1[C:26](=[O:27])[CH:25]=[CH:24][C:23]1=[O:28].O1CCOCC1>[Rh].O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:6]=[C:5]2[CH:24]1[CH2:25][C:26](=[O:27])[N:22]([CH3:21])[C:23]1=[O:28]
Reactant: CN1C(=O)C=CC1=O
Reactant: CC(C)(C)[Si](C)(C)n1cc(B(O)O)c2cc(Br)ccc21
Agent: [Rh]
Solvent: O
Solvent: C1COCCO1
Product: CN1C(=O)CC(c2cn([Si](C)(C)C(C)(C)C)c3ccc(Br)cc23)C1=O

Procedure:
To an oven dried, argon purged flask fitted with magnetic stir-bar is charged 5-bromo-1-(tert-butyldimethylsilyl)-1H-indol-3-ylboronic acid 15 (141.6 mg, 0.400 mmol), N-Methyl maleimide 16 (22.2 mg, 0.200 mmol), Rhodium catalyst (0.05 equiv.), anhydrous dioxane (1 mL) and stirring begun. H2O (0.05 mL) added, and mixture heated in an oil bath as per the conditions outlined in Table 9 below. The reaction mixture was filtered through silica gel bed, and the solvent was evaporated to obtain crude product. The crude product was purified via chromatography on silica gel (20% Ethylacetate/80% Hexanes) to yield 3-(5-bromo-1-(tert-butyldimethylsilyl)-1H-indol-3-yl)-1-methylpyrrolidine-2,5-dione 17. The enantiomeric excess was determined with chiral HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]#[N:12])=[C:5]2[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14].Cl.[CH2:23]([OH:25])[CH3:24]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[NH:12])[O:25][CH2:23][CH3:24])=[C:5]2[S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14]
Reactant: N#Cc1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1

Procedure:
5-Chloro-3-phenylsulfonylindole-2-carbonitrile is allowed to react with ethanol saturated with hydrogen chloride at 0°-10° C. for 7 days. Evaporation to dryness affords the title compound as a hydrochloride salt. The title compound is obtained as a free base by adding the reaction mixture to an ice cold solution of excess potassium carbonate and extracting the product with chloroform.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:6](=[O:13])[NH:5][C:4](=[O:14])[CH:3]=1.[CH3:15]OS(OC)(=O)=O>[OH-].[Na+]>[NH2:1][C:2]1[N:7]([CH2:8][C:9]([CH3:11])([CH3:10])[CH3:12])[C:6](=[O:13])[N:5]([CH3:15])[C:4](=[O:14])[CH:3]=1
Reactant: CC(C)(C)Cn1c(N)cc(=O)[nH]c1=O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(=O)cc(N)n(CC(C)(C)C)c1=O
Yield: 90.9 %

Procedure:
6-Amino-1-neopentyluracil (90c) (5.9 g, 0.03 mol) were dissolved in 1 N NaOH (50 ml) and then under vigorous stirring dimethylsulfate (3.9 ml, 0.033 mol) dropwise added at room temp. A precipitate separated and was collected after 2 hours. After washing with water and drying in a vacuum desiccator resulted 5.76 g (91%) of colorless crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][C:19]2[CH:18]=[CH:17][C:16]([S:13]([C:6]3([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]3)(=[O:14])=[O:15])=[CH:21][CH:20]=2)=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCN(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCC(C(=O)O)(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC1

Procedure:
4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-1-methyl-piperidine-4-carboxylic acid was prepared starting from 4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-1-methyl-piperidine-4-carboxylic acid ethyl ester (4.3 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (100 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.5 g (86%); white solid; mp 185° C.; MS:410(M+H)+
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>O.O1CCOCC1>[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([O:12][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=2)[CH2:10]1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Reactant: Fc1ccc(CCl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccc(F)cc3)[C@@H](CO)O2)cc1F
Temperature: 35 °C
Reaction time: 48 h
Yield: 20 %

Procedure:
A 7.5 g quantity of potassium hydroxide was dissolved in a mixture of 300 ml of water and 80 ml of dioxane. To the solution were added 2.00 g of 2'-deoxy-5-fluorouridine and 4.9 ml of 4-fluorobenzyl chloride, and the resulting mixture was stirred at 35° C. for 2 days. After the reaction, the same subsequent procedure as in Reference Examples 4 and 5 was carried out, and the residue was placed on a silica gel column and eluted with 2% methanol-chloroform, thereby producing 0.57 g of the title compound in a yield of 20%.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.O>CC1C=CC(C)=CC=1>[CH2:12]([C:7]1[CH:8]=[C:2]([C:1]([O:10][CH3:11])=[O:9])[C:3]([NH2:4])=[CH:5][CH:6]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccccc1
Reactant: COC(=O)c1ccccc1N
Agent: Cl
Solvent: O
Solvent: Cc1ccc(C)cc1
Product: COC(=O)c1cc(Cc2ccccc2)ccc1N
Reaction time: 3 h
Yield: 4.4 %

Procedure:
Methyl anthranilate (30.9 g; 205 mmols) and benzyl alcohol (4.43 g; 40,9 mmols) were dissolved in 50 mL of p-xylene. Montmorillonite (1.3 g), activated with hydrochloric acid, was added to the reaction mixture, which was then heated to boiling. The water produced during the reaction was collected using a Dean-Starck-apparatus. After three hours the solvent and the excess of methyl anthranilate were distilled off at reduced pressure. Chromatography using silica gel 60 and heptane/ethyl acetate (19/1->9/1) as eluent afforded 430 mg (4.4%) of the desired methyl 5-benzylanthranilate.
Reaction SMILES: [Cl:1][C:2]1[O:12][C:5]2=[C:6]([O:10]C)[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[O:12][C:5]2=[C:6]([OH:10])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1
Reactant: COc1nccc2cc(Cl)oc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1nccc2cc(Cl)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
A 0.25M solution of 2-chloro-7-methoxyfuro[2,3-c]pyridine (263 mg, 1.4 mmol) in DCM stirred at −0° C. under an atmosphere of nitrogen was treated with BBr3 (1 M in DCM, 4.3 mL, 4.3 mmol) dropwise over 5 min. The mixture was allowed to warm gradually to rt. After the mixture was allowed to stir overnight, it was poured into ice water and extracted with DCM (3×15 mL). The combined organic layers were washed with water and brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of EtOAc (15 to 75%) in hexanes to afford the title compound (115 mg, 47%) as light yellow solid. LCMS (M+H)+=170.
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[OH:23])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:24]C1C=C2C(C=C(C)C(C(O)C(OCC)=O)=C2O)=CC=1>>[C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][C:16]([Cl:24])=[CH:17][CH:18]=2)[C:13]=1[OH:23])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccccc2c1O
Reactant: CCOC(=O)C(O)c1c(C)cc2ccc(Cl)cc2c1O
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Cl)cc2c1O

Procedure:
Prepared in a similar manner to ethyl 2-tert-butoxy-2-(1-hydroxy-3-methylnaphthalen-2-yl)acetate of Example 120, except using ethyl 2-(7-chloro-1-hydroxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate. 1H-NMR: (400 MHz, CDCl3): δ 9.01 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.35 (dd, J=8.6, 2.0 Hz, 1H), 7.13 (s, 1H), 5.49 (s, 1H), 4.22-4.08 (m, 2H), 2.56 (s, 3H), 1.31 (s, 9H), 1.19 (t, J=7.0 Hz, 3H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH2:9](I)[CH3:10]>>[CH2:9]([N:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]1=[O:8])[CH3:10]
Reactant: CCI
Reactant: O=c1cc(I)cc[nH]1
Product: CCn1ccc(I)cc1=O

Procedure:
1-ethyl-4-iodopyridin-2(1H)-one was prepared from 4-iodopyridin-2(1H)-one and ethyl iodide following a procedure analogous to that described in Example 59 Step 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[N:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:28]=[O:29]>N1C=CC=CC=1>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][NH:27][C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])[CH:7]=1)=[O:29])[CH3:35]
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: CCOC(=O)CN=C=O
Solvent: c1ccncc1
Product: CCOC(=O)CNC(=O)Nc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 494 (0.047 g, 0.13 mmol) was dissolved in pyridine (0.3 mL) and ethyl isocyanatoacetate (0.022 mL, 0.19 mmol) was added. The solution was stirred at room temperature for 2 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:1 as the eluent. This afforded the title compound as a slightly coloured solid. 13C NMR (DMSO-d6) δ 195.2, 170.7, 158.7 (dd), 155.7 (dd), 155.0, 149.0, 139.0, 137.8, 133.3, 131.4, 129.1, 127.0, 126.3 (dd), 124.3 (dd), 120.0, 118.1, 114.8, 111.9 (dd), 111.8, 105.0 (dd), 60.2, 41.3, 19.0, 14.0
Reaction SMILES: [F:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=[O:9].[C:16]1([CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Br)C1C=CC=CC=1>[CH2:22]([N:13]1[CH2:14][CH:15]=[C:10]([CH:8]([OH:9])[CH2:7][C:6]2[CH:5]=[CH:4][S:3][C:2]=2[F:1])[CH2:11][CH2:12]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccccc1
Reactant: O=C(Cc1ccsc1F)c1ccncc1
Agent: BrCc1ccccc1
Product: OC(Cc1ccsc1F)C1=CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
After dissolving 304 mg of 2-(2-fluoro-3-thienyl)-1-(4-pyridyl)ethanone in 2 ml of toluene, 0.20 ml of benzyl bromide was added, the mixture was stirred at 100° C. for 8 hours and the precipitate was filtered out. The filtered substance was dissolved in 10 ml of methanol, 157 mg of sodium borohydride was added thereto in small portions at a time while cooling on ice, and the mixture was stirred for 1 hour. The reaction solution was distilled off under reduced pressure, water was added and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (384 mg, 88% yield).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].C([Mg:16][Br:17])(C)C>CCOCC>[F:8][C:7]1[C:2]([Mg:16][Br:17])=[C:3]([F:12])[C:4]([F:11])=[C:5]([F:10])[C:6]=1[F:9]
Reactant: Fc1c(F)c(F)c(Cl)c(F)c1F
Reactant: CC(C)[Mg]Br
Solvent: CCOCC
Product: Fc1c(F)c(F)c([Mg]Br)c(F)c1F
Temperature: 60 °C

Procedure:
In a drybox, 31.45 g of chloropentafluorobenzene prepared as in Example 21 above (0.155 mole) and 64.42 g of a 2 molar ether solution of isopropylmagnesium bromide (iPrMgBr) (0.141 mole) are charged to a Fisher Porter reactor and heated to 60° C. for 4.5 hours. Pentafluorophenylmagnesium bromide is formed.