Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([OH:25])([CH3:24])[CH3:23])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:26])=[CH:10][CH:11]=3)[N:6]=1.CO.[CH3:29]S(O)(=O)=O>>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([O:25][CH3:29])([CH3:23])[CH3:24])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:26])=[CH:10][CH:11]=3)[N:6]=1
Reactant: CS(=O)(=O)O
Reactant: CC(C)(O)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(O)ccc1O2
Solvent: CO
Product: COC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(O)ccc1O2

Procedure:
A vessel was charged with (S)-2′-amino-3-(3-hydroxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (0.679 g, 1.933 mmol) in methanol (23.51 mL, 580 mmol). methane sulfonic acid (0.627 mL, 9.66 mmol) was added, and the vial was sealed and placed in a 70° C. oil bath for 5 hours. The volatiles were evaporated, and the residue was loaded onto a silica gel cartridge in MeOH/DCM. The column was eluted onto an 80-g Redi-Sep column with 30-100% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM. The fractions containing product were evaporated to give (S)-2′-amino-3-(3-methoxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Cl.[CH3:22][O:23]C(=O)[C@H](CO)N.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH:16]([CH2:22][OH:23])[NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)NC(CO)C2=O)cn1
Temperature: 25 °C
Yield: 5.5 %

Procedure:
4-((4-isocyanato-1H-pyrazol-1-yl)methyl)-3,5-dimethylisoxazole (example 10-1) (784 mg, 3.6 mmol), serine methyl ester hydrochloride (672 mg, 4.32 mmol) and triethylamine (1 mL, 7.2 mmol) were refluxed in toluene (16 mL) for 8 hours. The reaction was allowed to cool to room temperature and then the solution was concentrated on the rotovap. The product was purified by reverse phase HPLC (5 to 95% acetonitrile in H2O:16 minute gradient) to afford 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5-(hydroxymethyl)imidazolidine-2,4-dione as a white solid (60 mg, 25%). 1H NMR (CDCl3, 400 MHz): δ (s, 3H), 2.40 (s, 3H), 3.13-3.07 (m, 1H), 3.94-3.93 (d, J=4 Hz, 2H), 4.21-4.19 (t, J=4 Hz, 1H), 5.03 (s, 2H), 6.68 (bs, 1H), 7.87 (s, 1H), 7.99 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 3 μM.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]1[NH:16][N:17]=[CH:18][C:13]=1[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[H-].[Na+].Br[CH2:22][CH3:23]>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]1=[N:16][N:17]([CH2:22][CH3:23])[CH:18]=[C:13]1[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3ccccc13)CCc1cn[nH]c1-2
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc2c(n1)-c1c(nc3ccccc3c1N)CC2
Temperature: 25 °C

Procedure:
To a solution of 11-amino-4,5-dihydro-1H-pyrazolo[3,4-a]acridine (3.0 g) in dry DMF (90 ml) was added NaH (60%)(0.63 g) slowly. The reaction was stirred at room temperature for a half hour, bromoethane (1.2 ml) was added and the reaction was stirred at room temperature overnight.
Reaction SMILES: [CH2:1]([C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH3:17])[C:4]=1[NH:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[Cl:18][CH2:19][C:20](Cl)=[O:21].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:18][CH2:19][C:20]([N:5]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4]1[C:12]([CH2:16][CH3:17])=[CH:13][CH:14]=[CH:15][C:3]=1[CH2:1][CH3:2])=[O:21]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)CNc1c(CC)cccc1CC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)CN(C(=O)CCl)c1c(CC)cccc1CC
Reaction time: 2 h

Procedure:
23.5 Grams (0.1 mol) of ethyl 2,6-diethylanilinoacetate and 11.3 g (0.1 mol) of monochloroacetic acid chloride were dissolved in 100 ml of benzene, 11.0 g of triethylamine was then added dropwise thereto with stirring maintaining the reaction temperature at 10°-20° C. and, thereafter, stirring was continued for further 2 hours at a room temperature. The reaction solution was washed with successive, 5% sodium hydroxide aqueous solution, 5% hydrochloric acid aqueous solution, and water. Then, the benzene layer was dried over anhydrous sodium sulfate. Thereafter, benzene was removed under reduced pressure to obtain the end product, ethyl N-chloroacetyl-2,6-diethylanilinoacetate. nD26 : 1.5225.
Reaction SMILES: [O:1]([C:8]1[C:21](C(C)(C)C)=[CH:20][C:19]([CH3:26])=[CH:18][C:9]=1/[N:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(CCCC)CCCC.[C:36]1([Li])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1>[O:1]([C:8]1[CH:21]=[CH:20][C:19]([CH3:26])=[CH:18][C:9]=1[NH:10][CH:11]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]c1ccccc1
Reactant: Cc1cc(/N=C/c2ccccn2)c(Oc2ccccc2)c(C(C)(C)C)c1
Solvent: C1CCOC1
Solvent: CCCCOCCCC
Product: Cc1ccc(Oc2ccccc2)c(NC(c2ccccc2)c2ccccn2)c1
Reaction time: 0.25 h
Yield: 62 %

Procedure:
To a solution of 12 (300 mg, 1.12 mmol) in THF was added 1.24 mL of a 1.8M nBu2O solution of phenyl lithium at −40° C. After stirring for 15 min, the reaction was quenched with water (1 mL). MgSO4 was added and the mixture filtered to give a yellow solution. Removal of the solvent under vacuum gave C1 as a yellow oil (240 mg, 62% yield).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][CH2:11]O.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I-:37]>C1(C)C=CC=CC=1>[I:37][CH2:11][CH2:10][CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1
Reactant: OCCC1Cc2ccccc2C1
Reactant: [I-]
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: ICCC1Cc2ccccc2C1
Temperature: 90 °C
Yield: 87.7 %

Procedure:
A mixture of 2-(indan-2-yl)ethanol (19.3 g), imidazole (12.1 g), triphenylphosphine (34.3 g), and toluene (250 ml) was heated to 90° C. To this mixture, iodide (33.2 g) was added, and the resulting mixture was stirred at 90° C. for 20 mi. The mixture was allowed to cool to room temperature, filtered, and concentrated in vacuo. The residue was purified on silica gel eluted with ethyl acetate-heptane (1:4) to give an oil (28.4 g, 87%).
Reaction SMILES: Br[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:10]([NH2:12])=[O:11]>CN(C)C1C=CN=CC=1.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.CC(N(C)C)=O>[C:10]([NH2:12])(=[O:11])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NC=O
Reactant: BrC=Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)N(C)C
Product: NC(=O)C=Cc1ccccc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
0.249 g of bis(triphenylphosphine)-palladium(II) chloride, 6.51 g of (2-bromovinyl)benzene, 3.03 g of formamide, 4.78 g of 4-dimethylamino-pyridine and 25 ml of dimethylacetamide are placed in a 200 ml glass autoclave. The autoclave is closed, flushed with nitrogen three times and then 5 bars carbon monoxide are applied. The reaction mixture is heated to 120° C. and stirred for 18 hours. It is then cooled, and the solution is diluted with diethylether and water, and extracted. The aqueous phase is extracted by shaking 3 times with diethylether, and afterwards the organic phases are collected, dried over magnesium sulphate and concentrated. The oil obtained is chromatographed over silica gel. The yield of title compound is 26% (part of the product remains in the water phase).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:33]1([NH2:36])[CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:36][CH:33]3[CH2:35][CH2:34]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: NC1CC1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)NC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.5 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Then, under nitrogen atmosphere, cyclopropylamine (2.40 g, 0.042 mole) was added and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated and the residue was recrystallized from isopropyl alcohol with refrigeration. The solid was collected by filtration, washed with cold isopropyl alcohol and water, and dried under high vacuum at 50° C. over the weekend to give 2.4 g (53%) of title compound, mp 231°-232° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([S:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[CH:4][CH:3]=1.S(OCC)(O[CH2:25][CH3:26])(=O)=O.CC(C)([O-])C.[K+]>C(O)C>[CH2:25]([O:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([S:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[CH:4][CH:3]=1)[CH3:26]
Reactant: CCOC(=O)CSc1cccc(O)c1CC(=O)OCC
Reactant: CCOS(=O)(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CSc1cccc(OCC)c1CC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 6-hydroxy-2-(ethoxycarbonylmethylthio)-phenylacetate (20.0 g) in anhydrous ethanol (200 mL) is added diethyl sulfate (10.3 g). To this is added in portions solid potassium t-butoxide (7.52 g), keeping the temperature below 30° with a cold-water bath. After stirring overnight at room temperature, the solvent is removed in vacuo and the residue is mixed with ether and water. The layers are separated and the organic layer is washed with ice-cold sodium hydroxide (0.5N, 40 mL) to remove starting material. The ether layer is washed with water to neutrality, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated in vacuo to give (as shown by NMR) ethyl 6-ethoxy-2-(ethoxycarbonylmethylthio)-phenylacetate as an oil.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]([CH3:4])=[O:3].[NH:7]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[C:20]([O:19][C:17]([CH:8]1[CH2:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][N:7]1[C:1](=[O:6])[C:2](=[O:3])[CH3:4])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(=O)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1Cc2ccccc2CN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: CC(=O)C(=O)N1Cc2ccccc2CC1C(=O)OC(C)(C)C
Temperature: -50 °C
Reaction time: 16 h

Procedure:
A cooled and freshly distilled solution of 270 mg of pyruvic acid in 5 ml of chloroform is rapidly stirred into a solution of 700 mg of Tic-OBut and 630 mg of dicyclohexylcarbodiimide in 15 ml of anhydrous chloroform, the latter solution having been cooled to -50° C. The mixture is left for 16 hours in a deep-freezing cabinet (-20° C.), and the precipitated dicyclohexylurea is filtered off. The solution is washed with KHSO4 solution and then with KHCO3 solution, dried over Na2SO4, and concentrated in vacuo. The compound (oil) contains a little dicyclohexylurea, and was analyzed by chromatography over silica gel in the system CHCl3 /CH3OH 15:1.
Reaction SMILES: C1(C)C(S(O)(=O)=O)=CC=CC=1.[C:12]1([C:18]2([C:24]([OH:26])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:27]([O:34][C:35](ON1C(=O)CCC1=O)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)(Cl)Cl.C(Cl)Cl>[CH2:27]([O:34][C:35]([N:21]1[CH2:20][CH2:19][C:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:24]([OH:26])=[O:25])[CH2:23][CH2:22]1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)N1CCC(C(=O)O)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of commercially available 4-phenyl-4-carboxypiperidine toluenesulfonate (7.55 g, 20 mmol), N-(benzyloxycarbonyloxy)succinimide (5.0 g, 20 mmol) and TEA (5 mL, 36 mmol) in CHCl3 (100 mL) is stirred at r.t. for 48 h. The mixture is diluted with CH2Cl2 (100 mL) and extracted with 1 M aq. NaOH (3×50 mL). The aq. phase is extracted with Et2O (2×50 mL), acidified (pH 2) with 6N aq. HCl and extracted with CH2Cl2 (4×50 mL). The combined CH2Cl2 extracts are dried (Na2SO4), filtered and evaporated to provide the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[S:25][C:24]([CH2:26]O)=[CH:23][CH:22]=4)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:53]1[CH2:56][CH:55]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:54]1.C(N(CC)C(C)C)(C)C>>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[S:25][C:24]([CH2:26][N:53]5[CH2:56][CH:55]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:54]5)=[CH:23][CH:22]=4)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1ccc(-c2noc(-c3cc(-c4ccccc4)c(C(F)(F)F)s3)n2)s1
Reactant: CCOC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(Cc2ccc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)s2)C1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1f) using (5-{5-[4-phenyl-5-(trifluoromethyl)-2-thienyl]-1,2,4-oxadiazol-3-yl}-2-thienyl)methanol (0.12 g, 0.29 mmol) that was obtained in Example 4 (4c), carbon tetrabromide (0.19 g, 0.58 mmol), triphenylphosphine (0.15 g, 0.58 mmol), ethyl 3-azetidinecarboxylate hydrochloride (62 mg, 0.38 mmol), and N,N-diisopropylethylamine (0.13 ml, 0.73 mmol). Subsequently, the crude product of the title compound thus obtained was purified by thin layer chromatography on a silica gel plate using a mixed solvent of ethyl acetate and hexane (4:5) as the developing solvent to afford the title compound (0.12 g) in a yield of 80% as a colourless oily product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[CH:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13]>CN(C=O)C.C1COCC1>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:4]=[CH:3][C:2]([CH:12]=[CH2:13])=[CH:7][N:6]=1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=Cc1ccc(C(F)(F)F)nc1
Temperature: 100 °C
Yield: 1324.9 %

Procedure:
2 g of 5-bromo-2-(trifluoromethyl)pyridine was dissolved in DMF:THF (3:1, 12 mL). vinyltributyltin (3 g) and tetrakis (triphenylphosphine)palladium (135 mg) were added to this solution. The reaction mixture was degassed and purged with nitrogen for 5 min and then heated at 100° C. for 2 h. at which point the reaction was found complete (monitored by TLC). The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure (Caution: product may be volatile) and the residue was purified by SiO2 chromatography (100-200 mesh, eluent: hexane-ethyl acetate gradient). The requisite fractions were concentrated below 40° C. under reduced pressure to obtain 20.3 g of 2-(trifluoromethyl)-5-vinylpyridine as oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1.S(C1C=CC(C)=CC=1)(O[CH2:18][C@@H:19]1[O:21][CH2:20]1)(=O)=O>CN(C=O)C>[O:21]1[CH2:20][C@@H:19]1[CH2:18][O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: Oc1ccnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2c(OC[C@H]3CO3)ccnc2c1
Temperature: 5 °C
Reaction time: 20.5 h
Yield: 16 %

Procedure:
Sodium hydride (60 weight %; 1.79 g; 44.8 mmol) is washed with hexanes (3×10 mL) under an argon blanket. DMF (17 mL) is then added at ambient temperature and the stirred slurry is cooled to 5° C. A solution of 4-hydroxyquinoline (5.00 g; 34.4 mmol) in DMF (65 mL) is added dropwise over 10 minutes. The resulting mixture is allowed to warm to ambient temperature over 1 hour affording a clear, reddish-brown solution. A solution of (R)-(−)-glycidyl tosylate (10.22 g; 44.8 mmol) in DMF (50 mL) is added dropwise over 10 minutes. The resulting mixture is stirred at ambient temperature for 20.5 hours, quenched by the addition of saturated aqueous ammonium chloride (25 mL), poured onto water (750 mL), and extracted with ether (3×375 mL). The combined ether layers are washed with saturated aqueous sodium bicarbonate (2×375 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography with gradient elution (50%→60% acetone in hexanes) affording the desired product (1.11 g) as a tan solid. ESMS: MH+ 202.2.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:37]3[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=3)[C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1ccc(F)cc1)N1CCN(C2CCCC2)CC1
Yield: 34 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), 4-fluorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light yellow solid (34%).
Reaction SMILES: [OH:1][C@H:2]1[C@H:9]2[C@H:5]([N:6]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[C:7](=[O:10])[O:8]2)[CH2:4][CH2:3]1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])(=O)=O>C(Cl)Cl>[Si:37]([O:1][C@H:2]1[C@H:9]2[C@H:5]([N:6]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[C:7](=[O:10])[O:8]2)[CH2:4][CH2:3]1)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O=C1O[C@H]2[C@H](O)CC[C@H]2N1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@@H]2[C@H]1OC(=O)N2S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (3aR*,6R*,6aR*)-6-hydroxy-3-((2-nitrophenyl)sulfonyl)hexahydro-2H-cyclo-penta[d]oxazol-2-one (1.2 g, 3.66 mmol) and 2,6-lutidine (0.851 mL, 7.31 mmol) in CH2Cl2 (25 mL) was added dropwise at 0° C. the tert-butyldimethylsilyl trifluoromethanesulfonate (1.091 mL, 4.75 mmol). The reaction mixture was stirred for 1 h at 0° C. followed by 2 h at RT. The reaction mixture was diluted with CH2Cl2 and washed with 20% aqueous NaH2PO4 solution and H2O, dried over MgSO4, filtered and concentrated. The title compound was obtained after crystallization from EtOAc/heptane as white solid (1.5 g, 88%): TLC (heptane/EtOAc 1:1) Rf=0.54; tR=1.58 min (UPLC 1), tR=1.43 min (LC-MS 3); ESI-MS: 460 [M+NH4]+ (LC-MS 3).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.[CH2:11]([O:13][CH2:14][C:15](N)=[NH:16])[CH3:12]>>[NH2:10][C:9]1[C:3]2[C:2](=[N:7][CH:6]=[C:5]([CH3:8])[N:4]=2)[N:1]=[C:15]([CH2:14][O:13][CH2:11][CH3:12])[N:16]=1
Reactant: CCOCC(=N)N
Reactant: Cc1cnc(N)c(C#N)n1
Product: CCOCc1nc(N)c2nc(C)cnc2n1

Procedure:
A suspension of 15.1 g (0.113 mole) of 3-amino-6-methyl-2-pyrazinecarbonitrile [prepared according to E. C. Taylor et al., J. Am. Chem. Soc. 1973, 95, 6413] in the above ethanolic solution of 2-ethoxyacetamidine is refluxed for 2 hours. After cooling, the solution obtained is concentrated to dryness under reduced pressure. The residue is purified by washing with acetone and recrystallization from a mixture of acetone and isopropyl ether. Yld: 8.4 g (34%), m.p. 166°-168° C.
Reaction SMILES: CN1CCCC1=O.[NH2:8][C:9]1[C:14]([F:15])=[C:13]([CH3:16])[C:12]([F:17])=[C:11](F)[N:10]=1.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[NH2:8][C:9]1[C:14]([F:15])=[C:13]([CH3:16])[C:12]([F:17])=[C:11]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[N:10]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1c(F)c(N)nc(F)c1F
Solvent: ClC(Cl)Cl
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nc(N)c(F)c(C)c2F)cc1
Temperature: 140 °C
Reaction time: 18 h
Yield: 38.7 %

Procedure:
To 3 ml of N-methylpyrrolidone were added 1.35 g of 2-amino-3,5,6-trifluoro-4-methylpyridine together with 3.0 g of p-methoxybenzylamine, and the mixture was stirred under nitrogen atmosphere at 140° C. for 18 hours and allowed to cool. After adding 30 ml of chloroform, the mixture was washed three times with 300 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography (silica gel, 20 g; eluent: chloroform:n-hexane, 1:1, and then, chloroform) to obtain 0.90 g of the title compound as a pale yellow crude oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:26](OC(OCC)OCC)C.Cl.[NH+]1C=CC=CC=1.C>C1(C)C=CC=CC=1.CO>[N:12]1([CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[CH:26]1
Reactant: CC(C)(C)OC(=O)NCCOCCNc1c(N)cnc2ccccc12
Reactant: CCOC(OCC)OCC
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCOCCn1cnc2cnc3ccccc3c21
Reaction time: 2 h
Yield: 73.6 %

Procedure:
A solution of tert-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (6.92 g, 20.0 mmol) in 100 mL of toluene was treated with triethylorthoformate (4.65 mL, 28.0 mmol) and the reaction mixture was heated to reflux. A 100 mg portion of pyridinium hydrochloride was then added and refluxing was continued for 2 h. The reaction was then concentrated to dryness under reduced pressure. The residue was dissolved in 200 mL of CH2Cl2 and washed with saturated NaHCO3, H2O and brine. The organic portion was dried over Na2SO4 and concentrated to give a green oil. The green oil was dissolved in 200 mL of hot MeOH and treated with 10 g of activated charcoal. The hot solution was filtered and concentrated to give 5.25 g of tert-butyl 2-[2-(1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light yellow syrup.