Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:5]([C:7]2[O:8][C:9]3[C:15]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=[CH2:31])[N:25]=1.C(O)(=O)C>CO>[N:1]1([C:5]([C:7]2[O:8][C:9]3[C:15]([N:16]4[CH2:17][CH2:18][N:19]([CH2:31][CH2:30][C:26]5[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[N:25]=5)[CH2:20][CH2:21]4)=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: C=Cc1cccc(OC)n1
Reactant: O=C(c1cc2cccc(N3CCNCC3)c2o1)N1CCC1
Solvent: CC(=O)O
Solvent: CO
Product: COc1cccc(CCN2CCN(c3cccc4cc(C(=O)N5CCC5)oc34)CC2)n1
Temperature: 120 °C

Procedure:
Azetidin-1-yl(7-(piperazin-1-yl)benzofuran-2-yl)methanone (0.070 g, 0.25 mmol) was dissolved in methanol (1 mL). 2-Methoxy-6-vinylpyridine (0.066 g, 0.49 mmol) and acetic acid (0.014 mL, 0.25 mmol) were added. The mixture was heated by microwave irradiation to 120° C. for 10 h. The product was purified by preparative HPLC to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C@@H:3]1[CH2:7][NH:6][C@@H:5]([CH3:8])[CH2:4]1.[NH2:10][C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13](F)[CH:12]=1.CCN(CC)CC>CN1CCCC1=O.O>[CH3:1][N:2]([CH3:9])[C@@H:3]1[CH2:7][N:6]([C:13]2[CH:12]=[C:11]([NH2:10])[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=2)[C@@H:5]([CH3:8])[CH2:4]1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: C[C@H]1C[C@H](N(C)C)CN1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@H]1C[C@H](N(C)C)CN1c1ccc([N+](=O)[O-])c(N)c1
Temperature: 100 °C

Procedure:
(2S,4S)-4-dimethylamino-2-methylpyrrolidine (1.0 equivalent) and 1-amino-3-fluoro-6-nitrobenzene (1.2 equivalents) were dissolved in N-methylpyrrolidinone, and Et3N (5.0 equivalents) was added. The solution was heated for 5 hours at 100° C. The solution was then cooled and diluted with water. The aqueous layer was extracted with ethyl acetate. The organic layer was then washed twice with H2O, once with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by column chromatography (1:1 ethyl acetate:hexane to 1:20 MeOH:ethyl acetate to 1:1 MeOH: ethyl acetate to give the title compound as a yellow gum. LC/MS (m/z) 265.2 (MH+), Rt 1.65 minutes.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].Cl.[CH3:23][NH:24][O:25][CH3:26].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C>[CH3:26][O:25][N:24]([CH3:23])[C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])=[O:21]
Reactant: CNOC
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (420 mg), N,O-dimethylhydroxylamine hydrochloride (150 mg), triethylamine (0.24 mL), 1H-1,2,3-benzotriazol-1-ol (300 mg) and N,N-dimethylformamide (10 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (380 mg) at 4° C., and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=5:95-1:1), and the obtained crystals were recrystallized from ethyl acetate-diethyl ether to give the title compound (395 mg, yield 83%) as pale-yellow needle crystals. melting point 180-181° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[N:14][CH:15]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 103 %

Procedure:
A mixture of methyl 3-hydroxybenzoate (8.14 g, 53.5 g), 2-chloro-5-nitropyridine (8.08 g, 51.0 mmol), potassium carbonate (11.1 g, 80.3 mmol) and N,N-dimethylformamide (100 mL) was stirred at 60° C. for 3 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (14.4 g, 98%) as a white solid.
Reaction SMILES: [CH2:1](Cl)[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[I-].[K+]>Cl>[C:9]1([NH:8][CH2:1][CH:2]2[CH2:3][CH2:4][CH2:5][O:6]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccc1
Reactant: ClCC1CCCO1
Agent: Cl
Agent: [I-]
Agent: [K+]
Product: c1ccc(NCC2CCCO2)cc1
Temperature: 130 °C
Yield: 4.3 %

Procedure:
A mixture of tetrahydrofurfuryl chloride (100 g, 0.829 mol), aniline (2.09 g, 2.25 mol) and potassium iodide (1.0 g) was heated at 130° C. under nitrogen for 36 hours and cooled to room temperature. A 3N hydrochloric acid solution (400 mL) was added and the solution was washed several times with isopropyl ether and made basic with a 50% sodium hydroxide solution. The product was extracted three times into isopropyl ether, washed twice with water and once with a saturated sodium chloride solution, dried (sodium sulfate), filtered and evaporated to a liquid that was added to water (3L) and extracted into three portions of isopropyl ether. The combined extracts were washed twice with water and once with a saturated sodium chloride solution, dried (magnesium sulfate), treated with charcoal, filtered and evaporated under reduced pressure to a liquid (91.4 g). A 6.0 g portion was dissolved in isopropanol and a solution of oxalic acid (3.1 g) in isopropanol was added. The resulting solid was collected by filtration and rinsed with isopropyl ether to give 6.3 g of solid. A 1.5 g portion was recrystallized from isopropanol/isopropyl ether/light pet ether to give a solid that was removed by filtration. A second crop of crystals was obtained from the filtrate, dried under high vacuum at 60° C. to give 0.31 g, mp 149°-156° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([F:17])[C:10]=1[F:16])[CH2:27]2
Reactant: Clc1cccc2c1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4cccc(Cl)c4C3)c(F)c(F)c2c1=O
Yield: 21.1 %

Procedure:
210 mg of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 120 mg of 4-chloroisoindoline, 213 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 64 mg of the target compound.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][Cl:23].[Cl-].[NH4+]>C1CCCCC1>[Cl:23][CH2:22][CH2:21][CH2:20][CH2:19][C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[O:7][CH3:6]
Reactant: COc1cccc2ccccc12
Reactant: ClCCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCCCC1
Product: COc1c(CCCCCl)ccc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.9 %

Procedure:
A solution of N,N,N',N'-tetramethylenediamine (18.12 mL, 0.120 mole) in cyclohexane (36 mL) was treated with n-butyllithium (1.55M in hexane; 79.8 mL, 0.123 mole) at room temperature. A solution of 1-methoxynaphthalene (17.4 mL, 0.120 mole) in cyclohexane (20 mL) was added over 30 minutes, and the resulting solution was stirred for 1.5 hours. It was then cooled to 0°, and 1-bromo-4-chlorobutane (27.0 mL, 0.234 mole) was added over 15 minutes. The mixture was warmed to room temperature and stirred for 17 hours, then poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The crude product was chromatographed with 98:2 hexane/ether to provide the title compound (11.60 g, 39%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:16][CH2:17]O>Cl>[CH2:16]([O:14][C:13]([C:10]1([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=2)[CH2:11][CH2:12]1)=[O:15])[CH3:17]
Reactant: CCO
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1Cl
Agent: Cl
Product: CCOC(=O)C1(c2ccc(OC)c(Cl)c2)CC1
Temperature: 25 °C

Procedure:
A solution of 1-(3-chloro-4-methoxy-phenyl)-cyclopropanecarboxylic acid (250 mg, 0.96 mmol, 1 eq.) in 1.25M HCl in EtOH (2.4 mL) was stirred at r.t. for 2 hours and further at 50° C. for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was purified by flashmaster (column: 25 g, flow: 30 mL/min, 30 fractions of 30 mL, Heptane 100% to Heptane+20% AcOEt) to yield the title compound as a colorless oil. LC-MS 3: tR=0.91 min; [M+H]+=255.2
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][C:15]([NH:19]C(OCC3C=CC=CC=3)=O)([CH3:18])[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.I[Si](C)(C)C>C(#N)C>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:5]=[CH:6][C:7]([C:10]([N:12]2[CH2:13][CH2:14][C:15]([NH2:19])([CH3:18])[CH2:16][CH2:17]2)=[O:11])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(C(=O)N2CCC(C)(NC(=O)OCc3ccccc3)CC2)cc1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: COC(=O)c1ccc(C(=O)N2CCC(C)(N)CC2)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of Example 32A (0.2 g, 0.49 mmol) in acetonitrile (4.0 mL) at room temperature was added iodotrimethysilane (0.11 mL, 0.75 mmol). The reaction mixture was stirred at 50° C. for 30 minutes and then concentrated under reduced pressure. The solid residue was washed with acetone and ether and filtered to provide titled compound. MS (CI) m/z 277(M+1)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.04(d, 2H), 7.90 (bs, 2H NH2-DMSO solvent), 7.50(d, 2H), 3.88 (s, 3H), 3.35-3.20 (m, 4H), 1.79-1.58 (m, 4H), 1.35 (s, 3H).
Reaction SMILES: Cl.N1C=CC=[CH:4][CH:3]=1.C(OC)(OC)(OC)C.[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]1[C:28]([CH3:29])=[C:27]([CH3:30])[N:26]=[C:25]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:24]=1[NH2:38]>O1CCCC1.C(OCC)(=O)C>[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:23]2[C:28]([CH3:29])=[C:27]([CH3:30])[N:26]=[C:25]([O:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:24]=2[N:38]=[C:3]1[CH3:4]
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCCCCCl)c1C
Reactant: c1ccncc1
Agent: COC(C)(OC)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(Oc2ccccc2)c2nc(C)n(CCCCCCl)c2c1C
Temperature: 25 °C
Yield: 340.5 %

Procedure:
Pyridine hydrochloride (2 g) and trimethyl orthoacetate (10.5 mL, 82 mmol) were added to a solution of N4-(5-chloropentyl)-5,6-dimethyl-2-phenoxypyridine-3,4-diamine (24.97 g, 75 mmol) in anhydrous tetrahydrofuran (200 mL). The reaction mixture was heated at reflux for 25 hours, cooled to ambient temperature and then concentrated under reduced pressure. The residue was dissolved in hot ethyl acetate, titrated with hexanes and then cooled. The resulting precipitate was isolated by filtration and then it was dissolved in ethyl acetate (300 mL), washed with water (2×100 mL) and with brine (1×100 mL), dried over magnesium sulfate and then concentrated under reduced pressure to provide 21.09 g of 1-(5-chloropentyl)-2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridine.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:26])=[CH:10][CH2:11][CH2:12][C:13]([CH3:25])=[CH:14][CH2:15][CH2:16][C:17]([CH3:24])=[CH:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[C:3]([OH:5])=O.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:26])=[CH:10][CH2:11][CH2:12][C:13]([CH3:25])=[CH:14][CH2:15][CH2:16][C:17]([CH3:24])=[CH:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[C:3]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:5]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: C1CCNCC1
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N1CCCCC1

Procedure:
Starting materials: 2,6,10,14-tetramethyl-18-oxo-2,6,10,14-nonadecatetraenoic acid and piperidine.
Reaction SMILES: [CH2:1](OC=O)[CH3:2].[CH:6]([SH:9])([SH:8])[CH3:7].[CH2:10]([N:12]([CH2:34][CH3:35])[C:13]([NH:15][C@H:16]1[CH2:30][C@H:29]2[C@@H:19]([CH2:20][C:21]3[C:31]4[C:24](=[CH:25][CH:26]=[CH:27][C:28]2=4)[N:23](C)[CH:22]=3)[N:18]([CH3:33])[CH2:17]1)=[O:14])[CH3:11].N>C(Cl)(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl.O.CO>[CH2:34]([N:12]([CH2:10][CH3:11])[C:13]([NH:15][C@H:16]1[CH2:30][C@H:29]2[C@@H:19]([CH2:20][C:21]3[C:31]4[C:24](=[CH:25][CH:26]=[CH:27][C:28]2=4)[N:23]([CH3:22])[C:7]=3[CH:6]2[S:9][CH2:2][CH2:1][S:8]2)[N:18]([CH3:33])[CH2:17]1)=[O:14])[CH3:35]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4c3c(cn4C)C[C@H]2N(C)C1
Reactant: CC(S)S
Reactant: CCOC=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: N
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4c3c(c(C3SCCS3)n4C)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 37 %

Procedure:
At room temperature under argon, 7 ml of formic acid ethyl ester and 3.6 ml (44 mmol) of ethanedithiol are added in succession to a solution of 6.9 g of 1,1-diethyl-3-(1,6-dimethyl-8α-ergolinyl)urea in 200 ml of chloroform. Then, 8.8 ml (80 mmol) of titanium(IV) chloride dissolved in 100 ml of chloroform is added gradually dropwise to the reaction mixture and the latter is stirred for 20 hours at room temperature. Although the starting material at this point in time has not as yet been completely reacted, the reaction mixture is worked up to avoid further formation of the disubstituted compound. For this purpose, the reaction mixture is cooled in an ice bath and combined, in succession, dropwise with 50 ml of methanol and 40 ml of water. Then the mixture is made alkaline with 25% strength ammonia solution and extracted with methylene cloride. The organic phases are washed with water and dried over magnesium sulfate. The evaporated residue is crystallized under boiling heat from methanol/ethyl acetate, thus obtaining 3.0 g of 1,1-diethyl-3[2-(1,3-dithiolan-2-yl)-1,6-dimethyl-8α-ergolinyl]urea (37% yield).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][N:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>CO.C(OCC)(=O)C>[S:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]([NH:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:3]1
Reactant: Brc1nsc2ncccc12
Reactant: NCCCN
Solvent: CCOC(C)=O
Solvent: CO
Product: NCCCNc1nsc2ncccc12
Temperature: 64 °C

Procedure:
A mixture of 3-bromoisothiazolo[5,4-b]pyridine (1.9 g, 8.8 mmol), and 1,3-diaminopropane (6.7 g, 90 mmol) in methanol (10 ml) was heated at 64° C. for 1.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Lyophilization of the crude sample in acetonitrile/water mixture yielded N1-(isothiazolo[5,4-b]pyridin-3-yl)propane-1,3-diamine. 1H NMR (300 MHz, DMSO-d6): 8.68 (d, 1H), 8.53 (d, 1H), 7.73 (br s, 1H), 7.40 (dd, 1H), 3.46 (dd, 2H), 2.85 (t, 2H), 1.75 (t, 2H), 1.45 ppm (t, 2H). MW=208 confirmed by LC-MS, tr=5.55 min (Method Y) MH+=209.
Reaction SMILES: [CH:1]([C:3]1[C:15]([O:16][CH3:17])=[CH:14][C:6]([O:7][C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])=[C:5]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[CH:4]=1)=O.[C:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)(=[O:25])[CH3:24].C[O-].[Li+].Cl>CN(C)C=O.CO.O>[C:9]([C:8]([CH3:13])([O:7][C:6]1[C:5]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[CH:4][C:3](/[CH:1]=[CH:24]/[C:23]([C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)=[O:25])=[C:15]([O:16][CH3:17])[CH:14]=1)[CH3:12])([OH:11])=[O:10]
Reactant: COc1cc(OC(C)(C)C(=O)O)c(-c2cccs2)cc1C=O
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(OC(C)(C)C(=O)O)c(-c2cccs2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
2-(4-Formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propionic acid (Ex-47, 0.23 g, 0.72 mmol) and 4-acetylbenzoic acid (0.12 g, 0.72 mmol) were dissolved in a dimethylformamide-methanol solution (5 mL, 7:3). After complete dissolution, lithium methoxide (0.11 g, 2.9 mmol) was added and the resulting orange slurry was stirred in the dark at room temperature for 4 h. Upon completion, as determined by HPLC, the mixture was diluted with water (15 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate (4×25 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in a tetrahydrofuran-heptane solution (5 mL, 10:1) and warmed to 60° C. to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 0.30 g (90%) of the title compound as a dark yellow solid, mp 135–137° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.23 (d, 2H, J=8.4 Hz), 8.10 (d, 2H, J=8.4 Hz), 7.99 (d, 2H, J=15.6 Hz), 7.71 (d, 1H, J=3.0 Hz), 7.54 (d, 1H, J=5.1 Hz), 7.14 (dd, 1H, J=5.1, 3.0 Hz), 6.49 (s, 1H), 3.85 (s, 3H), 1.69 (s, 6H). MS (ESI) m/z=467 ([M+H]+, 100%). Anal. Calcd. for C25H28O8S.EtOH: C, 63.27; H, 5.51; S, 6.26. Found: C, 63.40; H, 5.19; S, 6.38.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@@H:6]2[CH2:9][OH:10].[H-].[Na+].[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>CN(C)C=O>[F:14][C:15]1[CH:22]=[CH:21][C:20]([O:10][CH2:9][C@H:6]2[CH2:5][CH2:4][C@H:3]3[CH2:8][C@@H:7]2[C:2]3([CH3:11])[CH3:1])=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: CC1(C)[C@H]2CC[C@H](CO)[C@@H]1C2
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2CC[C@H](COc3ccc(F)c(C#N)c3)[C@@H]1C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
A solution of (1S,2S,5S)-(−)-myrtanol (1.0 g, 6.48 mmol) in dimethylformamide was added to a cooled (0° C.) slurry of sodium hydride (310 mg, 7.78 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour. Again, cooled (0° C.), then a solution of 2,6-difluorobenzonitrile (1.08 g, 7.78 mmol) in dimethylfomamide was added, stirred overnight at room temperature. The reaction mixture was poured on crushed-ice water, stirred. The reaction mixture was extracted with ethyl acetate, dried, filtered and concentrated. Purification by silica gel chromatography (1:1 hexanes in dichloromethane) yielded 1.36 g of 2-fluoro-5-((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-ylmethoxy)benzonitrile.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]=1.[I:12][CH3:13]>CC(C)=O>[I-:12].[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N+:3]=1[CH3:13]
Reactant: CC1=NCCc2ccccc21
Reactant: CI
Solvent: CC(C)=O
Product: CC1=[N+](C)CCc2ccccc21
Product: [I-]
Reaction time: 8 h

Procedure:
1-Methyl-3,4-dihydroisoquinoline (780 mg) was dissolved in acetone (7 ml) and iodomethane (0.38 ml) added. The solution was allowed to stand overnight at room temperature. The product was obtained as pale yellow crystals (1.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH2:10]1[O:12][CH2:11]1.[C:13](O)(=[O:15])[CH3:14]>O>[OH:15][CH2:13][CH2:14][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH2:11][CH2:10][OH:12]
Reactant: C1CO1
Reactant: COc1ccccc1N
Reactant: CC(=O)O
Solvent: O
Product: COc1ccccc1N(CCO)CCO
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of 7.38 g (59.9 mmols) of o-anisidine, 10 ml (202.3 mmols) of ethylene oxide and 150 ml of a solvent mixture of acetic acid and water (9/1) was stirred at room temperature for 40 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol =30/1) to afford o-[N,N-bis(hydroxyethyl)amino]anisole.
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.[NH:23]1[C:27](=[O:28])[CH2:26][CH2:25][CH:24]1[C:29]([OH:31])=[O:30].N12CCCN=C1CCCCC2>CN(C)C=O>[O:28]=[C:27]1[NH:23][CH:24]([C:29]([O:31][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:3]2[C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]=2)=[O:30])[CH2:25][CH2:26]1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: O=C1CCC(C(=O)O)N1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(C(=O)OC2c3ccccc3C(=O)N2c2ccc3ccc(Cl)nc3n2)N1
Yield: 69.4 %

Procedure:
The procedure is as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (9.9 g) in anhydrous dimethylformamide (100 cc), DL-pyroglutamic acid (3.9 g) and 1,8-diazabicyclo[5.4.0]-undec-7ene (4.6 g). After recrystallization in dimethylformamide, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 5-oxo-2-pyrrolidinecarboxylate (8.8 g), m.p. 255° C. (decomposition), is obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].[N:18]1([CH:23]([CH3:27])[CH2:24][CH2:25]O)[CH2:22][CH2:21][CH2:20][CH2:19]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl.CO.C1COCC1>[CH3:3][N:2]([CH3:1])[CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:25][CH2:24][CH:23]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH3:27])=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: CC(CCO)N1CCCC1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(CCOc1ccc(C2(CN(C)C)CCOCC2)cc1)N1CCCC1
Yield: 23.7 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (925 mg, 3.93 mmol), 3-pyrrolidin-1-yl-butan-1-ol (450 mg, 3.14 mmol), PPh3 (1.03 g, 3.93 mmol), THF (9 ml) and DIAD (0.77 ml, 3.93 mmol) were reacted together according to general procedure C. The crude material was subjected to chromatography on silica eluting with DCM:MeOH (99.5:0.5) to provide the title compound (268 mg, 24%) as a colourless oil. 1H NMR (400 MHz, CDCl3) δ7.21 (d, 2H), 6.88 (d, 2H), 4.11-3.97 (m, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 2.66-2.52 (m, 5H), 2.40 (s, 2H), 2.19-2.05 (m, 3H), 1.96 (s, 6H), 1.93-1.70 (m, 7H), 1.16 (d, 3H).