Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][O:12][C:8]=2[CH:7]=1.[H-].[Na+].I[CH3:27]>CN(C=O)C>[Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[C:10]([CH3:27])([C:13]([O:15][CH3:16])=[O:14])[CH2:11][O:12][C:8]=2[CH:7]=1
Reactant: CI
Reactant: COC(=O)C1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C)COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of methyl 6-((2,4-dichlorobenzyl)oxy)-2,3-dihydro-1-benzofuran-3-carboxylate (150 mg) in DMF (dry) (3.0 mL) was added sodium hydride (18.7 mg) at 0° C. After 30 min, to the mixture was added iodomethane (0.034 mL) at 0° C. The mixture was allowed to room temperature and stirred at room temperature overnight. The mixture was quenched with water at 0° C. and extracted with EtOAc. The combined organic layer was washed successively with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (103.8 mg).
Reaction SMILES: CCO[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[F:16][C:17]1[CH:18]=[C:19]2[C:20](=[CH:22][CH:23]=1)[N:21]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]2[OH:13]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(F)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(F)cc2c1O

Procedure:
Using the procedure of Example 2, ethyl ethoxymethylene malonate and 4-fluoro-aniline were reacted and treated with phenyl oxide to obtain ethyl 6-fluoro-4-hydroxy-3-quinoline-carboxylate melting at >260° C.
Reaction SMILES: [H-].[Na+].[CH:3]([OH:6])([CH3:5])[CH3:4].Cl[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=1>C1COCC1>[Cl:14][C:13]1[C:8]([O:6][CH:3]([CH3:5])[CH3:4])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)O
Reactant: Clc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1ncccc1Cl
Temperature: 5 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a 3-necked flask equipped with a dropping funnel, thermometer and a condenser was added sodium hydride (64.10 g, 60% w/w dispersion in oil, 1.07 mol) followed by THF (1.65 L). The suspension was cooled to 5° C. and iso-propanol (128 mL, 1.07 mol) was added dropwise over 50 minutes. Upon complete addition the ice bath was removed and the mixture was brought to room temperature and left to stir for 1 hour. Then 2,3-dichloropyridine (154.6 g, 1.11 mol) was added and the reaction mixture brought to a gentle reflux and left to stir for 18 hours. The reaction mixture was cooled to 5-10° C. and was carefully quenched with brine:water mixture (50:50; 100 mL) followed by water (300 mL). The aqueous layer was extracted with ethyl acetate (3×600 mL), the organic layers combined and washed with brine, dried over magnesium sulphate, filtered and evaporated in vacuo to give the title compound as a dark red oil (164 g, 89%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[Cl:17][C:18]1[CH:19]=[C:20]([S:25](Cl)(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1[Cl:24].Cl>N1C=CC=CC=1>[Cl:17][C:18]1[CH:19]=[C:20]([S:25]([NH:16][C:13]2[S:14][CH:15]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=3)[N:12]=2)(=[O:26])=[O:27])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(-c2csc(NS(=O)(=O)c3ccc(Cl)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrochloride with 0.52 g of 3,4-dichlorobenzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 25 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a mixture of 30 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated upon neutralization with concentrated hydrochloric acid. Recrystallization from 80 ml of 50% ethanol yielded 0.39 g of 3,4-dichloro-N-[4-(3-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide as yellowish crystals.
Reaction SMILES: CO.[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12](=O)[CH3:13])[N:7]=1)(=O)[CH3:4].[CH3:15][C:16]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:17]=1[NH2:18]>C(O)=O>[CH3:15][C:16]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:17]=1[N:18]=[C:3]([C:6]1[N:7]=[C:8]([C:12](=[N:18][C:17]2[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:16]=2[CH3:15])[CH3:13])[CH:9]=[CH:10][CH:11]=1)[CH3:4]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: Cc1ccc(N)c(C)c1
Solvent: CO
Solvent: O=CO
Product: CC(=Nc1ccc(C)cc1C)c1cccc(C(C)=Nc2ccc(C)cc2C)n1
Reaction time: 1 h
Yield: 43.3 %

Procedure:
100 ml of methanol, 1.63 g of 2,6-diacetylpyridine (molecular weight 163.18; 10 mmols), and 4.84 g of 2,4-dimethylaniline (molecular weight 121.18; 40 mmols) were put into a 300 ml flask, and thoroughly stirred to prepare a homogeneous mixture. 0.6 ml of formic acid was added to this, and further the mixture was stirred for 12 hours to make the compounds reacted completely. The reaction mixture was left at −78° C. for 1 hour, and the resulting pale yellow crystal was taken out through filtration, washed with methanol, and dried under reduced pressure. Its 1H-NMR spectrum was assigned as the intended product, 2,6-diacetylpyridine-bis(2,4-dimethylphenylimine) (molecular weight 369.52; 1.60 g, 4.33 mmols, yield 43%).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[O-]CC.[Na+].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:22][N:21]=1)([O-])=O>C(O)C>[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:22][N:21]=1
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1cccnc1
Reactant: NCCSCc1cccs1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c(NCCSCc2cccs2)ncc1Cc1cccnc1
Reaction time: 0.5 h

Procedure:
2-(2-Thienylmethylthio)ethylamine hydrochloride (2 g) in ethanol (25 ml) was added to a solution of sodium ethoxide (prepared from 0.218 g sodium) in ethanol and the mixture was stirred for 0.5 hour. 2-Nitroamino-5-(3-pyridylmethyl)-4-pyrimidone (2.34 g) was added and the mixture was boiled under reflux for 40 hours and evaporated to dryness. Pyridine (50 ml) was added to the residue and the mixture was boiled under reflux for 24 hours and evaporated. The residue was crystallised from ethanol/ethyl acetate and further purified by elution from a column of silica gel with ethyl acetate/methanol (5:1) and recrystallisation from 2-propanol to give 2-[2-(2-thienylmethylthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone m.p. 145°-148°.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:7]=1[C:8](=[O:33])[N:9]([C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:10]2)=[O:4].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>CC#N>[Cl:15][C:12]1[CH:13]=[CH:14][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)=[C:7]2[C:11]=1[CH2:10][N:9]([C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:17][S:18]([CH3:21])(=[O:19])=[O:20])[C:8]2=[O:33]
Reactant: CN1CCNCC1
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(Cl)ccc(NC(=O)CCl)c3C2=O)ccc1OC
Solvent: CC#N
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(Cl)ccc(NC(=O)CN4CCN(C)CC4)c3C2=O)ccc1OC
Temperature: 70 °C
Yield: 25.2 %

Procedure:
To a solution of (1S)-2-chloro-N-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide (250 mg, 0.48 mmol) in CH3CN (10 ml) was added 1-methylpiperazine (0.21 ml, 1.9 mmol). The mixture was heated at 70° C. for 2 hrs. The reaction mixture was concentrated on rota-vap and extracted with water (50 ml) and EtOAc (50 ml). The organic layer was washed with water (50 ml), brine (25 ml), dried over Na2SO4 and concentrated. The resulted oil was purified by chromatography to give (1S)-N-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-2-(4-methyl-piperazin-1-yl)-acetamide as a white solid (70 mg, 25% yield): mp, 205-207° C.; 1H NMR (CDCl3) δ 1.47 (t, J=7.0 Hz, 3H, OCH2CH3), 2.36 (s, 3H, CH3), 2.64 (broad, 8H, CH2 on piperazine ring), 2.99 (S, 3H, NCH3), 3.21 (d, J=2 Hz, 2H, CH2NCO), 3.73 (dd, J=5, 15 Hz, 1H, CHHSO2), 3.88 (s, 3H, OCH3), 4.05-4.20 (m, 4H, CHHSO2+CNHH+OCH2CH3), 4.39 (d, J=15 Hz, 1H, CHHN), 5.74-5.80 (m, 1H, NCH), 6.86-6.98 (m, 3H, Ar), 7.40 (d, J=8 Hz, 1H, Ar), 8.55 (d, J=8 Hz, 1H, Ar), 11.45 (s, 1H, NHCO); 13C NMR (CDCl3) δ 14.73, 41.37, 46.11, 46.81, 51.57, 53.46, 54.81, 55.76, 55.98, 62.18, 64.62, 111.61, 112.42, 119.46, 119.77, 119.87, 122.32, 129.20, 132.95, 135.98, 139.21, 148.93, 149.87, 168.50, 170.01. Anal Calcd for C27H35ClN4O6S: C, 56.00; H, 6.09; N, 9.67. Found: C, 55.82; H, 5.79; N, 9.42.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH2:9]Br)[C:3]=1[F:11].O.C(=O)([O-])[O-:14].[Ca+2].Cl>O1CCOCC1>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH2:9][OH:14])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(Br)c(F)c1CBr
Agent: Cl
Agent: [Ca+2]
Solvent: O
Solvent: C1COCCO1
Product: OCc1c(F)ccc(Br)c1F
Yield: 114.3 %

Procedure:
1-Bromo-3-(bromomethyl)-2,4-difluoro-benzene (45.2 g, 0.158 M) was dissolved in dioxane (800 mL), water (800 mL) and calcium carbonate (80 g, 0.80 M) were added and the mixture was refluxed for 16 h. The mixture was cooled, acidified with 2N HCl and extracted with dichloromethane. Organic phases were pooled, dried with Na2SO4 and and evaporated to yield a brownish oil (40.3 g). The residue was purified by column chromatography (silica gel; n-hexane/ethyl acetate 9:1) to yield 31.2 g (88%) of the title compound as a colorless solid. MS (EI): 224.0 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:10][C@@H:9]1[C@H:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:12][Cl:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1([Mg]Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1COCC1.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[Si:15]([O:14][C@@H:11]([C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:10][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:12][Cl:13])([C:18]([CH3:21])([CH3:19])[CH3:20])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]1[C@@H](CCl)O[Si](C)(C)C(C)(C)C
Reactant: Cl[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](CCl)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a magnetically stirred solution of N-t-butyloxycarbonyl-2(R)-(1(S)-t-butyldimetylsilyloxy-2-chloroethyl)aziridine (36.0 mg, 0.107 mmol) in toluene was added copper bromide dimethyl sulfide complex (11.0 mg, 0.054 mmol) at rt under N2. The reaction mixture was cooled to −78° C. then treated with a 2 M solution of PhMgCl in THF (0.54 mL, 1.072 mmol). The resulting mixture was warmed to −20° C. and stirred overnight. The reaction mixture was treated with sat NH4Cl (4 mL) and extracted with EtOAc(5 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, concentrated and column-chromatographed (3% EtAc in n-Hex) to provide 2(S)-t-butyldimetylsilyloxy-3(R)-(t-butyloxycarbonyl)amino-1-chloro-4-phenylbutane (33.5 mg) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH:17]1[CH2:19][CH2:18]1)=[CH:6]2)#[N:2].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32](O)=O)[CH:27]=1>>[CH:17]1([C:7]2[N:8]([CH2:12][C:13]3[N:16]=[C:32]([C:28]4[CH:27]=[C:26]([C:25]([F:35])([F:24])[F:36])[CH:31]=[CH:30][N:29]=4)[O:15][N:14]=3)[C:9]3[C:5]([CH:6]=2)=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH2:19][CH2:18]1
Reactant: N#Cc1ccc2c(cc(C3CC3)n2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1cc(C(F)(F)F)ccn1
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2noc(-c3cc(C(F)(F)F)ccn3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-2-cyclopropyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 364B) and 4-(trifluoromethyl)-2-pyridinecarboxylic acid: 1H NMR (400 MHz, CDCl3) δ 9.01 (d, J=4.7 Hz, 1H), 8.33 (s, 1H), 7.75 (d, J=4.7 Hz, 1H), 7.68 (d, J=8.5 Hz 1H), 7.56 (d, J=8.5 Hz 1H), 6.49 (s, 1H), 5.70 (s, 2H), 2.14 (m, 1H), 1.16 (m, 2H), 0.90 (m, 2H); MS (ES) m/z 478 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C@@H:5]([NH:11][C:12]([C:14]1[C:15](=[O:29])[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=2)[CH:17]=[CH:18][CH:19]=1)=[O:13])[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.CN(C)C=O.[Br:36]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]([C:6]1[S:7][C:8]([Br:36])=[CH:9][CH:10]=1)[NH:11][C:12]([C:14]1[C:15](=[O:29])[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=2)[CH:17]=[CH:18][CH:19]=1)=[O:13]
Reactant: COC(=O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1cccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(Br)s1

Procedure:
(R)-3-{[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-3-thiophen-2-yl-propionic acid methyl ester (0.420 g, 0.000971 mol;) was dissolved in N,N-Dimethylformamide (20 mL, 0.2 mol;) and N-Bromosuccinimide (0.19 g, 0.0011 mol;) was added. The reaction was allowed to stir o/n and LC-MS showed formation of product at 1.87 510.95. The reaction was diluted with methylene chloride and washed 1× with saturated bicarbonate, 1× with 5% citric acid, and 1× with brine. The organic layer was then dried with magnesium sulfate and concentrated to give the crude material. The crude was dissolved in methylene chloride and purified by combiflash 0-100% hexanes/ethyl acetate to give the pure product. ES (+) MS m/e=510.95
Reaction SMILES: [Si:1]([CH3:5])([CH3:4])(Cl)[Cl:2].[CH:6]1[CH2:10][CH:9]=[CH:8][CH:7]=1.[Na]>C(OCC)C>[Cl:2][Si:1]([C:7]1[CH2:6][CH:10]=[CH:9][CH:8]=1)([CH3:5])[CH3:4]
Reactant: C1=CCC=C1
Reactant: C[Si](C)(Cl)Cl
Agent: [Na]
Solvent: CCOCC
Product: C[Si](C)(Cl)C1=CC=CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
A solution of Me2SiCl2 (225 mL, 1.86 mol) in 450 mL of diethyl ether was cooled to 0° C., after which a sodium cyclopentadiene (compound 1) solution (1.68 M, 950 mL, 1.60 mol) was added dropwise. A white precipitate formed immediately. The reaction was allowed to warm up to room temperature and was stirred for an additional 4 hours. The resulting reaction mixture was centrifuged to separate precipitate from supernatant. The volatiles of the isolated supernatant were removed in vacuo. Fractional distillation yielded 122.76 g (48%) of the desired product as a colorless liquid (48-52° C./15 mmHg).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([OH:10])=O.ClC(OCC(C)C)=O.C(N(CC)CC)C.[NH2:26][CH2:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([C:36]([NH2:38])=[O:37])[CH2:32][CH2:31]1)=[O:29]>O1CCCC1>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([NH:26][CH2:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([C:36]([NH2:38])=[O:37])[CH2:32][CH2:31]1)=[O:29])=[O:10]
Reactant: O=C(O)CN1CCCC1=O
Reactant: NCC(=O)N1CCC(C(N)=O)CC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)C1CCN(C(=O)CNC(=O)CN2CCCC2=O)CC1
Reaction time: 0.25 h

Procedure:
27.8 g of (2-oxo-1-pyrrolidinyl)acetic acid was suspended in 450 ml of tetrahydrofuran, to which 27.8 g of isobutyl chloroformate at -15° C. and 20.3 g of triethylamine at -15° to -5° C. were added. After stirring at -10° to -5° C. for 15 minutes, 36.0 g of 1-glycyl-4-piperidinecarboxamide was added at -10° to -5° C. and then the reaction liquid was allowed to stand so as to rise its temperature to room temperature over 2 hours. The insoluble matter was filtered off and suspended in 500 ml of chloroform. The suspension was filtered off to obtain the crude crystal. The crude crystal was recrystallized from methanol to obtain the titled compound.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:14][CH2:15][C:16](O)=[O:17].S(=O)(=O)(O)O>C1C=CC=CC=1>[Cl:14][CH2:15][C:16]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:17]
Reactant: CCCCCCCCCCCCO
Reactant: O=C(O)CCl
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCOC(=O)CCl
Yield: 90 %

Procedure:
The mixture of 1-dodecanol (0.2 mol, 37.27 g), chloroacetic acid (0.2 mol, 18.9 g), benzene (200 ml) and sulfuric acid (2 ml) was refluxed for 12 hrs. After the reaction, the mixture was washed with 25% Na2CO3 (100 ml). The organic layer was dried with magnesium sulfate and then evaporated, the remaining liquid was distilled under vacuum to provide a colorless oil (bp 150° C./3 mmHg) in 90% yield.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=1>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:35]3[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OB(O)c1cccnc1
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Product: CCCCCCc1cccc(-c2nc(-c3cccnc3)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 7, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 2) was reacted with pyridin-3-yl-boronic acid to give the title compound as light yellow oil. MS: 500.3 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13]S(C)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[C:28]2[C:23](=[CH:24][C:25](O)=[CH:26][CH:27]=2)[CH:22]=[CH:21][N:20]=1>>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][C:25]2[CH:24]=[C:23]3[C:28](=[CH:27][CH:26]=2)[C:19]([NH2:18])=[N:20][CH:21]=[CH:22]3)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nccc2cc(O)ccc12
Reactant: CS(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1
Product: Nc1nccc2cc(O[C@@H]3CCN(Cc4ccccc4)C3)ccc12

Procedure:
This compound was prepared from (S)-methanesulfonic acid 1-benzylpyrrolidin-3-yl ester and 1-amino-6-hydroxyisoquinoline by the procedure described in Example 1 to give the (R) 6-(1-benzylpyrrolidin-3-yloxy)-isoquinolin-1-ylamine product, El-MS: m/z=320.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][C@H:22]([CH2:24][O:25]S(C)(=O)=O)[O:21][C:20]4=[O:30])=[CH:15][C:14]=3[F:31])=[CH:9][N:8]=2)=[N:3]1.[CH3:32][O-].[Na+]>CO>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][C@H:22]([CH2:24][O:25][CH3:32])[O:21][C:20]4=[O:30])=[CH:15][C:14]=3[F:31])=[CH:9][N:8]=2)=[N:3]1
Reactant: C[O-]
Reactant: Cn1nnc(-c2ccc(-c3ccc(N4C[C@H](COS(C)(=O)=O)OC4=O)cc3F)cn2)n1
Agent: [Na+]
Solvent: CO
Product: COC[C@H]1CN(c2ccc(-c3ccc(-c4nnn(C)n4)nc3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.3 %

Procedure:
In 10 ml of methanol was dissolved 400 mg of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methansulfonyloxymethyl oxazolidin-2-on prepared in the secondary step of the Example 24. The solution was added with 90 mg of sodium methoxide at room temperature and then stirred for one day at room temperature. The solution was extracted with ethyl acetate and the organic layer, thus separated, was washed with water and brine. The organic layer was dehydrated, filtered, concentrated in vacuo and purified by column chromatography to provide the title compound 200 mg. Yield 58%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[CH3:21].[NH2:23][C@@H:24]([CH2:27][CH3:28])[CH2:25][OH:26]>CN1CCCC1=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([NH:23][CH:24]([CH2:25][OH:26])[CH2:27][CH3:28])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[CH3:21]
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(Cl)cc1C
Reactant: CC[C@H](N)CO
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCC(CO)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC
Temperature: 130 °C
Yield: 64 %

Procedure:
A mixture of 4-chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-nicotinic acid methyl ester (9.000 g, 26.45 mmol) and (S)-2-amino-1-butanol (12.7 ml) in 1-methyl-2-pyrrolidinone was heated at 130° C. for 2 hr, then at 100° C. overnight. The mixture cooled to rt and poured into ice-water and diluted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give 13.6 g of crude product as a light yellow oil. The oil was purified through silica gel column chromatography using chloroform to 2% MeOH in chloroform as eluent to give 6.6839 g (64%) of the title compound as a white glass foam. The glass foam was triturated with hexane to give a white solid. The solid was recrystallized from di-iso-propyl ether to give a white crystals, mp 122.5–124° C. Anal. calc. for C20H25CIN2O4: C, 61.14; H, 6.41; N, 7.13; found: C, 60.98; H, 6.43; N, 6.95.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:2]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34](O)=[O:35])=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:33]3[C:28](=[CH:29][C:30]([C:34]([N:1]4[CH2:2][CH:3]([N:5]5[CH2:6][CH2:7][N:8]([C:11]([C:13]6[S:14][CH:15]=[CH:16][N:17]=6)=[O:12])[CH2:9][CH2:10]5)[CH2:4]4)=[O:35])=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc2c(c1)CCN2c1ccc(F)cc1
Reactant: O=C(c1nccs1)N1CCN(C2CNC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc2c(c1)CCN2c1ccc(F)cc1)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
To a mixture of compound 5e (42.9 mg, 0.132 mmol), compound 55d (30.9 mg, 0.12 mmol), and Et3N (0.084 mL, 0.6 mmol) in CH2Cl2 (1 mL) at room temperature was added HATU (70 mg, 0.168 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and washed with H2O, aqueous NaHCO3 and brine, and then dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 2-4% MeOH/EtOAc) to give compound Cpd 885 (44.4 mg). 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J=3.2 Hz, 1H), 7.55 (d, J=3.2 Hz, 1H), 7.51 (d, J=1.2 Hz, 1H), 7.38 (dd, J=8.3, 1.7 Hz, 1H), 7.16-7.25 (m, 2H), 7.03-7.12 (m, 2H), 6.88 (d, J=8.3 Hz, 1H), 4.05-4.67 (m, 6H), 3.99 (t, J=8.6 Hz, 2H), 3.76-3.94 (m, 2H), 3.20-3.30 (m, 1H), 3.16 (t, J=8.6 Hz, 2H), 2.37-2.64 (m, 4H); MS m/z (M+H+) 492.1.